8350 lines
1 MiB
8350 lines
1 MiB
|
|
|
|
|
|
|
|
|
|
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" lang="en-us" xml:lang="en-us" >
|
|
|
|
<head>
|
|
|
|
|
|
|
|
<!--
|
|
################################# CRAWLER WARNING #################################
|
|
|
|
- The terms of service and the robots.txt file disallows crawling of this site,
|
|
please see https://omim.org/help/agreement for more information.
|
|
|
|
- A number of data files are available for download at https://omim.org/downloads.
|
|
|
|
- We have an API which you can learn about at https://omim.org/help/api and register
|
|
for at https://omim.org/api, this provides access to the data in JSON & XML formats.
|
|
|
|
- You should feel free to contact us at https://omim.org/contact to figure out the best
|
|
approach to getting the data you need for your work.
|
|
|
|
- WE WILL AUTOMATICALLY BLOCK YOUR IP ADDRESS IF YOU CRAWL THIS SITE.
|
|
|
|
- WE WILL ALSO AUTOMATICALLY BLOCK SUB-DOMAINS AND ADDRESS RANGES IMPLICATED IN
|
|
DISTRIBUTED CRAWLS OF THIS SITE.
|
|
|
|
################################# CRAWLER WARNING #################################
|
|
-->
|
|
|
|
|
|
|
|
<meta http-equiv="content-type" content="text/html; charset=utf-8" />
|
|
<meta http-equiv="cache-control" content="no-cache" />
|
|
<meta http-equiv="pragma" content="no-cache" />
|
|
<meta name="robots" content="index, follow" />
|
|
|
|
|
|
<meta name="viewport" content="width=device-width, initial-scale=1" />
|
|
<meta http-equiv="X-UA-Compatible" content="IE=edge" />
|
|
|
|
|
|
<meta name="title" content="Online Mendelian Inheritance in Man (OMIM)" />
|
|
<meta name="description" content="Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative
|
|
compendium of human genes and genetic phenotypes that is freely available and updated daily. The full-text,
|
|
referenced overviews in OMIM contain information on all known mendelian disorders and over 15,000 genes.
|
|
OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries
|
|
contain copious links to other genetics resources." />
|
|
<meta name="keywords" content="Mendelian Inheritance in Man, OMIM, Mendelian diseases, Mendelian disorders, genetic diseases,
|
|
genetic disorders, genetic disorders in humans, genetic phenotypes, phenotype and genotype, disease models, alleles,
|
|
genes, dna, genetics, dna testing, gene testing, clinical synopsis, medical genetics" />
|
|
<meta name="theme-color" content="#333333" />
|
|
<link rel="icon" href="/static/omim/favicon.png" />
|
|
<link rel="apple-touch-icon" href="/static/omim/favicon.png" />
|
|
<link rel="manifest" href="/static/omim/manifest.json" />
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script id='mimBrowserCapability'>
|
|
function _0x5069(){const _0x4b1387=['91sZIeLc','mimBrowserCapability','15627zshTnf','710004yxXedd','34LxqNYj','match','disconnect','1755955rnzTod','observe','1206216ZRfBWB','575728fqgsYy','webdriver','documentElement','close','open','3086704utbakv','7984143PpiTpt'];_0x5069=function(){return _0x4b1387;};return _0x5069();}function _0xe429(_0x472ead,_0x43eb70){const _0x506916=_0x5069();return _0xe429=function(_0xe42949,_0x1aaefc){_0xe42949=_0xe42949-0x1a9;let _0xe6add8=_0x506916[_0xe42949];return _0xe6add8;},_0xe429(_0x472ead,_0x43eb70);}(function(_0x337daa,_0x401915){const _0x293f03=_0xe429,_0x5811dd=_0x337daa();while(!![]){try{const _0x3dc3a3=parseInt(_0x293f03(0x1b4))/0x1*(-parseInt(_0x293f03(0x1b6))/0x2)+parseInt(_0x293f03(0x1b5))/0x3+parseInt(_0x293f03(0x1b0))/0x4+-parseInt(_0x293f03(0x1b9))/0x5+parseInt(_0x293f03(0x1aa))/0x6+-parseInt(_0x293f03(0x1b2))/0x7*(parseInt(_0x293f03(0x1ab))/0x8)+parseInt(_0x293f03(0x1b1))/0x9;if(_0x3dc3a3===_0x401915)break;else _0x5811dd['push'](_0x5811dd['shift']());}catch(_0x4dd27b){_0x5811dd['push'](_0x5811dd['shift']());}}}(_0x5069,0x84d63),(function(){const _0x9e4c5f=_0xe429,_0x363a26=new MutationObserver(function(){const _0x458b09=_0xe429;if(document!==null){let _0x2f0621=![];navigator[_0x458b09(0x1ac)]!==![]&&(_0x2f0621=!![]);for(const _0x427dda in window){_0x427dda[_0x458b09(0x1b7)](/cdc_[a-z0-9]/ig)&&(_0x2f0621=!![]);}_0x2f0621===!![]?document[_0x458b09(0x1af)]()[_0x458b09(0x1ae)]():(_0x363a26[_0x458b09(0x1b8)](),document['getElementById'](_0x458b09(0x1b3))['remove']());}});_0x363a26[_0x9e4c5f(0x1a9)](document[_0x9e4c5f(0x1ad)],{'childList':!![]});}()));
|
|
</script>
|
|
|
|
|
|
|
|
<link rel='preconnect' href='https://cdn.jsdelivr.net' />
|
|
<link rel='preconnect' href='https://cdnjs.cloudflare.com' />
|
|
|
|
<link rel="preconnect" href="https://www.googletagmanager.com" />
|
|
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery@3.7.1/dist/jquery.min.js" integrity="sha256-/JqT3SQfawRcv/BIHPThkBvs0OEvtFFmqPF/lYI/Cxo=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-migrate@3.5.2/dist/jquery-migrate.js" integrity="sha256-ThFcNr/v1xKVt5cmolJIauUHvtXFOwwqiTP7IbgP8EU=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/js/bootstrap.min.js" integrity="sha256-nuL8/2cJ5NDSSwnKD8VqreErSWHtnEP9E7AySL+1ev4=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap.min.css" integrity="sha256-bZLfwXAP04zRMK2BjiO8iu9pf4FbLqX6zitd+tIvLhE=" crossorigin="anonymous">
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap-theme.min.css" integrity="sha256-8uHMIn1ru0GS5KO+zf7Zccf8Uw12IA5DrdEcmMuWLFM=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/moment@2.29.4/min/moment.min.js" integrity="sha256-80OqMZoXo/w3LuatWvSCub9qKYyyJlK0qnUCYEghBx8=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/js/bootstrap-datetimepicker.min.js" integrity="sha256-dYxUtecag9x4IaB2vUNM34sEso6rWTgEche5J6ahwEQ=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/css/bootstrap-datetimepicker.min.css" integrity="sha256-9FNpuXEYWYfrusiXLO73oIURKAOVzqzkn69cVqgKMRY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.js" integrity="sha256-a+PRq3NbyK3G08Boio9X6+yFiHpTSIrbE7uzZvqmDac=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.css" integrity="sha256-JvdVmxv7Q0LsN1EJo2zc1rACwzatOzkyx11YI4aP9PY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/devbridge-autocomplete@1.4.11/dist/jquery.autocomplete.min.js" integrity="sha256-BNpu3uLkB3SwY3a2H3Ue7WU69QFdSRlJVBrDTnVKjiA=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-validation@1.21.0/dist/jquery.validate.min.js" integrity="sha256-umbTaFxP31Fv6O1itpLS/3+v5fOAWDLOUzlmvOGaKV4=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/js-cookie@3.0.5/dist/js.cookie.min.js" integrity="sha256-WCzAhd2P6gRJF9Hv3oOOd+hFJi/QJbv+Azn4CGB8gfY=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdnjs.cloudflare.com/ajax/libs/ScrollToFixed/1.0.8/jquery-scrolltofixed-min.js" integrity="sha512-ohXbv1eFvjIHMXG/jY057oHdBZ/jhthP1U3jES/nYyFdc9g6xBpjDjKIacGoPG6hY//xVQeqpWx8tNjexXWdqA==" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script async src="https://www.googletagmanager.com/gtag/js?id=G-HMPSQC23JJ"></script>
|
|
<script>
|
|
window.dataLayer = window.dataLayer || [];
|
|
function gtag(){window.dataLayer.push(arguments);}
|
|
gtag("js", new Date());
|
|
gtag("config", "G-HMPSQC23JJ");
|
|
</script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script src="/static/omim/js/site.js?version=Zmk5Y1" integrity="sha256-fi9cXywxCO5p0mU1OSWcMp0DTQB4s8ncFR8j+IO840s="></script>
|
|
|
|
|
|
<link rel="stylesheet" href="/static/omim/css/site.css?version=VGE4MF" integrity="sha256-Ta80Qpm3w1S8kmnN0ornbsZxdfA32R42R4ncsbos0YU=" />
|
|
|
|
|
|
<script src="/static/omim/js/entry/entry.js?version=anMvRU" integrity="sha256-js/EBOBZzGDctUqr1VhnNPzEiA7w3HM5JbFmOj2CW84="></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimBootstrapDeviceSize">
|
|
<div class="visible-xs" data-mim-bootstrap-device-size="xs"></div>
|
|
<div class="visible-sm" data-mim-bootstrap-device-size="sm"></div>
|
|
<div class="visible-md" data-mim-bootstrap-device-size="md"></div>
|
|
<div class="visible-lg" data-mim-bootstrap-device-size="lg"></div>
|
|
</div>
|
|
|
|
|
|
|
|
<title>
|
|
|
|
Entry
|
|
|
|
- *190198 - NOTCH RECEPTOR 1; NOTCH1
|
|
|
|
|
|
- OMIM
|
|
|
|
</title>
|
|
|
|
|
|
|
|
</head>
|
|
|
|
<body>
|
|
<div id="mimBody">
|
|
|
|
|
|
|
|
<div id="mimHeader" class="hidden-print">
|
|
|
|
|
|
|
|
<nav class="navbar navbar-inverse navbar-fixed-top mim-navbar-background">
|
|
<div class="container-fluid">
|
|
|
|
<!-- Brand and toggle get grouped for better mobile display -->
|
|
<div class="navbar-header">
|
|
<button type="button" class="navbar-toggle collapsed" data-toggle="collapse" data-target="#mimNavbarCollapse" aria-expanded="false">
|
|
<span class="sr-only"> Toggle navigation </span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
</button>
|
|
<a class="navbar-brand" href="/"><img alt="OMIM" src="/static/omim/icons/OMIM_davinciman.001.png" height="30" width="30"></a>
|
|
</div>
|
|
|
|
<div id="mimNavbarCollapse" class="collapse navbar-collapse">
|
|
|
|
<ul class="nav navbar-nav">
|
|
|
|
|
|
<li>
|
|
<a href="/help/about"><span class="mim-navbar-menu-font"> About </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimStatisticsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Statistics <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="statisticsDropdown">
|
|
<li>
|
|
<a href="/statistics/update"> Update List </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/entry"> Entry Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/geneMap"> Phenotype-Gene Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/paceGraph"> Pace of Gene Discovery Graph </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDownloadsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Downloads <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="downloadsDropdown">
|
|
|
|
<li>
|
|
<a href="/downloads/"> Register for Downloads </a>
|
|
</li>
|
|
<li>
|
|
<a href="/api"> Register for API Access </a>
|
|
</li>
|
|
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="/contact?mimNumber=190198"><span class="mim-navbar-menu-font"> Contact Us </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li>
|
|
|
|
<a href="/mimmatch/">
|
|
|
|
<span class="mim-navbar-menu-font">
|
|
<span class="mim-tip-bottom" qtip_title="<strong>MIMmatch</strong>" qtip_text="MIMmatch is a way to follow OMIM entries that interest you and to find other researchers who may share interest in the same entries. <br /><br />A bonus to all MIMmatch users is the option to sign up for updates on new gene-phenotype relationships.">
|
|
MIMmatch
|
|
</span>
|
|
</span>
|
|
</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDonateDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Donate <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="donateDropdown">
|
|
<li>
|
|
<a href="https://secure.jhu.edu/form/OMIM" target="_blank" onclick="gtag('event', 'mim_donation', {'destination': 'secure.jhu.edu'})"> Donate! </a>
|
|
</li>
|
|
<li>
|
|
<a href="/donors"> Donors </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimHelpDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Help <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="helpDropdown">
|
|
<li>
|
|
<a href="/help/faq"> Frequently Asked Questions (FAQs) </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/search"> Search Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/linking"> Linking Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/api"> API Help </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/external"> External Links </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/agreement"> Use Agreement </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/copyright"> Copyright </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="#" id="mimShowTips" class="mim-tip-hint" title="Click to reveal all tips on the page. You can also hover over individual elements to reveal the tip."><span class="mim-navbar-menu-font"><span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span></span></a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimSearch" class="hidden-print">
|
|
|
|
<div class="container">
|
|
|
|
<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
|
|
|
|
<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
|
|
<input type="hidden" id="mimSearchStart" name="start" value="1" />
|
|
<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
|
|
<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
|
|
<div class="form-group">
|
|
<div class="input-group">
|
|
<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
|
|
<div class="input-group-btn">
|
|
<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
|
|
<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
|
|
<ul class="dropdown-menu dropdown-menu-right">
|
|
<li class="dropdown-header">
|
|
Advanced Search
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/entry"> OMIM </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/geneMap"> Gene Map </a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/history"> Search History </a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
</div>
|
|
</div>
|
|
<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="col-lg-4 col-md-4 col-sm-4 col-xs-4">
|
|
<span class="small">
|
|
|
|
|
|
|
|
|
|
|
|
<span class="hidden-sm hidden-xs">
|
|
|
|
|
|
Display:
|
|
|
|
|
|
<label style="font-weight: normal"><input type="checkbox" id="mimToggleChangeBars" checked /> Change Bars </label>
|
|
|
|
|
|
</span>
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</form>
|
|
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
<!-- <div id="mimSearch"> -->
|
|
|
|
|
|
|
|
|
|
<div id="mimContent">
|
|
|
|
|
|
|
|
<div class="container hidden-print">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
|
|
<div id="mimAlertBanner">
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
|
|
|
|
<div id="mimFloatingTocMenu" class="small" role="navigation">
|
|
|
|
<p>
|
|
<span class="h4">*190198</span>
|
|
<br />
|
|
<strong>Table of Contents</strong>
|
|
</p>
|
|
|
|
<nav>
|
|
<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
|
|
|
|
<li role="presentation">
|
|
<a href="#title"><strong>Title</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#description">Description</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cloning">Cloning and Expression</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#biochemicalFeatures">Biochemical Features</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneFunction">Gene Function</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cytogenetics">Cytogenetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#animalModel">Animal Model</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
|
|
</li>
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="/allelicVariants/190198">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000148400;t=ENST00000651671" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=4851" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=190198" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000148400;t=ENST00000651671" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_017617,XM_011518717" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_017617" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=190198" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://hprd.org/summary?hprd_id=01827&isoform_id=01827_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.proteinatlas.org/search/NOTCH1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/protein/338675,7019819,11275980,48146559,62089332,119608647,148833508,206729936,311643954,375312872,375312874,379331274,380509013,444738985,577703016,584614704,1034665364,2462624803" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.uniprot.org/uniprotkb/P46531" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Gene Info</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="http://biogps.org/#goto=genereport&id=4851" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000148400;t=ENST00000651671" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=NOTCH1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=NOTCH1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+4851" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
<dd><a href="http://v1.marrvel.org/search/gene/NOTCH1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
|
|
|
|
|
|
|
|
<dd><a href="https://monarchinitiative.org/NCBIGene:4851" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/4851" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr9&hgg_gene=ENST00000651671.1&hgg_start=136494433&hgg_end=136546048&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7881" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7881" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=190198[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=190198[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.deciphergenomics.org/gene/NOTCH1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000148400" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ebi.ac.uk/gwas/search?query=NOTCH1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.gwascentral.org/search?q=NOTCH1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NOTCH1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NOTCH1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.pharmgkb.org/gene/PA31683" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Animal Models</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.alliancegenome.org/gene/HGNC:7881" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://flybase.org/reports/FBgn0004647.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mousephenotype.org/data/genes/MGI:97363" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://v1.marrvel.org/search/gene/NOTCH1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.informatics.jax.org/marker/MGI:97363" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/4851/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.orthodb.org/?ncbi=4851" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001609;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://zfin.org/ZDB-GENE-990415-173" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4851" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://reactome.org/content/query?q=NOTCH1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
190198
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
NOTCH RECEPTOR 1; NOTCH1
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
NOTCH, DROSOPHILA, HOMOLOG OF, 1<br />
|
|
TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NOTCH1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NOTCH1</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/9/656?start=-3&limit=10&highlight=656">9q34.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:136494433-136546048&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">9:136,494,433-136,546,048</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616028,109730" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/656?start=-3&limit=10&highlight=656">
|
|
9q34.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Adams-Oliver syndrome 5
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616028"> 616028 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Aortic valve disease 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/109730"> 109730 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/190198" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/190198" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimDescriptionFold" class="collapse in ">
|
|
<span class="mim-text-font">
|
|
<p>Notch proteins are single-pass transmembrane receptors that regulate cell fate decisions during development. The Notch family includes 4 receptors, NOTCH1, NOTCH2 (<a href="/entry/600275">600275</a>), NOTCH3 (<a href="/entry/600276">600276</a>), and NOTCH4 (<a href="/entry/164951">164951</a>), whose ligands include JAG1 (<a href="/entry/601920">601920</a>), JAG2 (<a href="/entry/602570">602570</a>), DLL1 (<a href="/entry/606582">606582</a>), DLL3 (<a href="/entry/602768">602768</a>), and DLL4 (<a href="/entry/605185">605185</a>). All of the receptors have an extracellular domain containing multiple epidermal growth factor (EGF; <a href="/entry/131530">131530</a>)-like repeats and an intracellular region containing the RAM domain, ankyrin repeats, and a C-terminal PEST domain (<a href="#16" class="mim-tip-reference" title="Das, I., Craig, C., Funahashi, Y., Jung, K.-M., Kim, T.-W., Byers, R., Weng, A. P., Kutok, J. L., Aster, J. C., Kitajewski, J. <strong>Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.</strong> J. Biol. Chem. 279: 30771-30780, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123653</a>] [<a href="https://doi.org/10.1074/jbc.M309252200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15123653">Das et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>In a translocation t(7;9)(q34;q34.3) found in a case of acute T-cell lymphoblastic leukemia, <a href="#21" class="mim-tip-reference" title="Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., Sklar, J. <strong>TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.</strong> Cell 66: 649-661, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1831692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1831692</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90111-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1831692">Ellisen et al. (1991)</a> found that the locus on chromosome 9 contains a gene, NOTCH1, highly homologous to the Drosophila gene Notch. Transcripts of the human NOTCH1 gene, which <a href="#21" class="mim-tip-reference" title="Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., Sklar, J. <strong>TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.</strong> Cell 66: 649-661, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1831692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1831692</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90111-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1831692">Ellisen et al. (1991)</a> called TAN1, and its murine counterpart were demonstrated in many normal human fetal and adult mouse tissues, but were most abundant in lymphoid tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1831692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Milner, L. A., Kopan, R., Martin, D. I. K., Bernstein, I. D. <strong>A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors.</strong> Blood 83: 2057-2062, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7512837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7512837</a>]" pmid="7512837">Milner et al. (1994)</a> found that at least 1 Notch homolog was expressed in human bone marrow CD34 (<a href="/entry/142230">142230</a>)-positive cells, a population enriched for hematopoietic precursors. On the basis of these findings, they suggested that members of the Notch family, including TAN1, may be involved in mediating cell-fate decisions during hematopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7512837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In addition to the EGF-like repeats in the extracellular region of Notch, known motifs in the intracellular region of Notch include a nuclear localization signal (NLS) and a RAM motif, 6 ankyrin/CDC10 repeats, a second NLS, PEST sequences, and a glutamine-rich domain. By luciferase and Western blot analysis, <a href="#114" class="mim-tip-reference" title="Wang, J., Shelly, L., Miele, L., Boykins, R., Norcross, M. A., Guan, E. <strong>Human Notch-1 inhibits NF-kappa-B activity in the nucleus through a direct interaction involving a novel domain.</strong> J. Immun. 167: 289-295, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11418662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11418662</a>] [<a href="https://doi.org/10.4049/jimmunol.167.1.289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11418662">Wang et al. (2001)</a> determined that a highly conserved 109-amino acid region (residues 1773-1881) N-terminal of the 6 ankyrin repeats of intracellular NOTCH1 inhibits NFKB (<a href="/entry/164011">164011</a>) DNA binding and gene expression. They termed this protein-protein interaction domain, which includes an NLS, the NFKB-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11418662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="biochemicalFeatures" class="mim-anchor"></a>
|
|
<h4 href="#mimBiochemicalFeaturesFold" id="mimBiochemicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimBiochemicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimBiochemicalFeaturesFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
<a href="#54" class="mim-tip-reference" title="Luca, V. C., Jude, K. M., Pierce, N. W., Nachury, M. V., Fischer, S., Garcia, K. C. <strong>Structural basis for Notch1 engagement of delta-like 4.</strong> Science 347: 847-853, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25700513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25700513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25700513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1261093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25700513">Luca et al. (2015)</a> determined the crystal structure of the interacting regions of the NOTCH1-DLL4 complex at 2.3-angstrom resolution. The complex reveals a 2-site, antiparallel binding orientation assisted by NOTCH1 O-linked glycosylation. NOTCH1 EGF-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag2 (DSL) domain and module at the N terminus of Notch ligand (MNNL) domains, respectively. Threonine and serine residues on NOTCH1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific and essential contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in NOTCH1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25700513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Luca, V. C., Kim, B. C., Ge, C., Kakuda, S., Wu, D., Roein-Peikar, M., Haltiwanger, R. S., Zhu, C., Ha, T., Garcia, K. C. <strong>Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity.</strong> Science 355: 1320-1324, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28254785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28254785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28254785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaf9739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28254785">Luca et al. (2017)</a> determined the 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jag1. The structure revealed a binding interface that extends approximately 120 angstroms along 5 consecutive domains of each protein. O-Linked fucose modifications on Notch1 EGF domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Dll4 ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. This mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28254785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
<a href="#120" class="mim-tip-reference" title="Yang, G., Zhou, R., Zhou, Q., Guo, X., Yan, C., Ke, M., Lei, J., Shi, Y. <strong>Structural basis of Notch recognition by human gamma-secretase.</strong> Nature 565: 192-197, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30598546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30598546</a>] [<a href="https://doi.org/10.1038/s41586-018-0813-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30598546">Yang et al. (2019)</a> reported the cryoelectron microscopy structure of human gamma-secretase (see PS1, <a href="/entry/104311">104311</a>) in complex with a Notch fragment at a resolution of 2.7 angstroms. The transmembrane helix of Notch is surrounded by 3 transmembrane domains of PS1, and the carboxyl-terminal beta-strand of the Notch fragment forms a beta-sheet with 2 substrate-induced beta-strands of PS1 on the intracellular side. Formation of the hybrid beta-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. <a href="#120" class="mim-tip-reference" title="Yang, G., Zhou, R., Zhou, Q., Guo, X., Yan, C., Ke, M., Lei, J., Shi, Y. <strong>Structural basis of Notch recognition by human gamma-secretase.</strong> Nature 565: 192-197, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30598546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30598546</a>] [<a href="https://doi.org/10.1038/s41586-018-0813-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30598546">Yang et al. (2019)</a> concluded that these features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by gamma-secretase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30598546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="mapping" class="mim-anchor"></a>
|
|
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMappingFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>By analysis of somatic cell hybrids and FISH, <a href="#46" class="mim-tip-reference" title="Larsson, C., Lardelli, M., White, I., Lendahl, U. <strong>The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.</strong> Genomics 24: 253-258, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698746</a>] [<a href="https://doi.org/10.1006/geno.1994.1613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7698746">Larsson et al. (1994)</a> mapped the NOTCH1 gene to chromosome 9q34. They mapped the NOTCH2 and NOTCH3 genes to chromosomes 1p13-p11 and 19p13.2-p13.1, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7698746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="del Amo, F., Gendron-Maguire, M., Swiatek, P. J., Jenkins, N. A., Copeland, N. G., Gridley, T. <strong>Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch.</strong> Genomics 15: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8449489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8449489</a>] [<a href="https://doi.org/10.1006/geno.1993.1055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8449489">Del Amo et al. (1993)</a> and <a href="#77" class="mim-tip-reference" title="Pilz, A., Prohaska, R., Peters, J., Abbott, C. <strong>Genetic linkage analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notch1 genes in the region of mouse chromosome 2 homologous to human chromosome 9q.</strong> Genomics 21: 104-109, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088777</a>] [<a href="https://doi.org/10.1006/geno.1994.1230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088777">Pilz et al. (1994)</a> demonstrated that the mouse Notch1 gene maps to chromosome 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8449489+8088777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="geneFunction" class="mim-anchor"></a>
|
|
<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGeneFunctionFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Notch Ligand Selectivity</em></strong>
|
|
</p>
|
|
|
|
<p>To identify the specific domains in the Notch receptor responsible for ligand selectivity, <a href="#119" class="mim-tip-reference" title="Yamamoto, S., Charng, W.-L., Rana, N. A., Kakuda, S., Jaiswal, M., Bayat, V., Xiong, B., Zhang, K., Sandoval, H., David, G., Wang, H., Haltiwanger, R. S., Bellen, H. J. <strong>A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.</strong> Science 338: 1229-1232, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23197537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23197537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23197537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1228745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23197537">Yamamoto et al. (2012)</a> performed genetic screens in Drosophila and isolated a mutation, Notch(Jigsaw), that affects Serrate- but not Delta-dependent signaling. Notch(Jigsaw) carries a missense mutation in epidermal growth factor repeat-8 (Egfr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 (<a href="/entry/600275">600275</a>) results in defects in signaling of a mammalian Serrate homolog, Jagged1 (<a href="/entry/601920">601920</a>). <a href="#119" class="mim-tip-reference" title="Yamamoto, S., Charng, W.-L., Rana, N. A., Kakuda, S., Jaiswal, M., Bayat, V., Xiong, B., Zhang, K., Sandoval, H., David, G., Wang, H., Haltiwanger, R. S., Bellen, H. J. <strong>A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.</strong> Science 338: 1229-1232, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23197537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23197537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23197537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1228745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23197537">Yamamoto et al. (2012)</a> concluded that an evolutionarily conserved valine in Egfr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23197537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Processing of Notch</em></strong>
|
|
</p>
|
|
|
|
<p>There is proteolytic processing in maturation and activation of NOTCH1 (<a href="#11" class="mim-tip-reference" title="Chan, Y.-M., Jan, Y. N. <strong>Roles for proteolysis and trafficking in Notch maturation and signal transduction.</strong> Cell 94: 423-426, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9727485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9727485</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81583-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9727485">Chan and Jan, 1998</a>). Maturation of the NOTCH1 protein is mediated by a furin (<a href="/entry/136950">136950</a>)-like convertase within the secretory pathway; cleavage occurs at an extracellular site, called site 1 (S1), after the recognition sequence RQRR (<a href="#51" class="mim-tip-reference" title="Logeat, F., Bessia, C., Brou, C., LeBail, O., Jarriault, S., Seidah, N. G., Israel, A. <strong>The Notch1 receptor is cleaved constitutively by a furin-like convertase.</strong> Proc. Nat. Acad. Sci. 95: 8108-8112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653148">Logeat et al., 1998</a>). The resultant polypeptides associate as an intramolecular heterodimer thought to be the only form of the NOTCH1 receptor found on the cell surface (<a href="#51" class="mim-tip-reference" title="Logeat, F., Bessia, C., Brou, C., LeBail, O., Jarriault, S., Seidah, N. G., Israel, A. <strong>The Notch1 receptor is cleaved constitutively by a furin-like convertase.</strong> Proc. Nat. Acad. Sci. 95: 8108-8112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653148">Logeat et al., 1998</a>). Activation of NOTCH1 involves cleavage between gly1743 and val1744 (termed site 3, or S3) (<a href="#92" class="mim-tip-reference" title="Schroeter, E. H., Kisslinger, J. A., Kopan, R. <strong>Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.</strong> Nature 393: 382-386, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620803</a>] [<a href="https://doi.org/10.1038/30756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620803">Schroeter et al., 1998</a>). S3 cleavage serves to release the NOTCH1 intracellular domain (NICD) from the membrane. NICD then translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL family members (RBPSUH (<a href="/entry/147183">147183</a>), 'suppressor of hairless,' and LAG1) (<a href="#37" class="mim-tip-reference" title="Jarriault, S., Brou, C., Logeat, F., Schroeter, E. H., Kopan, R., Israel, A. <strong>Signalling downstream of activated mammalian Notch.</strong> Nature 377: 355-358, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7566092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7566092</a>] [<a href="https://doi.org/10.1038/377355a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7566092">Jarriault et al., 1995</a>). S3 processing occurs only in response to ligand binding. <a href="#68" class="mim-tip-reference" title="Mumm, J. S., Schroeter, E. H., Saxena, M. T., Griesemer, A., Tian, X., Pan, D. J., Ray, W. J., Kopan, R. <strong>A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.</strong> Molec. Cell 5: 197-206, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882062</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80416-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10882062">Mumm et al. (2000)</a> demonstrated that ligand binding facilitates cleavage at another site, which they named S2, within the extracellular juxtamembrane region. This serves to release ectodomain repression of NICD production. S2 cleavage occurs between ala1710 and val1711, approximately 12 amino acids outside the transmembrane domain. Cleavage at S2 generates a transient intermediate peptide termed NEXT (Notch extracellular truncation). NEXT accumulates when NICD production is blocked by point mutations or gamma-secretase inhibitors, or by loss of presenilin-1 (PSEN1; <a href="/entry/104311">104311</a>), and inhibition of NEXT eliminates NICD production. These data demonstrated that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to NOTCH1 activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9653148+7566092+9620803+10882062+9727485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#8" class="mim-tip-reference" title="Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J. R., Cumano, A., Roux, P., Black, R. A., Israel, A. <strong>A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.</strong> Molec. Cell 5: 207-216, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882063</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80417-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10882063">Brou et al. (2000)</a> purified the gamma-secretase-like activity that accounts for the S2 cleavage in vitro and showed that it is due to tumor necrosis factor-converting enzyme, or TACE (ADAM17; <a href="/entry/603639">603639</a>), a member of the ADAM family of metalloproteases. Furthermore, experiments on TACE -/- bone marrow-derived monocytic precursor cells suggested that TACE plays a prominent role in the activation of the Notch pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Role of Presenilins in Notch Processing</em></strong>
|
|
</p>
|
|
|
|
<p>The connection between Notch and the presenilins (PSEN1, <a href="/entry/104311">104311</a>; PSEN2, <a href="/entry/600759">600759</a>) was indicated by the work of <a href="#17" class="mim-tip-reference" title="De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., Goate, A., Kopan, R. <strong>A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.</strong> Nature 398: 518-522, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206645</a>] [<a href="https://doi.org/10.1038/19083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206645">De Strooper et al. (1999)</a>, <a href="#103" class="mim-tip-reference" title="Struhl, G., Greenwald, I. <strong>Presenilin is required for activity and nuclear access of Notch in Drosophila.</strong> Nature 398: 522-525, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206646</a>] [<a href="https://doi.org/10.1038/19091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206646">Struhl and Greenwald (1999)</a>, and <a href="#121" class="mim-tip-reference" title="Ye, Y., Lukinova, N., Fortini, M. E. <strong>Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants.</strong> Nature 398: 525-529, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206647</a>] [<a href="https://doi.org/10.1038/19096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206647">Ye et al. (1999)</a>. <a href="#103" class="mim-tip-reference" title="Struhl, G., Greenwald, I. <strong>Presenilin is required for activity and nuclear access of Notch in Drosophila.</strong> Nature 398: 522-525, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206646</a>] [<a href="https://doi.org/10.1038/19091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206646">Struhl and Greenwald (1999)</a> and <a href="#121" class="mim-tip-reference" title="Ye, Y., Lukinova, N., Fortini, M. E. <strong>Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants.</strong> Nature 398: 525-529, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206647</a>] [<a href="https://doi.org/10.1038/19096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206647">Ye et al. (1999)</a> showed that loss-of-function mutations in the Drosophila presenilin gene exhibited a lethal Notch-like phenotype. <a href="#17" class="mim-tip-reference" title="De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., Goate, A., Kopan, R. <strong>A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.</strong> Nature 398: 518-522, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206645</a>] [<a href="https://doi.org/10.1038/19083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206645">De Strooper et al. (1999)</a> investigated the effect of presenilin on Notch processing by introducing a constitutively active form of murine Notch1 into fibroblasts derived from presenilin-1 knockout mice. This construct had previously been used to identify a proteolytic cleavage site located in or near the transmembrane region of Notch. All 3 groups concluded that presenilin is required for release of the intracellular domain of Notch from the plasma membrane. The significance of this work was discussed by <a href="#31" class="mim-tip-reference" title="Hardy, J., Israel, A. <strong>In search of gamma-secretase.</strong> Nature 398: 466-467, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206639</a>] [<a href="https://doi.org/10.1038/18979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206639">Hardy and Israel (1999)</a>. By analyzing a Psen1 conditional knockout mouse, <a href="#123" class="mim-tip-reference" title="Yu, H., Saura, C. A., Choi, S.-Y., Sun, L. D., Yang, X., Handler, M., Kawarabayashi, T., Younkin, L., Fedeles, B., Wilson, M. A., Younkin, S., Kandel, E. R., Kirkwood, A., Shen, J. <strong>APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.</strong> Neuron 31: 713-726, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11567612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11567612</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00417-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11567612">Yu et al. (2001)</a> concluded that inactivation of Psen1 function in the adult cerebral cortex does not affect expression of Notch downstream target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10206647+10206639+11567612+10206645+10206646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>A major therapeutic target in the search for a cure for Alzheimer disease (<a href="/entry/104300">104300</a>) is gamma-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of A-beta-42 peptides, precipitates of which are thought to cause Alzheimer disease. Presenilins are thought to contain the active site for gamma-secretase. Gamma-secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This fact led to concern that therapeutic inhibition of gamma-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. <a href="#29" class="mim-tip-reference" title="Hadland, B. K., Manley, N. R., Su, D., Longmore, G. D., Moore, C. L., Wolfe, M. S., Schroeter, E. H., Kopan, R. <strong>Gamma-secretase inhibitors repress thymocyte development.</strong> Proc. Nat. Acad. Sci. 98: 7487-7491, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11416218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11416218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11416218[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.131202798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11416218">Hadland et al. (2001)</a> showed that application of gamma-secretase inhibitors to fetal thymus organ cultures interfered with T-cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8- state to an intermediate CD4+/CD8+ double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ single-positive cells. These results demonstrated that pharmacologic gamma-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and presented a system in which rapid evaluation of gamma-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11416218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Modulation of Notch Signaling by Fringe Proteins</em></strong>
|
|
</p>
|
|
|
|
<p>Notch receptors function in highly conserved intercellular signaling pathways that direct cell-fate decisions, proliferation, and apoptosis in metazoans. Fringe proteins, such as 'lunatic fringe' (LFNG; <a href="/entry/602576">602576</a>), can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. <a href="#64" class="mim-tip-reference" title="Moloney, D. J., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K. D., Haltiwanger, R. S., Vogt, T. F. <strong>Fringe is a glycosyltransferase that modifies Notch.</strong> Nature 406: 369-375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10935626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10935626</a>] [<a href="https://doi.org/10.1038/35019000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10935626">Moloney et al. (2000)</a> established the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta-1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor (EGF; <a href="/entry/131530">131530</a>)-like sequence repeats of Notch. <a href="#64" class="mim-tip-reference" title="Moloney, D. J., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K. D., Haltiwanger, R. S., Vogt, T. F. <strong>Fringe is a glycosyltransferase that modifies Notch.</strong> Nature 406: 369-375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10935626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10935626</a>] [<a href="https://doi.org/10.1038/35019000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10935626">Moloney et al. (2000)</a> obtained biologic evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signaling by using coculture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The authors stated that the posttranslational modification of Notch by Fringe represents a striking example of modulation of a signaling event by differential receptor glycosylation and identifies a mechanism they considered likely to be relevant to other signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10935626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Studying Drosophila, <a href="#9" class="mim-tip-reference" title="Bruckner, K., Perez, L., Clausen, H., Cohen, S. <strong>Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.</strong> Nature 406: 411-415, 2000. Note: Erratum: Nature 407: 654 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10935637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10935637</a>] [<a href="https://doi.org/10.1038/35019075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10935637">Bruckner et al. (2000)</a> showed that Fringe acts in the Golgi as a glycosyltransferase enzyme that modifies the EGF modules of Notch and alters the ability of Notch to bind its ligand Delta (<a href="/entry/602768">602768</a>). The authors demonstrated that Fringe catalyzes the addition of N-acetylglucosamine to fucose, which is consistent with a role in the elongation of O-linked fucose O-glycosylation that is associated with EGF repeats. They suggested that cell type-specific modification of glycosylation may provide a general mechanism to regulate ligand-receptor interactions in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10935637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#113" class="mim-tip-reference" title="Visan, I., Tan, J. B., Yuan, J. S., Harper, J. A., Koch, U., Guidos, C. J. <strong>Regulation of T lymphopoiesis by Notch1 and lunatic fringe-mediated competition for intrathymic niches.</strong> Nature Immun. 7: 634-643, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16699526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16699526</a>] [<a href="https://doi.org/10.1038/ni1345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16699526">Visan et al. (2006)</a> found that developmental stage-specific expression of Lfng was required for coordinating access of mouse T-cell progenitors to intrathymic niches supporting Notch1-dependent phases of T-cell development. Progenitors lacking Lfng generated few thymocytes in competitive assays, whereas overexpression of Lfng resulted in 'supercompetitive' thymocytes that showed enhanced binding to delta-like ligands (e.g., DLL1) and blocked T lymphopoiesis by normal progenitors. <a href="#113" class="mim-tip-reference" title="Visan, I., Tan, J. B., Yuan, J. S., Harper, J. A., Koch, U., Guidos, C. J. <strong>Regulation of T lymphopoiesis by Notch1 and lunatic fringe-mediated competition for intrathymic niches.</strong> Nature Immun. 7: 634-643, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16699526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16699526</a>] [<a href="https://doi.org/10.1038/ni1345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16699526">Visan et al. (2006)</a> proposed that LFNG and NOTCH1 control of progenitor competition for cortical niches that suppress the B-cell potential of progenitors is important in regulation of thymus size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16699526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Modulation of Notch Signaling by POFUT1</em></strong>
|
|
</p>
|
|
|
|
<p>Notch and its ligands are modified by POFUT1 (<a href="/entry/607491">607491</a>), which attaches fucose to a serine or threonine within EGF domains. Using RNA interference to decrease Pofut1 expression in Drosophila, <a href="#73" class="mim-tip-reference" title="Okajima, T., Irvine, K. D. <strong>Regulation of Notch signaling by O-linked fucose.</strong> Cell 111: 893-904, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526814</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01114-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12526814">Okajima and Irvine (2002)</a> demonstrated that O-linked fucose is positively required for Notch signaling, including both fringe-dependent and fringe-independent processes. The requirement for Pofut1 was found to be cell autonomous, in the signal-receiving cell, and upstream of Notch activation. The transcription of Pofut1 was developmentally regulated, and overexpression of Pofut1 inhibited Notch signaling. The authors concluded that POFUT1 is a core component of the Notch pathway that is required for the activation of Notch by its ligands and whose regulation may contribute to the pattern of Notch activation during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12526814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Modulation of Notch Signaling by PIN1</em></strong>
|
|
</p>
|
|
|
|
<p><a href="#90" class="mim-tip-reference" title="Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., Kaplan, F., Capobianco, A., Pece, S., De Fiore, P. P., Del Sal, G. <strong>The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.</strong> Nature Cell Biol. 11: 133-142, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19151708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19151708</a>] [<a href="https://doi.org/10.1038/ncb1822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19151708">Rustighi et al. (2009)</a> showed that PIN1 (<a href="/entry/601052">601052</a>) enhanced NOTCH1 signaling in human cancer cell lines through its prolyl-isomerase activity. PIN1 interacted directly with phosphorylated NOTCH1 and enhanced NOTCH1 cleavage by gamma-secretase. Accordingly, PIN1 contributed to NOTCH1 transforming properties both in vitro and in vivo. NOTCH1 in turn upregulated PIN1, thus establishing a positive feedback loop that amplified NOTCH1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19151708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Modulation of Notch Signaling by USP10</em></strong>
|
|
</p>
|
|
|
|
<p><a href="#49" class="mim-tip-reference" title="Lim, R., Sugino, T., Nolte, H., Andrade, J., Zimmermann, B., Shi, C., Doddaballapur, A., Ong, Y. T., Wilhelm, K., Fasse, J. W. D., Ernst, A., Kaulich, M., Husnjak, K., Boettger, T., Guenther, S., Braun, T., Kruger, M., Benedito, R., Dikic, I., Potente, M. <strong>Deubiquitinase USP10 regulates Notch signaling in the endothelium.</strong> Science 364: 188-193, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30975888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30975888</a>] [<a href="https://doi.org/10.1126/science.aat0778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30975888">Lim et al. (2019)</a> found that human USP10 (<a href="/entry/609818">609818</a>) interacted with NICD to slow ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Inactivation of USP10 reduced NICD abundance and stability and diminished Notch-induced target gene expression in human endothelial cells. In mice, loss of endothelial Usp10 increased vessel sprouting and partially restored patterning defects caused by ectopic expression of NICD. The authors concluded that USP10 functions as an NICD deubiquitinase that modulates endothelial Notch responses during angiogenic sprouting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30975888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Notch Signaling Pathway</em></strong>
|
|
</p>
|
|
|
|
<p><a href="#3" class="mim-tip-reference" title="Artavanis-Tsakonas, S., Matsuno, K., Fortini, M. <strong>Notch signaling.</strong> Science 268: 225-232, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7716513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7716513</a>] [<a href="https://doi.org/10.1126/science.7716513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7716513">Artavanis-Tsakonas et al. (1995)</a> reviewed the Notch signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7716513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#4" class="mim-tip-reference" title="Axelrod, J. D., Matsuno, K., Artavanis-Tsakonas, S., Perrimon, N. <strong>Interaction between Wingless and Notch signaling pathways mediated by Dishevelled.</strong> Science 271: 1826-1832, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596950</a>] [<a href="https://doi.org/10.1126/science.271.5257.1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8596950">Axelrod et al. (1996)</a> reported that the Drosophila Dishevelled gene (<a href="/entry/601225">601225</a>), which encodes a component of the Wingless (<a href="/entry/164820">164820</a>) signaling pathway, interacts antagonistically with Notch and one of its ligands, Delta. A direct physical interaction between Dishevelled and the Notch C terminus suggested to the authors that Dishevelled blocks Notch signaling directly and provides a molecular mechanism for the inhibitory crosstalk observed between the Notch and Wingless signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8596950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#82" class="mim-tip-reference" title="Rangarajan, A., Talora, C., Okuvama, R., Nicolas, M., Mammucari, C., Oh, H., Aster, J. C., Krishna, S., Metzger, D., Chambon, P., Miele, L., Aguet, M., Radtke, F., Dotto, G. P. <strong>Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.</strong> EMBO J. 20: 3427-3436, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11432830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11432830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11432830[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/20.13.3427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11432830">Rangarajan et al. (2001)</a> found that Notch1 activation induced p21 (CDKN1A; <a href="/entry/116899">116899</a>) in differentiating mouse keratinocytes, and the induction was associated with the targeting of Rbpjk (RBPSUH; <a href="/entry/147183">147183</a>) to the p21 promoter. <a href="#58" class="mim-tip-reference" title="Mammucari, C., Tommasi di Vignano, A., Sharov, A. A., Neilson, J., Havrda, M. C., Roop, D. R., Botchkarev, V. A., Crabtree, G. R., Dotto, G. P. <strong>Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.</strong> Dev. Cell 8: 665-676, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15866158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15866158</a>] [<a href="https://doi.org/10.1016/j.devcel.2005.02.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15866158">Mammucari et al. (2005)</a> showed that Notch1 also activated p21 through a calcineurin (see <a href="/entry/114105">114105</a>)-dependent mechanism acting on the p21 TATA box-proximal region. Notch signaling through the calcineurin/NFAT (see <a href="/entry/600490">600490</a>) pathway also involved calcipressin (see <a href="/entry/602917">602917</a>) and Hes1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15866158+11432830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#116" class="mim-tip-reference" title="Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C., Hahn, W. C., Rudolf, M., Siziopikou, K., Kast, W. M., Miele, L. <strong>Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.</strong> Nature Med. 8: 979-986, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12185362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12185362</a>] [<a href="https://doi.org/10.1038/nm754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12185362">Weijzen et al. (2002)</a> demonstrated that oncogenic Ras (<a href="/entry/190020">190020</a>) activates Notch signaling and that wildtype Notch1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch1, and upregulates Notch1 ligand Delta1 (<a href="/entry/606582">606582</a>) and also presenilin-1 (<a href="/entry/104311">104311</a>), a protein involved in Notch processing, through a p38 (<a href="/entry/600289">600289</a>)-mediated pathway. <a href="#116" class="mim-tip-reference" title="Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C., Hahn, W. C., Rudolf, M., Siziopikou, K., Kast, W. M., Miele, L. <strong>Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.</strong> Nature Med. 8: 979-986, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12185362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12185362</a>] [<a href="https://doi.org/10.1038/nm754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12185362">Weijzen et al. (2002)</a> concluded that their observations placed Notch signaling among key downstream effectors of oncogenic Ras. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12185362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#5" class="mim-tip-reference" title="Balint, K., Xiao, M., Pinnix, C. C., Soma, A., Veres, I., Juhasz, I., Brown, E. J., Capobianco, A. J., Herlyn, M., Liu, Z.-J. <strong>Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.</strong> J. Clin. Invest. 115: 3166-3176, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16239965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239965">Balint et al. (2005)</a> demonstrated that the NOTCH1 pathway was activated in melanoma (see <a href="/entry/155600">155600</a>) specimens compared to nevus specimens. Blocking NOTCH signaling suppressed primary melanoma cell growth, whereas constitutive activation of the NOTCH1 pathway enhanced primary melanoma cell growth both in vitro and in vivo, but NOTCH1 had little effect on metastatic melanoma cells. Activation of NOTCH1 signaling enabled primary melanoma cells to gain metastatic capability. The oncogenic effect of NOTCH1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following NOTCH1 activation; inhibiting beta-catenin expression reversed NOTCH1-enhanced tumor growth and metastasis. <a href="#5" class="mim-tip-reference" title="Balint, K., Xiao, M., Pinnix, C. C., Soma, A., Veres, I., Juhasz, I., Brown, E. J., Capobianco, A. J., Herlyn, M., Liu, Z.-J. <strong>Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.</strong> J. Clin. Invest. 115: 3166-3176, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16239965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239965">Balint et al. (2005)</a> suggested that there is a beta-catenin-dependent, stage-specific role for NOTCH1 signaling in promoting the progression of primary melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using microarray studies of the mouse presomitic mesoderm transcriptome, <a href="#20" class="mim-tip-reference" title="Dequeant, M.-L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O. <strong>A complex oscillating network of signaling genes underlies the mouse segmentation clock.</strong> Science 314: 1595-1598, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17095659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17095659</a>] [<a href="https://doi.org/10.1126/science.1133141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17095659">Dequeant et al. (2006)</a> demonstrated that the oscillator associated with this process, the segmentation clock, drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the Notch-fibroblast growth factor (FGF) and Wnt (see <a href="/entry/164820">164820</a>) pathways during each cycle suggested that coordinated regulation of these 3 pathways underlies the clock oscillator. <a href="#20" class="mim-tip-reference" title="Dequeant, M.-L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O. <strong>A complex oscillating network of signaling genes underlies the mouse segmentation clock.</strong> Science 314: 1595-1598, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17095659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17095659</a>] [<a href="https://doi.org/10.1126/science.1133141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17095659">Dequeant et al. (2006)</a> collected presomitic mesoderm samples from 40 mouse embryos ranging from 19 to 23 somites and used their Lfng (<a href="/entry/602576">602576</a>) expression patterns as a proxy to select 17 samples covering an entire oscillation cycle. Six of the 8 known mouse cyclic genes, Hes1 (<a href="/entry/139605">139605</a>), Hes5 (<a href="/entry/607348">607348</a>), Hey1 (<a href="/entry/602953">602953</a>), Lfng, Axin2 (<a href="/entry/604025">604025</a>), and Nkd1 (<a href="/entry/607851">607851</a>), were identified with periods of 94, 102, 112, 81, 102, and 112 minutes, respectively. Two clusters were identified. One cluster contains the known cyclic genes of the Notch pathway: Hes1, Hes5, and Hey1, as well as Id1 (<a href="/entry/600349">600349</a>). This cluster also contains Nrarp (<a href="/entry/619987">619987</a>), a direct target of Notch signaling. In the same cluster as the Notch pathway were members of the FGF-MAPK pathway, including Spry2 (<a href="/entry/602466">602466</a>) and Dusp6 (<a href="/entry/602748">602748</a>). The second cluster of periodic genes contained genes cycling in opposite phase to the Notch-FGF cluster; in this cluster were a majority of the cyclic genes associated with Wnt signaling, including Dkk1 (<a href="/entry/605189">605189</a>), cMyc (<a href="/entry/190080">190080</a>), Axin2, Sp5 (<a href="/entry/609391">609391</a>), and Tnfrsf19 (<a href="/entry/606122">606122</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17095659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>By examining gene expression profiles, <a href="#75" class="mim-tip-reference" title="Palomero, T., Lim, W. K., Odom, D. T., Sulis, M. L., Real, P. J., Margolin, A., Barnes, K. C., O'Neil, J., Neuberg, D., Weng, A. P., Aster, J. C., Sigaux, F., Soulier, J., Look, A. T., Young, R. A., Califano, A., Ferrando, A. A. <strong>NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.</strong> Proc. Nat. Acad. Sci. 103: 18261-18266, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 104: 4240 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17114293[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0606108103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17114293">Palomero et al. (2006)</a> found that NOTCH and MYC (<a href="/entry/190080">190080</a>) regulate 2 interconnected transcriptional programs containing common target genes that regulate cell growth in primary human T-cell lymphoblastic leukemias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17114293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>In studies involving bone marrow progenitor cells and T-cell acute lymphoblastic leukemia (T-ALL) cell lines, <a href="#112" class="mim-tip-reference" title="Vilimas, T., Mascarenhas, J., Palomero, T., Mandal, M., Buonamici, S., Meng, F., Thompson, B., Spaulding, C., Macaroun, S., Alegre, M.-L., Kee, B. L., Ferrando, A., Miele, L., Aifantis, I. <strong>Targeting the NF-kappa-B signaling pathway in Notch1-induced T-cell leukemia.</strong> Nature Med. 13: 70-77, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173050</a>] [<a href="https://doi.org/10.1038/nm1524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173050">Vilimas et al. (2007)</a> found that constitutively active NOTCH1 activated the NFKB pathway transcriptionally and via the IKK complex (see <a href="/entry/600664">600664</a>), thereby causing increased expression of NFKB target genes. The NFKB pathway was highly active in establishing human T-ALL, and inhibition of the pathway efficiently restricted tumor growth both in vitro and in vivo. <a href="#112" class="mim-tip-reference" title="Vilimas, T., Mascarenhas, J., Palomero, T., Mandal, M., Buonamici, S., Meng, F., Thompson, B., Spaulding, C., Macaroun, S., Alegre, M.-L., Kee, B. L., Ferrando, A., Miele, L., Aifantis, I. <strong>Targeting the NF-kappa-B signaling pathway in Notch1-induced T-cell leukemia.</strong> Nature Med. 13: 70-77, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173050</a>] [<a href="https://doi.org/10.1038/nm1524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173050">Vilimas et al. (2007)</a> concluded that NFKB is one of the major mediators of NOTCH1-induced transformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17173050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#47" class="mim-tip-reference" title="Lefort, K., Mandinova, A., Ostano, P., Kolev, V., Calpini, V., Kolfschoten, I., Devgan, V., Lieb, J., Raffoul, W., Hohl, D., Neel, V., Garlick, J., Chiorino, G., Dotto, G. P. <strong>Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK-alpha kinases.</strong> Genes Dev. 21: 562-577, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344417</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344417[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1484707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17344417">Lefort et al. (2007)</a> found that NOTCH1 protein and mRNA were reduced in a panel of skin and oral squamous cell carcinoma (SCC) cell lines and in a panel of skin SCCs relative to normal epidermis controls. They found that inhibition of Notch signaling in human primary keratinocytes suppressed keratinocyte commitment to differentiation, expanded a cell population with stem cell potential, and promoted aggressive SCC formation. Expression of NOTCH1 in human keratinocytes was under the control of P53 (TP53; <a href="/entry/191170">191170</a>), and NOTCH1 suppressed tumor formation through negative regulation of ROCK1 (<a href="/entry/601702">601702</a>)/ROCK2 (<a href="/entry/604002">604002</a>) and MRCK-alpha (CDC42BPA; <a href="/entry/603412">603412</a>), which are effectors of small RHO GTPases (see ARHA; <a href="/entry/165390">165390</a>) implicated in neoplastic progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Some T-ALL cells show resistance to gamma-secretase inhibitors, which act by blocking NOTCH1 activation. Using microarray analysis, <a href="#76" class="mim-tip-reference" title="Palomero, T., Sulis, M. L., Cortina, M., Real, P. J., Barnes, K., Ciofani, M., Caparros, E., Buteau, J., Brown, K., Perkins, S. L., Bhagat, G., Agarwal, A. M., Basso, G., Castillo, M., Nagase, S., Cordon-Cardo, C., Parsons, R., Zuniga-Pflucker, J. C., Dominguez, M., Ferrando, A. A. <strong>Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.</strong> Nature Med. 13: 1203-1210, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17873882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17873882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17873882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17873882">Palomero et al. (2007)</a> identified PTEN (<a href="/entry/601728">601728</a>) as the gene most consistently downregulated in gamma-secretase inhibitor-resistant T-cell lines. Further analysis showed that these resistant cell lines had truncating mutations in the PTEN gene. Loss of PTEN function resulted in aberrant activation of the PI3-kinase (<a href="/entry/171834">171834</a>)-AKT (<a href="/entry/164730">164730</a>) signaling pathway, which induced resistance to gamma-secretase inhibitors. Studies in normal mouse thymocytes indicated that Notch1 regulated Pten expression downstream. Notch signaling and the PI3-kinase-AKT pathway acted synergistically in a Drosophila model of Notch-induced tumorigenesis. The findings demonstrated that NOTCH1 controls a transcriptional network that regulates PTEN expression and PI3-kinase-AKT signaling activity in normal thymocytes and leukemic T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17873882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#61" class="mim-tip-reference" title="Mizutani, K., Yoon, K., Dang, L., Tokunaga, A., Gaiano, N. <strong>Differential Notch signalling distinguishes neural stem cells from intermediate progenitors.</strong> Nature 449: 351-355, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721509</a>] [<a href="https://doi.org/10.1038/nature06090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17721509">Mizutani et al. (2007)</a> showed that both neural stem cells and intermediate neural progenitors respond to Notch receptor activation, but that neural stem cells signal through the canonic Notch effector C-promoter binding factor (CBF1; <a href="/entry/147183">147183</a>), whereas intermediate neural progenitors have attenuated CBF1 signaling. Furthermore, whereas knockdown of CBF1 promotes the conversion of neural stem cells to intermediate neural progenitors, activation of CBF1 is insufficient to convert intermediate neural progenitors back to neural stem cells. Using both transgenic and transient in vivo reporter assays, <a href="#61" class="mim-tip-reference" title="Mizutani, K., Yoon, K., Dang, L., Tokunaga, A., Gaiano, N. <strong>Differential Notch signalling distinguishes neural stem cells from intermediate progenitors.</strong> Nature 449: 351-355, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721509</a>] [<a href="https://doi.org/10.1038/nature06090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17721509">Mizutani et al. (2007)</a> showed that neural stem cells and intermediate neural progenitors coexist in the telencephalic ventricular zone of mice and that they can be prospectively separated on the basis of CBF1 activity. Furthermore, using in vivo transplantation, they showed that whereas neural stem cells generate neurons, astrocytes, and oligodendrocytes at similar frequencies, intermediate neural progenitors are predominantly neurogenic. <a href="#61" class="mim-tip-reference" title="Mizutani, K., Yoon, K., Dang, L., Tokunaga, A., Gaiano, N. <strong>Differential Notch signalling distinguishes neural stem cells from intermediate progenitors.</strong> Nature 449: 351-355, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721509</a>] [<a href="https://doi.org/10.1038/nature06090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17721509">Mizutani et al. (2007)</a> concluded that their study, together with previous work on hematopoietic stem cells, suggested the use or blockade of the CBF1 cascade downstream of Notch as a general feature distinguishing stem cells from more limited progenitors in a variety of tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17721509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#97" class="mim-tip-reference" title="Sjolund, J., Johansson, M., Manna, S., Norin, C., Pietras, A., Beckman, S., Nilsson, E., Ljungberg, B., Axelson, H. <strong>Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo.</strong> J. Clin. Invest. 118: 217-228, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18079963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18079963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18079963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI32086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18079963">Sjolund et al. (2008)</a> found that Notch signaling was constitutively active in human clear cell renal cell carcinoma (CCRCC) cell lines. Blocking Notch signaling attenuated proliferation and restrained anchorage-independent growth of CCRCC cell lines and inhibited growth of xenotransplanted CCRCC cells in nude mice. Small interfering RNA against various Notch receptors showed that growth promotion was due to Notch1 activation, and Notch1 knockdown was accompanied by elevated levels of the negative cell cycle regulators p21(Cip1) and/or p27(Kip1) (CDKN1B; <a href="/entry/600778">600778</a>). Moreover, Notch1 and the Notch ligand Jagged1 were expressed at significantly higher levels in CCRCC tumors than in normal human renal tissue, and growth of primary CCRCC cells was attenuated upon inhibition of Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18079963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#71" class="mim-tip-reference" title="Niranjan, T., Bielesz, B., Gruenwald, A., Ponda, M. P., Kopp, J. B., Thomas, D. B., Susztak, K. <strong>The Notch pathway in podocytes plays a role in the development of glomerular disease.</strong> Nature Med. 14: 290-298, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311147</a>] [<a href="https://doi.org/10.1038/nm1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311147">Niranjan et al. (2008)</a> showed that genes in the Notch pathway were expressed in mature podocytes in humans and in rodent models of diabetic nephropathy and focal segmental glomerulosclerosis. In vitro and in vivo studies showed that the Notch intracellular domain induced apoptosis of podocytes, and genetic or pharmacologic inhibition of the Notch pathway protected rats with proteinuric kidney diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18311147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#62" class="mim-tip-reference" title="Moellering, R. E., Cornejo, M., Davis, T. N., Del Bianco, C., Aster, J. C., Blacklow, S. C., Kung, A. L., Gilliland, D. G., Verdine, G. L., Bradner, J. E. <strong>Direct inhibition of the NOTCH transcription factor complex.</strong> Nature 462: 182-188, 2009. Note: Erratum: Nature 463: 384 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19907488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19907488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19907488[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19907488">Moellering et al. (2009)</a> reported the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. The authors demonstrated that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 (stapled alpha-helical peptide derived from MAML1, <a href="/entry/605424">605424</a>) prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-ALL. The treatment of leukemic cells with SAHM1 resulted in genomewide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program caused potent, NOTCH-specific antiproliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19907488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Ligand binding in Notch receptors triggers a conformational change in the receptor-negative regulatory region (NRR) that enables ADAM (see <a href="/entry/601533">601533</a>) protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalyzed by the gamma-secretase complex liberates the intracellular domain to initiate downstream Notch transcriptional program. Aberrant signaling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for drugs (summary by <a href="#118" class="mim-tip-reference" title="Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others. <strong>Therapeutic antibody targeting of individual Notch receptors.</strong> Nature 464: 1052-1057, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393564</a>] [<a href="https://doi.org/10.1038/nature08878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20393564">Wu et al., 2010</a>). Although gamma-secretase inhibitors (GSIs) had progressed into the clinic, GSIs failed to distinguish individual Notch receptors, inhibited other signaling pathways, and caused intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (<a href="#87" class="mim-tip-reference" title="Riccio, O., van Gijn, M. E., Bezdek, A. C., Pellegrinet, L., van Es, J. H., Zimber-Strobl, U., Strobl, L. J., Honjo, T., Clevers, H., Radtke, F. <strong>Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27(Kip1) and p57(Kip2).</strong> EMBO Rep. 9: 377-383, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18274550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18274550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18274550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/embor.2008.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18274550">Riccio et al., 2008</a>). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, <a href="#118" class="mim-tip-reference" title="Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others. <strong>Therapeutic antibody targeting of individual Notch receptors.</strong> Nature 464: 1052-1057, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393564</a>] [<a href="https://doi.org/10.1038/nature08878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20393564">Wu et al. (2010)</a> used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralog and yet crossreact with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. The cocrystal structure showed that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibited tumor growth in preclinical models through 2 mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18274550+20393564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#22" class="mim-tip-reference" title="Engel, M. E., Nguyen, H. N., Mariotti, J., Hunt, A., Hiebert, S. W. <strong>Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification.</strong> Molec. Cell. Biol. 30: 1852-1863, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01342-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123979">Engel et al. (2010)</a> found that Mtg16 (CBFA2T3; <a href="/entry/603870">603870</a>) -/- mouse hematopoietic progenitor cells showed elevated expression of Notch targets, in addition to impaired differentiation, in response to Notch signaling. The defect was reversed by restoration of Mtg16 expression. Using mouse and human cells, <a href="#22" class="mim-tip-reference" title="Engel, M. E., Nguyen, H. N., Mariotti, J., Hunt, A., Hiebert, S. W. <strong>Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification.</strong> Molec. Cell. Biol. 30: 1852-1863, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01342-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123979">Engel et al. (2010)</a> showed that all MTG family proteins bound CSL and that MTG16 bound the ICDs of all Notch receptor proteins. Binding of MTG16 to Notch ICD disrupted MTG16-CSL and MTG16-NCOR (see <a href="/entry/600849">600849</a>) interactions and permitted Notch signaling. Mutation and coprecipitation analysis revealed that the N-terminal PST region of MTG16 interacted directly with Notch ICD and that binding was independent of the MTG16 NTR domains required for DNA, CSL, and histone deacetylase binding. The PST region of Mtg16 was also essential for Mtg16-dependent lineage specification in mouse hematopoietic progenitor cells. <a href="#22" class="mim-tip-reference" title="Engel, M. E., Nguyen, H. N., Mariotti, J., Hunt, A., Hiebert, S. W. <strong>Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification.</strong> Molec. Cell. Biol. 30: 1852-1863, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01342-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123979">Engel et al. (2010)</a> concluded that MTG16 is an integral component of Notch signaling that contributes to basal repression of canonical Notch target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20123979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#27" class="mim-tip-reference" title="Guarani, V., Deflorian, G., Franco, C. A., Kruger, M., Phng, L.-K., Bentley, K., Toussaint, L., Dequiedt, F., Mostoslavsky, R., Schmidt, M. H. H., Zimmermann, B., Brandes, R. P., Mione, M., Westphal, C. H., Braun, T., Zeiher, A. M., Gerhardt, H., Dimmeler, S., Potente, M. <strong>Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.</strong> Nature 473: 234-238, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21499261[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499261">Guarani et al. (2011)</a> reported that the NAD(+)-dependent deacetylase SIRT1 (<a href="/entry/604479">604479</a>) acts as an intrinsic negative modulator of Notch signaling in endothelial cells. They showed that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with the NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signaling, resulting in impaired growth, sprout elongation, and enhanced Notch target gene expression in response to DLL4 (<a href="/entry/605185">605185</a>) stimulation, thereby promoting a nonsprouting, stalk cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signaling. <a href="#27" class="mim-tip-reference" title="Guarani, V., Deflorian, G., Franco, C. A., Kruger, M., Phng, L.-K., Bentley, K., Toussaint, L., Dequiedt, F., Mostoslavsky, R., Schmidt, M. H. H., Zimmermann, B., Brandes, R. P., Mione, M., Westphal, C. H., Braun, T., Zeiher, A. M., Gerhardt, H., Dimmeler, S., Potente, M. <strong>Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.</strong> Nature 473: 234-238, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21499261[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499261">Guarani et al. (2011)</a> concluded that their findings identified reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signaling, and indicated that SIRT1 acts as rheostat to fine-tune endothelial Notch responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21499261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#88" class="mim-tip-reference" title="Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C. <strong>Neural crest regulates myogenesis through the transient activation of NOTCH.</strong> Nature 473: 532-535, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21572437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21572437</a>] [<a href="https://doi.org/10.1038/nature09970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21572437">Rios et al. (2011)</a> characterized the signaling events taking place during morphogenesis of chick skeletal muscle and showed that muscle progenitors present in somites require the transient activation of NOTCH signaling to undergo terminal differentiation. The NOTCH ligand Delta1 (<a href="/entry/606582">606582</a>) is expressed in a mosaic pattern in neural crest cells that migrate past the somites. Gain and loss of Delta1 function in neural crest modifies NOTCH signaling in somites, which results in delayed or premature myogenesis. <a href="#88" class="mim-tip-reference" title="Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C. <strong>Neural crest regulates myogenesis through the transient activation of NOTCH.</strong> Nature 473: 532-535, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21572437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21572437</a>] [<a href="https://doi.org/10.1038/nature09970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21572437">Rios et al. (2011)</a> concluded that the neural crest regulates early muscle formation by a unique mechanism that relies on the migration of Delta1-expressing neural crest cells to trigger the transient activation of NOTCH signaling in selected muscle progenitors. This dynamic signaling guarantees a balanced and progressive differentiation of the muscle progenitor pool. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21572437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<div class="mim-changed mim-change"><p>Using yeast 2-hybrid and immunoprecipitation assays, <a href="#91" class="mim-tip-reference" title="Sanchez-Solana, B., Nueda, M. L., Ruvira, M. D., Ruiz-Hidalgo, M. J., Monsalve, E. M., Rivero, S., Garcia-Ramirez, J. J., Diaz-Guerra, M. J., Baladron, V., Laborda, J. <strong>The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.</strong> Biochim. Biophys. Acta 1813: 1153-1164, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419176</a>] [<a href="https://doi.org/10.1016/j.bbamcr.2011.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419176">Sanchez-Solana et al. (2011)</a> showed that DLK1 (<a href="/entry/176290">176290</a>) and DLK2 (<a href="/entry/621120">621120</a>) interacted with themselves and with each other through their extracellular EGF-like regions to form homodimers and heterodimers. DLK1 and DLK2 also interacted with NOTCH1 through their extracellular regions. By interacting with NOTCH1, DLK1 and DLK2 inhibited NOTCH activation and signaling by competing with the NOTCH1-activating ligands DLL4 and JAGGED1 for NOTCH1 binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
|
|
|
|
<div class="mim-changed mim-change"><p><a href="#72" class="mim-tip-reference" title="Nueda, M. L., Gonzalez-Gomez, M. J., Rodriguez-Cano, M. M., Monsalve, E. M., Diaz-Guerra, M. J. M., Sanchez-Solana, B., Laborda, J., Baladron, V. <strong>DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate.</strong> Sci. Rep. 8: 16923, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30446682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30446682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30446682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-018-35252-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30446682">Nueda et al. (2018)</a> found that overexpression of any of the 4 Notch receptors enhanced adipogenesis of 3T3-L1 preadipocytes. Further analysis showed that Dlk1 and Dlk2 inhibited activity of all 4 Notch receptors to different degrees. Overexpression of Notch1 stimulated differentiation of 3T3-L1 cells towards a brown-like adipocyte phenotype, whereas overexpression of Notch2 (<a href="/entry/600275">600275</a>), Notch3 (<a href="/entry/600276">600276</a>), or Notch4 (<a href="/entry/164951">164951</a>), or of Dlk1 or Dlk2, promoted differentiation towards a white-like adipocyte phenotype. The authors observed a complex feedback mechanism involving the Notch and Dlk genes in regulation of their expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30446682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
|
|
|
|
<p><a href="#66" class="mim-tip-reference" title="Moretti, J., Chastagner, P., Liang, C.-C., Cohn, M. A., Israel, A., Brou, C. <strong>The ubiquitin-specific protease 12 (USP12) is a negative regulator of Notch signaling acting on Notch receptor trafficking toward degradation.</strong> J. Biol. Chem. 287: 29429-29441, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22778262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22778262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22778262[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.366807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22778262">Moretti et al. (2012)</a> stated that ITCH (<a href="/entry/606409">606409</a>) polyubiquitinates nonactivated membrane-anchored Notch receptor and targets Notch for lysosomal degradation. Using an inhibitor of lysosomal proteases, <a href="#66" class="mim-tip-reference" title="Moretti, J., Chastagner, P., Liang, C.-C., Cohn, M. A., Israel, A., Brou, C. <strong>The ubiquitin-specific protease 12 (USP12) is a negative regulator of Notch signaling acting on Notch receptor trafficking toward degradation.</strong> J. Biol. Chem. 287: 29429-29441, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22778262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22778262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22778262[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.366807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22778262">Moretti et al. (2012)</a> confirmed that nonactivated Notch is degraded via the lysosome. Using mouse and human cells and constructs, they found that the deubiquitinating enzyme USP12 (<a href="/entry/603091">603091</a>) interacted with ITCH and with UAF1 (WDR48; <a href="/entry/612167">612167</a>). The USP12-UAF1 complex deubiquitinated nonactivated Notch and was required for Notch degradation in lysosomes. Knockdown of USP12 or UAF1, or overexpression of inactive USP12, resulted in accumulation of Notch receptor in endosomes. <a href="#66" class="mim-tip-reference" title="Moretti, J., Chastagner, P., Liang, C.-C., Cohn, M. A., Israel, A., Brou, C. <strong>The ubiquitin-specific protease 12 (USP12) is a negative regulator of Notch signaling acting on Notch receptor trafficking toward degradation.</strong> J. Biol. Chem. 287: 29429-29441, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22778262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22778262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22778262[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.366807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22778262">Moretti et al. (2012)</a> proposed a model whereby USP12-UAF1 is recruited to Notch-Itch, resulting in proper trafficking of Notch receptor to lysosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22778262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using immunoprecipitation analysis, <a href="#79" class="mim-tip-reference" title="Puca, L., Chastagner, P., Meas-Yedid, V., Israel, A., Brou, C. <strong>Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals.</strong> J. Cell Sci. 126: 4457-4468, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23886940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23886940</a>] [<a href="https://doi.org/10.1242/jcs.130500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23886940">Puca et al. (2013)</a> showed that human ARRDC1 (<a href="/entry/619768">619768</a>) interacted directly with ITCH. Simultaneously, ARRDC1 interacted directly with beta-arrestin-1 (ARRB1; <a href="/entry/107940">107940</a>) and beta-arrestin-2 (ARRB2; <a href="/entry/107941">107941</a>) to form a complex that recruited ITCH to NOTCH. Through these interactions, ARRDC1 was involved in ITCH-mediated NOTCH ubiquitylation and lysosomal degradation at the same step, but not redundantly, with the beta-arrestins. Moreover, ARRDC1 and the beta-arrestins acted as negative regulators of NOTCH signaling as members of the same complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23886940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#39" class="mim-tip-reference" title="Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L. <strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong> Science 342: 734-737, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>] [<a href="https://doi.org/10.1126/science.1241359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24091702">Kasahara et al. (2013)</a> found that interruption of mitochondrial fusion disrupts the calcium/calcineurin (see <a href="/entry/114105">114105</a>) pathway that regulates the central cardiac development factor Notch1, interrupting cardiomyocyte proliferation and blocking fetal cardiac development. Ablation of mitochondrial fusion proteins mitofusin-1 (Mfn1; <a href="/entry/608506">608506</a>) and -2 (Mfn2; <a href="/entry/608507">608507</a>) in the embryonic mouse heart, or gene trapping of Mfn2 or optic atrophy-1 (Opa1; <a href="/entry/605290">605290</a>) in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (<a href="/entry/190180">190180</a>)/Bmp (see <a href="/entry/112264">112264</a>), serum response factor (SRF; <a href="/entry/600589">600589</a>), Gata4 (<a href="/entry/600576">600576</a>), and myocyte enhancer factor-2 (see <a href="/entry/600660">600660</a>), linked to increased calcium-dependent calcineurin activity and Notch1 signaling that impaired embryonic stem cell differentiation. <a href="#39" class="mim-tip-reference" title="Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L. <strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong> Science 342: 734-737, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>] [<a href="https://doi.org/10.1126/science.1241359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24091702">Kasahara et al. (2013)</a> concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24091702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#57" class="mim-tip-reference" title="Magnusson, J. P., Goritz, C., Tatarishvili, J., Dias, D. O., Smith, E. M. K., Lindvall, O., Kokaia, Z., Frisen, J. <strong>A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.</strong> Science 346: 237-241, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25301628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25301628</a>] [<a href="https://doi.org/10.1126/science.346.6206.237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25301628">Magnusson et al. (2014)</a> reported that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 +/- 210 (mean +/- SEM) new neurons in a mouse striatum. <a href="#57" class="mim-tip-reference" title="Magnusson, J. P., Goritz, C., Tatarishvili, J., Dias, D. O., Smith, E. M. K., Lindvall, O., Kokaia, Z., Frisen, J. <strong>A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.</strong> Science 346: 237-241, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25301628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25301628</a>] [<a href="https://doi.org/10.1126/science.346.6206.237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25301628">Magnusson et al. (2014)</a> concluded that under Notch signaling regulation, astrocytes in adult mouse parenchyma carry a latent neurogenic program that could be useful for neuronal replacement strategies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25301628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>By purifying NOTCH complexes from NOTCH-induced human T-cell lymphomas, followed by coimmunoprecipitation analysis, <a href="#115" class="mim-tip-reference" title="Weaver, K. L., Alves-Guerra, M.-C., Jin, K., Wang, Z., Han, X., Ranganathan, P., Zhu, X., DaSilva, T., Liu, W., Ratti, F., Demarest, R. M., Tzimas, C., Rice, M., Vasquez-Del Carpio, R., Dahmane, N., Robbins, D. J., Capobianco, A. J. <strong>NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.</strong> Cancer Res. 74: 4741-4751, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-14-1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25038227">Weaver et al. (2014)</a> identified PRAG1 (<a href="/entry/617344">617344</a>), which they called NACK, as a NOTCH-interacting protein. Fractionation experiments showed colocalization of PRAG1 and NOTCH1 in nucleus. Beta-galactosidase staining of transgenic knockin mice revealed coexpression of Prag1 and Notch1 in central nervous system of embryonic day-12.5 (E12.5) and E16.5 mouse embryos. Pull-down experiments showed that binding of PRAG1 to the NOTCH complex on DNA depended on binding of the complex to CSL and MAML1. Mutations in NOTCH1 or MAML1 that inhibited NOTCH complex transcriptional activity inhibited binding of PRAG1 to the complex on DNA. Cotransfection of PRAG1 with the NOTCH1 ICD in H1299 human lung carcinoma cells increased CSL-directed transcription, similar to the effect of cotransfection of MAML1 with the NOTCH1 ICD. Chromatin immunoprecipitation analysis of OE33 human esophageal adenocarcinoma cells, which are dependent on NOTCH activity, showed that PRAG1-NOTCH complexes specifically localized to the promoter region of the NOTCH target HES1. Knockdown of PRAG1 using short hairpin RNA resulted in decreased HES1 expression in OE33 cells and attenuation of NOTCH-induced Hes1 expression in HC11 mouse mammary epithelial cells. Expression of Prag1 was upregulated following expression of the ICD of any NOTCH family member in mouse embryonic fibroblasts, which lack endogenous NOTCH activity. Chromatin immunoprecipitation analysis showed binding of NOTCH to the PRAG1 promoter. Immunohistochemical and quantitative RT-PCR analyses of clinical samples of surgically resected pancreatic ductal adenocarcinoma and esophageal adenocarcinoma showed higher levels of PRAG1 and NOTCH compared with normal tissue, and this increased expression was also seen in pancreatic ductal adenocarcinoma by immunohistochemical analysis. Knockdown of Prag1 reduced anchorage-independent growth on soft agar in HC11 cells infected with NOTCH1 ICD. Furthermore, knockdown of PRAG1 in human esophageal adenocarcinoma cells prior to injection of cells into nude mice resulted in decreased tumor growth. <a href="#115" class="mim-tip-reference" title="Weaver, K. L., Alves-Guerra, M.-C., Jin, K., Wang, Z., Han, X., Ranganathan, P., Zhu, X., DaSilva, T., Liu, W., Ratti, F., Demarest, R. M., Tzimas, C., Rice, M., Vasquez-Del Carpio, R., Dahmane, N., Robbins, D. J., Capobianco, A. J. <strong>NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.</strong> Cancer Res. 74: 4741-4751, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-14-1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25038227">Weaver et al. (2014)</a> concluded that PRAG1 is an essential component of the NOTCH complex that regulates NOTCH-mediated tumorigenesis and development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25038227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#108" class="mim-tip-reference" title="Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M. <strong>A gp130-Src-YAP module links inflammation to epithelial regeneration.</strong> Nature 519: 57-62, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25731159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25731159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25731159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25731159">Taniguchi et al. (2015)</a> showed in mice and human cells that GP130 (<a href="/entry/600694">600694</a>), a coreceptor for IL6 (<a href="/entry/147620">147620</a>) cytokines, triggers activation of YAP (<a href="/entry/606608">606608</a>) and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the GP130 effector STAT3 (<a href="/entry/102582">102582</a>). Through YAP and Notch, intestinal GP130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation, and confers resistance to mucosal erosion. GP130 associates with the related tyrosine kinases SRC (<a href="/entry/190090">190090</a>) and YES (<a href="/entry/164880">164880</a>), which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25731159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using an engineered organotypic model of perfused microvessels, <a href="#78" class="mim-tip-reference" title="Polacheck, W. J., Kutys, M. L., Yang, J., Eyckmans, J., Wu, Y., Vasavada, H., Hirschi, K. K., Chen, C. S. <strong>A non-canonical Notch complex regulates adherens junctions and vascular barrier function.</strong> Nature 552: 258-262, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160307[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29160307">Polacheck et al. (2017)</a> showed that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a noncanonical, transcription-independent signaling mechanism that drives assembly of adherens junctions. They confirmed these findings in mouse models. Shear stress triggers DLL4 (<a href="/entry/605185">605185</a>)-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1. The transmembrane domain restores barrier function by catalyzing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin (CDH5; <a href="/entry/601120">601120</a>), the transmembrane protein tyrosine phosphatase LAR (PTPRF; <a href="/entry/179590">179590</a>), and the RAC1 guanidine-exchange factor TRIO (<a href="/entry/601893">601893</a>). This complex activates RAC1 (<a href="/entry/602048">602048</a>) to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signaling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial-venous differentiation, angiogenesis, and remodeling. <a href="#78" class="mim-tip-reference" title="Polacheck, W. J., Kutys, M. L., Yang, J., Eyckmans, J., Wu, Y., Vasavada, H., Hirschi, K. K., Chen, C. S. <strong>A non-canonical Notch complex regulates adherens junctions and vascular barrier function.</strong> Nature 552: 258-262, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160307[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29160307">Polacheck et al. (2017)</a> concluded that they established the existence of a noncanonical cortical NOTCH1 signaling pathway that regulates vascular barrier function, and thus provided a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29160307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#48" class="mim-tip-reference" title="Lim, J. S., Ibaseta, A., Fischer, M. M., Cancilla, B., O'Young, G., Cristea, S., Luca, V. C., Yang, D., Jahchan, N. S., Hamard, C., Antoine, M., Wislez, M., Kong, C., Cain, J., Liu, Y.-W., Kapoun, A. M., Garcia, K. C., Hoey, T., Murriel, C. L., Sage, J. <strong>Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.</strong> Nature 545: 360-364, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489825[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28489825">Lim et al. (2017)</a> showed that Notch signaling can be both tumor suppressive and protumorigenic in small cell lung cancer (see <a href="/entry/182280">182280</a>). Endogenous activation of the Notch pathway results in a neuroendocrine to nonneuroendocrine fate switch in 10 to 50% of tumor cells in a mouse model of small cell lung cancer and in human tumors. This switch is mediated in part by Rest (<a href="/entry/600571">600571</a>), a transcriptional repressor that inhibits neuroendocrine gene expression. Nonneuroendocrine Notch-active small cell lung cancer cells are slow growing, consistent with a tumor-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumor cells, consistent with a protumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumor growth and delays relapse in preclinical models. <a href="#48" class="mim-tip-reference" title="Lim, J. S., Ibaseta, A., Fischer, M. M., Cancilla, B., O'Young, G., Cristea, S., Luca, V. C., Yang, D., Jahchan, N. S., Hamard, C., Antoine, M., Wislez, M., Kong, C., Cain, J., Liu, Y.-W., Kapoun, A. M., Garcia, K. C., Hoey, T., Murriel, C. L., Sage, J. <strong>Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.</strong> Nature 545: 360-364, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489825[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28489825">Lim et al. (2017)</a> concluded that thus, small cell lung cancer tumors generate their own microenvironment via activation of Notch signaling in a subset of tumor cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small cell lung cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28489825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#50" class="mim-tip-reference" title="Loganathan, S. K., Schleicher, K., Malik, A., Quevedo, R., Langille, E., Teng, K., Oh, R. H., Rathod, B., Tsai, R., Samavarchi-Tehrani, P., Pugh, T. J., Gingras, A.-C., Schramek, D. <strong>Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.</strong> Science 367: 1264-1269, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32165588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32165588</a>] [<a href="https://doi.org/10.1126/science.aax0902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32165588">Loganathan et al. (2020)</a> focused on 484 genes harboring recurrent but rare mutations ('long tail' genes) in head and neck squamous cell carcinoma (HNSCC; <a href="/entry/275355">275355</a>) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 (<a href="/entry/602192">602192</a>) and AJUBA (<a href="/entry/609066">609066</a>) suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occurred in 28% of human HNSCC cases and were mutually exclusive with NOTCH receptor mutations. <a href="#50" class="mim-tip-reference" title="Loganathan, S. K., Schleicher, K., Malik, A., Quevedo, R., Langille, E., Teng, K., Oh, R. H., Rathod, B., Tsai, R., Samavarchi-Tehrani, P., Pugh, T. J., Gingras, A.-C., Schramek, D. <strong>Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.</strong> Science 367: 1264-1269, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32165588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32165588</a>] [<a href="https://doi.org/10.1126/science.aax0902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32165588">Loganathan et al. (2020)</a> concluded that their results showed that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of this cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32165588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Role of Notch in Early Embryonic Development</em></strong>
|
|
</p>
|
|
|
|
<p><a href="#105" class="mim-tip-reference" title="Takahashi, Y., Koizumi, K., Takagi, A., Kitajima, S., Inoue, T., Koseki, H., Saga, Y. <strong>Mesp2 initiates somite segmentation through the Notch signalling pathway.</strong> Nature Genet. 25: 390-396, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932180</a>] [<a href="https://doi.org/10.1038/78062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932180">Takahashi et al. (2000)</a> found that Mesp2 (<a href="/entry/605195">605195</a>) initiates the establishment of rostro-caudal polarity by controlling 2 Notch signaling pathways. Initially, Mesp2 activates a Ps1-independent Notch signaling cascade to suppress Dll1 (see <a href="/entry/602768">602768</a>) expression and specify the rostral half of the somite. Ps1-mediated Notch signaling is required to induce Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and Ps1-dependent activation of Notch signaling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using mouse embryos with deficient Notch signaling, <a href="#65" class="mim-tip-reference" title="Morales, A. V., Yasuda, Y., Ish-Horowicz, D. <strong>Periodic lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling.</strong> Dev. Cell 3: 63-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110168</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00211-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110168">Morales et al. (2002)</a> showed that dynamic expression of the mouse Lfng gene in the cycling presomitic mesoderm (PSM) is lost in the absence of Notch signaling. They concluded that periodic Lfng expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12110168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#14" class="mim-tip-reference" title="Dale, J. K., Maroto, M., Dequeant, M.-L., Malapert, P., McGrew, M., Pourquie, O. <strong>Periodic Notch inhibition by lunatic Fringe underlies the chick segmentation clock.</strong> Nature 421: 275-278, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529645</a>] [<a href="https://doi.org/10.1038/nature01244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529645">Dale et al. (2003)</a> demonstrated that the protein product of Lfng, which encodes a glycosyltransferase that can modify Notch activity, oscillates in the chick presomitic mesoderm. Overexpressing Lfng in the paraxial mesoderm abolishes the expression of cyclic genes including endogenous Lfng and leads to defects in segmentation. This effect on cyclic genes phenocopies inhibition of Notch signaling in the presomitic mesoderm. <a href="#14" class="mim-tip-reference" title="Dale, J. K., Maroto, M., Dequeant, M.-L., Malapert, P., McGrew, M., Pourquie, O. <strong>Periodic Notch inhibition by lunatic Fringe underlies the chick segmentation clock.</strong> Nature 421: 275-278, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529645</a>] [<a href="https://doi.org/10.1038/nature01244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529645">Dale et al. (2003)</a> therefore proposed that Lfng establishes a negative feedback loop that implements periodic inhibition of Notch, which in turn controls rhythmic expression of cyclic genes in the chick presomitic mesoderm. This feedback loop provides a molecular basis for the oscillator underlying the avian segmentation clock. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#84" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I. <strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong> Nature 427: 121-128, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>] [<a href="https://doi.org/10.1038/nature02190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14712268">Raya et al. (2004)</a> first investigated whether Notch activity is necessary for establishing proper left-right asymmetry during chick embryo development. Blocking the Notch signaling pathway by overexpressing a dominant-negative form of the Notch pathway effector RBPSUH resulted in laterality defects at both the morphologic and molecular levels similar to those described for mouse embryos. <a href="#84" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I. <strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong> Nature 427: 121-128, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>] [<a href="https://doi.org/10.1038/nature02190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14712268">Raya et al. (2004)</a> found that before the appearance of the left-sided perinodal expression domain of Nodal (<a href="/entry/601265">601265</a>), the Notch ligands Dll1 and Serrate1 showed complementary patterns of expression that form a sharp anterior/posterior interface across the Hensen node. During HH3 to HH7 stages of chick embryo development, Lfng is expressed in a complex, dynamic pattern of waves that sweep the AP axis of the embryo. <a href="#84" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I. <strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong> Nature 427: 121-128, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>] [<a href="https://doi.org/10.1038/nature02190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14712268">Raya et al. (2004)</a> noticed that the fifth wave of Lfng is clearly asymmetric when it reaches the node at HH6: the medial-most part of the left stripe is anteriorly displaced with respect to the right. <a href="#84" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I. <strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong> Nature 427: 121-128, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>] [<a href="https://doi.org/10.1038/nature02190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14712268">Raya et al. (2004)</a> developed a mathematical model which described the dynamics of the Notch signaling pathway during chick embryo gastrulation, which revealed a complex and highly robust genetic network that locally activates Notch on the left side of the Hensen node. <a href="#84" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I. <strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong> Nature 427: 121-128, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>] [<a href="https://doi.org/10.1038/nature02190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14712268">Raya et al. (2004)</a> identified the source of the asymmetric activation of Notch as a transient accumulation of extracellular calcium, which in turn depends on left-right differences in hydrogen/potassium-ATPase activity. <a href="#84" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I. <strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong> Nature 427: 121-128, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>] [<a href="https://doi.org/10.1038/nature02190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14712268">Raya et al. (2004)</a> concluded that their results uncovered a mechanism by which the Notch signaling pathway translates asymmetry in epigenetic factors into asymmetric gene expression around the node. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14712268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#67" class="mim-tip-reference" title="Morimoto, M., Takahashi, Y., Endo, M., Saga, Y. <strong>The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity.</strong> Nature 435: 354-359, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15902259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15902259</a>] [<a href="https://doi.org/10.1038/nature03591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15902259">Morimoto et al. (2005)</a> visualized endogenous levels of Notch1 activity in mice, showing that it oscillates in the posterior presomitic mesoderm but is arrested in the anterior presomitic mesoderm. Somite boundaries formed at the interface between Notch1-activated and -repressed domains. Genetic and biochemical studies indicated that this interface is generated by suppression of Notch activity by Mesp2 through induction of the Lfng gene. <a href="#67" class="mim-tip-reference" title="Morimoto, M., Takahashi, Y., Endo, M., Saga, Y. <strong>The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity.</strong> Nature 435: 354-359, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15902259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15902259</a>] [<a href="https://doi.org/10.1038/nature03591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15902259">Morimoto et al. (2005)</a> proposed that the oscillation of Notch activity is arrested and translated in the wavefront by Mesp2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15902259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#7" class="mim-tip-reference" title="Boskovski, M. T., Yuan, S., Pedersen, N. B., Goth, C. K., Makova, S., Clausen, H., Brueckner, M., Khokha, M. K. <strong>The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.</strong> Nature 504: 456-459, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24226769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24226769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24226769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24226769">Boskovski et al. (2013)</a> showed, in Xenopus tropicalis, that GALNT11 (<a href="/entry/615130">615130</a>) activates Notch signaling. GALNT11 O-glycosylated human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either by increasing ADAM17 (<a href="/entry/603639">603639</a>)-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats. <a href="#7" class="mim-tip-reference" title="Boskovski, M. T., Yuan, S., Pedersen, N. B., Goth, C. K., Makova, S., Clausen, H., Brueckner, M., Khokha, M. K. <strong>The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.</strong> Nature 504: 456-459, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24226769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24226769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24226769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24226769">Boskovski et al. (2013)</a> developed a quantitative live imaging technique for Xenopus left-right organizer cilia and showed that GALNT11-mediated NOTCH1 signaling modulates the spatial distribution and ratio of motile and immotile cilia at the left-right organizer. GALNT11 or NOTCH1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor PKD2 (<a href="/entry/173910">173910</a>). By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia-1 (CILD1; <a href="/entry/244400">244400</a>). <a href="#7" class="mim-tip-reference" title="Boskovski, M. T., Yuan, S., Pedersen, N. B., Goth, C. K., Makova, S., Clausen, H., Brueckner, M., Khokha, M. K. <strong>The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.</strong> Nature 504: 456-459, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24226769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24226769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24226769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24226769">Boskovski et al. (2013)</a> concluded that their data demonstrated that GALNT11 modifies Notch, establishing an essential balance between motile and immotile cilia at the left-right organizer to determine laterality, and revealed a novel mechanism for human heterotaxy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24226769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#19" class="mim-tip-reference" title="Del Monte-Nieto, G., Ramialison, M., Adam, A. A. S., Wu, B., Aharonov, A., D'Uva, G., Bourke, L. M., Pitulescu, M. E., Chen, H., de la Pompa, J. L., Shou, W., Adams, R. H., Harten, S. K., Tzahor, E., Zhou, B., Harvey, R. P. <strong>Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation.</strong> Nature 557: 439-445, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29743679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29743679</a>] [<a href="https://doi.org/10.1038/s41586-018-0110-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29743679">Del Monte-Nieto et al. (2018)</a> presented a model of trabeculation in mice that integrated dynamic endocardial and myocardial cell behaviors and extracellular matrix (ECM) remodeling, and revealed epistatic relationships between the involved signaling pathways. Notch1 signaling promotes extracellular matrix degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas Nrg1 (<a href="/entry/142445">142445</a>) promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through Nrg1 control of Vegfa (<a href="/entry/192240">192240</a>), but act antagonistically to establish trabecular architecture. <a href="#19" class="mim-tip-reference" title="Del Monte-Nieto, G., Ramialison, M., Adam, A. A. S., Wu, B., Aharonov, A., D'Uva, G., Bourke, L. M., Pitulescu, M. E., Chen, H., de la Pompa, J. L., Shou, W., Adams, R. H., Harten, S. K., Tzahor, E., Zhou, B., Harvey, R. P. <strong>Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation.</strong> Nature 557: 439-445, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29743679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29743679</a>] [<a href="https://doi.org/10.1038/s41586-018-0110-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29743679">Del Monte-Nieto et al. (2018)</a> concluded that their findings enabled the prediction of persistent extracellular matrix and cardiomyocyte growth in a mouse noncompaction cardiomyopathy model, providing insights into the pathophysiology of congenital heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29743679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Role of Notch in Cell Fate Determination</em></strong>
|
|
</p>
|
|
|
|
<p><a href="#106" class="mim-tip-reference" title="Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T. <strong>Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.</strong> Neuron 29: 45-55, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182080</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00179-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11182080">Tanigaki et al. (2001)</a> presented evidence that activated NOTCH1 and NOTCH3 promote the differentiation of astroglia from rat adult hippocampus-derived multipotent progenitors. Transient activation of Notch can direct commitment of adult hippocampal-derived progenitors irreversibly to astroglia. Astroglial induction by Notch signaling was shown to be independent of STAT3 (<a href="/entry/102582">102582</a>), which is a key regulatory transcriptional factor when ciliary neurotrophic factor (CNTF; <a href="/entry/118945">118945</a>) induces astroglia. <a href="#106" class="mim-tip-reference" title="Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T. <strong>Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.</strong> Neuron 29: 45-55, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182080</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00179-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11182080">Tanigaki et al. (2001)</a> suggested that Notch provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#94" class="mim-tip-reference" title="Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., Temple, S. <strong>Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells.</strong> Science 304: 1338-1340, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060285</a>] [<a href="https://doi.org/10.1126/science.1095505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060285">Shen et al. (2004)</a> demonstrated that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulated neuroepithelial cell contact, activating Notch and HES1 (<a href="/entry/139605">139605</a>) to promote self-renewal. These findings identified endothelial cells as a critical component of the neural stem cell niche. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#52" class="mim-tip-reference" title="Loomes, K. M., Taichman, D. B., Glover, C. L., Williams, P. T., Markowitz, J. E., Piccoli, D. A., Baldwin, H. S., Oakey, R. J. <strong>Characterization of Notch receptor expression in the developing mammalian heart and liver.</strong> Am. J. Med. Genet. 112: 181-189, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244553</a>] [<a href="https://doi.org/10.1002/ajmg.10592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244553">Loomes et al. (2002)</a> characterized Notch receptor expression in the developing mouse heart and liver, 2 organs significantly affected in Alagille syndrome (see <a href="/entry/118450">118450</a>). In the developing mouse heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, and in specific cell populations previously shown to express Jag1 (<a href="#53" class="mim-tip-reference" title="Loomes, K. M., Underkoffler, L. A., Morabito, J., Gottlieb, S., Piccoli, D. A., Spinner, N. B., Baldwin, H. S., Oakey, R. J. <strong>The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome.</strong> Hum. Molec. Genet. 8: 2443-2449, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556292</a>] [<a href="https://doi.org/10.1093/hmg/8.13.2443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556292">Loomes et al., 1999</a>). These cells are destined to undergo transformation from epithelial to mesenchymal cells. In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development. Jag1 is also expressed in cells adjacent to those expressing Notch2, suggesting a possible ligand-receptor interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10556292+12244553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Hematopoietic stem cells (HSCs) have the ability to renew themselves and to give rise to all lineages of the blood. <a href="#86" class="mim-tip-reference" title="Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L. <strong>A role for Wnt signalling in self-renewal of haematopoietic stem cells.</strong> Nature 423: 409-414, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717450</a>] [<a href="https://doi.org/10.1038/nature01593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717450">Reya et al. (2003)</a> showed that the WNT signaling pathway has an important role in this process. Overexpression of activated beta-catenin (<a href="/entry/116806">116806</a>) expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF1/TCF (<a href="/entry/153245">153245</a>) reporter, which indicates that HSCs respond to WNT signaling in vivo. To demonstrate the physiologic significance of this pathway for HSC proliferation, <a href="#86" class="mim-tip-reference" title="Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L. <strong>A role for Wnt signalling in self-renewal of haematopoietic stem cells.</strong> Nature 423: 409-414, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717450</a>] [<a href="https://doi.org/10.1038/nature01593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717450">Reya et al. (2003)</a> showed that the ectopic expression of axin (<a href="/entry/603816">603816</a>) or a frizzled (<a href="/entry/603408">603408</a>) ligand-binding domain, inhibitors of the WNT signaling pathway, led to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs induced increased expression of HOXB4 (<a href="/entry/142965">142965</a>) and NOTCH1, genes previously implicated in self-renewal of HSCs. <a href="#86" class="mim-tip-reference" title="Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L. <strong>A role for Wnt signalling in self-renewal of haematopoietic stem cells.</strong> Nature 423: 409-414, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717450</a>] [<a href="https://doi.org/10.1038/nature01593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717450">Reya et al. (2003)</a> concluded that the WNT signaling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#69" class="mim-tip-reference" title="Murtaugh, L. C., Stanger, B. Z., Kwan, K. M., Melton, D. A. <strong>Notch signaling controls multiple steps of pancreatic differentiation.</strong> Proc. Nat. Acad. Sci. 100: 14920-14925, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657333</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14657333[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.2436557100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14657333">Murtaugh et al. (2003)</a> found that misexpression of activated Notch in Pdx1 (IPF1; <a href="/entry/600733">600733</a>)-expressing mouse pancreatic progenitor cells prevented the differentiation of both exocrine and endocrine cell lineages. Progenitors remained trapped in an undifferentiated state even if Notch activation occurred after the pancreatic fate had been specified. Endocrine differentiation was associated with escape from Notch activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14657333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using immunoprecipitation and fluorescence microscopy, <a href="#35" class="mim-tip-reference" title="Hu, Q.-D., Ang, B.-T., Karsak, M., Hu, W.-P., Cui, X.-Y., Duka, T., Takeda, Y., Chia, W., Sankar, N., Ng, Y.-K., Ling, E.-A., Maciag, T., and 12 others. <strong>F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.</strong> Cell 115: 163-175, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14567914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14567914</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00810-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14567914">Hu et al. (2003)</a> identified mouse F3 (CNTN1; <a href="/entry/600016">600016</a>) as a physiologic ligand and activator of Notch. Upon activation by F3, Notch signals through Dtx1 (<a href="/entry/602582">602582</a>), which leads to oligodendrocyte maturation via upregulation of certain myelin-related proteins. Thus, <a href="#35" class="mim-tip-reference" title="Hu, Q.-D., Ang, B.-T., Karsak, M., Hu, W.-P., Cui, X.-Y., Duka, T., Takeda, Y., Chia, W., Sankar, N., Ng, Y.-K., Ling, E.-A., Maciag, T., and 12 others. <strong>F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.</strong> Cell 115: 163-175, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14567914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14567914</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00810-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14567914">Hu et al. (2003)</a> concluded that Notch does not solely function to inhibit oligodendrocyte precursor differentiation to mature cells, and they suggested that it may be useful in promoting remyelination in degenerative diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14567914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#74" class="mim-tip-reference" title="Okuyama, R., Nguyen, B.-C., Talora, C., Ogawa, E., Tommasi di Vignano, A., Lioumi, M., Chiorino, G., Tagami, H., Woo, M., Dotto, G. P. <strong>High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.</strong> Dev. Cell 6: 551-562, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15068794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15068794</a>] [<a href="https://doi.org/10.1016/s1534-5807(04)00098-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15068794">Okuyama et al. (2004)</a> found that pure keratinocytes cultured from embryonic day-15.5 mouse embryos committed irreversibly to differentiation much earlier than those cultured from newborn mice. Notch signaling, which promotes keratinocyte differentiation, was upregulated in embryonic keratinocytes and epidermis, and elevated caspase-3 (<a href="/entry/600636">600636</a>) expression, which the authors identified as a target for Notch1 transcriptional activation, accounted in part for the high commitment of embryonic keratinocytes to terminal differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15068794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#109" class="mim-tip-reference" title="van Es, J. H., van Gijn, M. E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D. J., Radtke, F., Clevers, H. <strong>Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. (Letter)</strong> Nature 435: 959-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15959515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15959515</a>] [<a href="https://doi.org/10.1038/nature03659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15959515">Van Es et al. (2005)</a> showed a rapid, massive conversion of proliferative crypt cells into postmitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (<a href="/entry/147183">147183</a>). The authors obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumor suppressor gene (<a href="/entry/611731">611731</a>). Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15959515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>By modulating Notch activity in the mouse intestine, <a href="#25" class="mim-tip-reference" title="Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., Artavanis-Tsakonas, S. <strong>Notch signals control the fate of immature progenitor cells in the intestine. (Letter)</strong> Nature 435: 964-968, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15959516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15959516</a>] [<a href="https://doi.org/10.1038/nature03589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15959516">Fre et al. (2005)</a> directly implicated Notch signals in intestinal cell lineage specification. <a href="#25" class="mim-tip-reference" title="Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., Artavanis-Tsakonas, S. <strong>Notch signals control the fate of immature progenitor cells in the intestine. (Letter)</strong> Nature 435: 964-968, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15959516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15959516</a>] [<a href="https://doi.org/10.1038/nature03589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15959516">Fre et al. (2005)</a> also showed that Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. The authors concluded that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15959516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#100" class="mim-tip-reference" title="Stanger, B. Z., Datar, R., Murtaugh, L. C., Melton, D. A. <strong>Direct regulation of intestinal fate by Notch.</strong> Proc. Nat. Acad. Sci. 102: 12443-12448, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16107537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16107537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16107537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505690102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16107537">Stanger et al. (2005)</a> found that ectopic expression of Notch in adult mouse intestinal progenitor cells biased differentiation against secretory fates, whereas ectopic Notch activation in the embryonic foregut resulted in reversible defects in villus morphogenesis and loss of proliferative progenitor compartment. <a href="#100" class="mim-tip-reference" title="Stanger, B. Z., Datar, R., Murtaugh, L. C., Melton, D. A. <strong>Direct regulation of intestinal fate by Notch.</strong> Proc. Nat. Acad. Sci. 102: 12443-12448, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16107537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16107537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16107537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505690102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16107537">Stanger et al. (2005)</a> concluded that Notch regulates adult intestinal development by controlling the balance between secretory and absorptive cell types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16107537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>RBPJ functions immediately downstream of Notch signaling. <a href="#30" class="mim-tip-reference" title="Han, H., Tanigaki, K., Yamamoto, N., Kuroda, K., Yoshimoto, M., Nakahata, T., Ikuta, K., Honjo, T. <strong>Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.</strong> Int. Immun. 14: 637-645, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12039915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12039915</a>] [<a href="https://doi.org/10.1093/intimm/dxf030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12039915">Han et al. (2002)</a> used a conditional gene knockout strategy to inactivate the DNA-binding domain of Rbpj in mouse bone marrow and found that Rbpj was required for T-cell development. In the absence of Rbpj, there was an increase in thymic B-cell development. <a href="#30" class="mim-tip-reference" title="Han, H., Tanigaki, K., Yamamoto, N., Kuroda, K., Yoshimoto, M., Nakahata, T., Ikuta, K., Honjo, T. <strong>Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.</strong> Int. Immun. 14: 637-645, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12039915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12039915</a>] [<a href="https://doi.org/10.1093/intimm/dxf030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12039915">Han et al. (2002)</a> proposed that RBPJ-mediated Notch signaling controls T- versus B-cell fate decisions in lymphoid progenitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12039915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Thymocytes can be divided into 4 subsets based on CD4 (<a href="/entry/186940">186940</a>) and CD8 (see <a href="/entry/186910">186910</a>) expression, with double-negative (DN) cells being the least mature. The DN population can be further subdivided into 4 subsets, DN1 through DN4. <a href="#107" class="mim-tip-reference" title="Tanigaki, K., Tsuji, M., Yamamoto, N., Han, H., Tsukada, J., Inoue, H., Kubo, M., Honjo, T. <strong>Regulation of alpha-beta/gamma-delta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling.</strong> Immunity 20: 611-622, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15142529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15142529</a>] [<a href="https://doi.org/10.1016/s1074-7613(04)00109-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15142529">Tanigaki et al. (2004)</a> used a conditional knockout strategy to inactivate Rbpj at the DN2 and DN4 stages in mice. Inactivation at DN2 resulted in severe developmental arrest of alpha-beta T cells at the DN3 stage and enhanced generation of gamma-delta T cells. Inactivation at DN4 caused no abnormalities in CD4/CD8 lineage commitment, but it resulted in enhanced Th1 responses and reduced T-cell proliferation. <a href="#107" class="mim-tip-reference" title="Tanigaki, K., Tsuji, M., Yamamoto, N., Han, H., Tsukada, J., Inoue, H., Kubo, M., Honjo, T. <strong>Regulation of alpha-beta/gamma-delta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling.</strong> Immunity 20: 611-622, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15142529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15142529</a>] [<a href="https://doi.org/10.1016/s1074-7613(04)00109-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15142529">Tanigaki et al. (2004)</a> concluded that Notch/RBPJ signaling regulates not only the T-cell developmental process, but also the direction and magnitude of immune responses via regulation of peripheral T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15142529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using Lrf (ZBTB7; <a href="/entry/605878">605878</a>) -/- mice and Lrf conditional knockout mice, <a href="#56" class="mim-tip-reference" title="Maeda, T., Merghoub, T., Hobbs, R. M., Dong, L., Maeda, M., Zakrzewski, J., van den Brink, M. R. M., Zelent, A., Shigematsu, H., Akashi, K., Teruya-Feldstein, J., Cattoretti, G., Pandolfi, P. P. <strong>Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF.</strong> Science 316: 860-866, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17495164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17495164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17495164[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1140881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17495164">Maeda et al. (2007)</a> showed that LRF acts as a master regulator in determination of B versus T lymphoid fate by negatively regulating T-lineage commitment by opposing NOTCH function. Thus, loss of LRF results in aberrant activation of the NOTCH pathway, with upregulation of NOTCH target genes in hematopoietic stem cells and common lymphoid progenitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17495164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#28" class="mim-tip-reference" title="Gustafsson, M. V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J. L., Poellinger, L., Lendahl, U., Bondesson, M. <strong>Hypoxia requires Notch signaling to maintain the undifferentiated cell state.</strong> Dev. Cell 9: 617-628, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16256737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16256737</a>] [<a href="https://doi.org/10.1016/j.devcel.2005.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16256737">Gustafsson et al. (2005)</a> found that hypoxia blocked differentiation of mammalian neuronal and myogenic progenitor cells in culture through a Notch signaling pathway. Hypoxia led to recruitment of Hif1a (<a href="/entry/603348">603348</a>) to Notch-responsive promoters and elevated expression of Notch downstream genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16256737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#32" class="mim-tip-reference" title="Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C. <strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong> Nature 445: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259973</a>] [<a href="https://doi.org/10.1038/nature05571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259973">Hellstrom et al. (2007)</a> presented evidence that Dll4 (<a href="/entry/605185">605185</a>)-Notch1 signaling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in mouse retina. They showed that inhibition of Notch signaling using gamma-secretase inhibitors, genetic inactivation of 1 allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1 all promoted increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 (<a href="/entry/601920">601920</a>) peptide led to fewer tip cells and vessel branches. Dll4 and reporters of Notch signaling were distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assumed tip cell characteristics. <a href="#32" class="mim-tip-reference" title="Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C. <strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong> Nature 445: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259973</a>] [<a href="https://doi.org/10.1038/nature05571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259973">Hellstrom et al. (2007)</a> concluded that DLL4 (<a href="/entry/605185">605185</a>)-Notch1 signaling between the endothelial cells within the angiogenic sprout restricts tip cell formation in response to VEGF (<a href="/entry/192240">192240</a>), thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. The authors further concluded that their model offered an explanation for the dose-dependency and haploinsufficiency of the DLL4 gene, and indicated that modulators of DLL4 or Notch signaling, such as gamma-secretase inhibitors developed for Alzheimer disease (<a href="/entry/104300">104300</a>), might find usage as pharmacologic regulators of angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#95" class="mim-tip-reference" title="Siekmann, A. F., Lawson, N. D. <strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong> Nature 445: 781-784, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>] [<a href="https://doi.org/10.1038/nature05577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259972">Siekmann and Lawson (2007)</a> demonstrated that Notch signaling is necessary to restrict angiogenic cell behavior to tip cells in developing segmental arteries in the zebrafish embryo. In the absence of the Notch signaling component Rbpsuh (<a href="/entry/147183">147183</a>), The authors observed excessive sprouting of segmental arteries, whereas Notch activation suppressed angiogenesis. Through mosaic analysis <a href="#95" class="mim-tip-reference" title="Siekmann, A. F., Lawson, N. D. <strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong> Nature 445: 781-784, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>] [<a href="https://doi.org/10.1038/nature05577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259972">Siekmann and Lawson (2007)</a> found that cells lacking Rbpsuh preferentially localized to the terminal position in developing sprouts. In contrast, cells in which Notch signaling had been activated were excluded from the tip cell position. In vivo time-lapse analysis revealed that endothelial tip cells undergo a stereotypical pattern of proliferation and migration during sprouting. In the absence of Notch, nearly all sprouting endothelial cells exhibited tip cell behavior, leading to excessive numbers of cells within segmental arteries. Furthermore, <a href="#95" class="mim-tip-reference" title="Siekmann, A. F., Lawson, N. D. <strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong> Nature 445: 781-784, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>] [<a href="https://doi.org/10.1038/nature05577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259972">Siekmann and Lawson (2007)</a> found that Flt4 (<a href="/entry/136352">136352</a>) was expressed in segmental artery tip cells and became ectopically expressed throughout the sprout in the absence of Notch. Loss of Flt4 partially restored normal endothelial cell number in Rbpsuh-deficient segmental arteries. Finally, loss of the Notch ligand Dll4 also led to an increased number of endothelial cells within segmental arteries. <a href="#95" class="mim-tip-reference" title="Siekmann, A. F., Lawson, N. D. <strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong> Nature 445: 781-784, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>] [<a href="https://doi.org/10.1038/nature05577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259972">Siekmann and Lawson (2007)</a> concluded that their studies taken together indicated that proper specification of cell identity, position, and behavior in a developing blood vessel sprout is required for normal angiogenesis, and implicated the Notch signaling pathway in this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#34" class="mim-tip-reference" title="Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S. <strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong> J. Exp. Med. 205: 2507-2513, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824583[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20080134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824583">Hozumi et al. (2008)</a> found that mice lacking Dll4 expression in thymic epithelial cells (TECs) exhibited a marked reduction of Notch1 in hematopoietic cells and a lack of Cd4 and Cd8 double- or single-positive T cells in thymus. The double-negative cell fraction also showed an absence of T-cell progenitors and an aberrant accumulation of B-lineage cells. Enforced expression of the intracellular fragment of Notch1 restored thymic T-cell differentiation. <a href="#34" class="mim-tip-reference" title="Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S. <strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong> J. Exp. Med. 205: 2507-2513, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824583[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20080134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824583">Hozumi et al. (2008)</a> concluded that the thymus-specific environment for T-cell fate determination requires DLL4 expression to induce NOTCH signaling in cells immigrating into thymus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>Using immunohistochemical analysis, <a href="#42" class="mim-tip-reference" title="Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F. <strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong> J. Exp. Med. 205: 2515-2523, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824585[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20080829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824585">Koch et al. (2008)</a> demonstrated expression of Dll4, but not Dll1 (<a href="/entry/606582">606582</a>), on TECs in mice. Inactivation of Dll4 in TECs or hematopoietic progenitors in mice resulted in loss of T-cell development with no loss of thymus development, as well as ectopic appearance of immature B cells in thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional Notch1-deficient mice. <a href="#42" class="mim-tip-reference" title="Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F. <strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong> J. Exp. Med. 205: 2515-2523, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824585[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20080829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824585">Koch et al. (2008)</a> concluded that DLL4 is the essential and nonredundant Notch1 ligand responsible for T-cell fate specification. They proposed that NOTCH1-expressing thymic progenitors interact with DLL4-expressing TECs to suppress B-lineage potential and to induce the first steps of intrathymic T-cell development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>To investigate how Delta (see <a href="/entry/606582">606582</a>) both transactivates Notch neighboring cells and cis-inhibits Notch in its own cell, <a href="#99" class="mim-tip-reference" title="Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B. <strong>Cis-interactions between Notch and Delta generate mutually exclusive signalling states.</strong> Nature 465: 86-91, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418862[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418862">Sprinzak et al. (2010)</a> developed a quantitative time-lapse microscopy platform for analyzing Notch-Delta signaling dynamics in individual mammalian cells. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, <a href="#99" class="mim-tip-reference" title="Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B. <strong>Cis-interactions between Notch and Delta generate mutually exclusive signalling states.</strong> Nature 465: 86-91, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418862[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418862">Sprinzak et al. (2010)</a> measured the combined cis-trans input-output relationship in the Notch-Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. <a href="#99" class="mim-tip-reference" title="Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B. <strong>Cis-interactions between Notch and Delta generate mutually exclusive signalling states.</strong> Nature 465: 86-91, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418862[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418862">Sprinzak et al. (2010)</a> developed a simple mathematical model that shows how these behaviors emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signaling states. At the multicellular level, this switch can amplify small differences between neighboring cells even without transcription-mediated feedback. <a href="#99" class="mim-tip-reference" title="Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B. <strong>Cis-interactions between Notch and Delta generate mutually exclusive signalling states.</strong> Nature 465: 86-91, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418862[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418862">Sprinzak et al. (2010)</a> concluded that this Notch-Delta signaling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20418862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#2" class="mim-tip-reference" title="Aguirre, A., Rubio, M. E., Gallo, V. <strong>Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal.</strong> Nature 467: 323-327, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20844536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20844536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20844536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20844536">Aguirre et al. (2010)</a> demonstrated that functional cell-cell interaction between neural progenitor cells (NPCs) and neural stem cells (NSCs) through EGFR (<a href="/entry/131550">131550</a>) and Notch signaling has a crucial role in maintaining the balance between these cell populations in the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. Enhanced EGFR signaling in vivo results in the expansion of the NPC pool and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signaling. <a href="#2" class="mim-tip-reference" title="Aguirre, A., Rubio, M. E., Gallo, V. <strong>Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal.</strong> Nature 467: 323-327, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20844536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20844536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20844536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20844536">Aguirre et al. (2010)</a> concluded that their findings defined a novel interaction between EGFR and Notch pathways in the adult subventricular zone, and thus provided a mechanism for NSC and NPC pool maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20844536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#6" class="mim-tip-reference" title="Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. <strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong> Nature 484: 110-114, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>] [<a href="https://doi.org/10.1038/nature10908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22426001">Benedito et al. (2012)</a> used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 (<a href="/entry/191306">191306</a>) signaling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3 (<a href="/entry/136352">136352</a>), the main receptor for VEGFC (<a href="/entry/601528">601528</a>), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. <a href="#6" class="mim-tip-reference" title="Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. <strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong> Nature 484: 110-114, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>] [<a href="https://doi.org/10.1038/nature10908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22426001">Benedito et al. (2012)</a> concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22426001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Role of Notch in Neural Development</em></strong>
|
|
</p>
|
|
|
|
<p>The exuberant growth of neurites during development becomes markedly reduced as cortical neurons mature. Using in vitro studies of neurons from mouse cerebral cortex, <a href="#93" class="mim-tip-reference" title="Sestan, N., Artavanis-Tsakonas, S., Rakic, P. <strong>Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling.</strong> Science 286: 741-746, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531053</a>] [<a href="https://doi.org/10.1126/science.286.5440.741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531053">Sestan et al. (1999)</a> demonstrated that contact-mediated Notch signaling regulates the capacity of neurons to extend and elaborate neurites. Upregulation of Notch activity was concomitant with an increase in the number of interneuronal contacts and cessation of neurite growth. In neurons with low Notch activity, which readily extend neurites, upregulation of Notch activity either inhibited extension or caused retraction of neurites. Conversely, in more mature neurons that had ceased their growth after establishing numerous connections and displayed high Notch activity, inhibition of Notch signaling promoted neurite extension. Thus, <a href="#93" class="mim-tip-reference" title="Sestan, N., Artavanis-Tsakonas, S., Rakic, P. <strong>Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling.</strong> Science 286: 741-746, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531053</a>] [<a href="https://doi.org/10.1126/science.286.5440.741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531053">Sestan et al. (1999)</a> concluded that the formation of neuronal contacts results in activation of Notch receptors, leading to restriction of neuronal growth and a subsequent arrest in maturity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10531053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Role of Notch in Muscle Regeneration</em></strong>
|
|
</p>
|
|
|
|
<p><a href="#12" class="mim-tip-reference" title="Conboy, I. M., Conboy, M. J., Smythe, G. M., Rando, T. A. <strong>Notch-mediated restoration of regenerative potential to aged muscle.</strong> Science 302: 1575-1577, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645852</a>] [<a href="https://doi.org/10.1126/science.1087573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14645852">Conboy et al. (2003)</a> analyzed injured muscle and observed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient upregulation of the Notch ligand Delta and thus diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, <a href="#12" class="mim-tip-reference" title="Conboy, I. M., Conboy, M. J., Smythe, G. M., Rando, T. A. <strong>Notch-mediated restoration of regenerative potential to aged muscle.</strong> Science 302: 1575-1577, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645852</a>] [<a href="https://doi.org/10.1126/science.1087573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14645852">Conboy et al. (2003)</a> concluded that Notch signaling is a key determinant of muscle regenerative potential that declines with age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p>In experiments using mouse muscle, <a href="#10" class="mim-tip-reference" title="Carlson, M. E., Hsu, M., Conboy, I. M. <strong>Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.</strong> Nature 454: 528-532, 2008. Note: Erratum: Nature 538: 274 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18552838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18552838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18552838[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18552838">Carlson et al. (2008)</a> found that, in addition to the loss of Notch activation, old muscle produces excessive TGF-beta (<a href="/entry/190180">190180</a>) (but not myostatin, <a href="/entry/601788">601788</a>), which induces unusually high levels of Smad3 (<a href="/entry/603109">603109</a>) in resident satellite cells and interfered with the regenerative capacity. Importantly, endogenous Notch and Smad3 antagonize each other in the control of satellite cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15 (<a href="/entry/600431">600431</a>), p16 (<a href="/entry/600160">600160</a>), p21 (<a href="/entry/116899">116899</a>), and p27 (<a href="/entry/600778">600778</a>), whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determined the binding of Smad3 to the promoters of these negative regulators of cell cycle progression. Attenuation of TGF-beta/Smad3 in old, injured muscle restored regeneration to satellite cells in vivo. Thus, a balance between endogenous Smad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18552838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><strong><em>Role of Notch in Bone Homeostasis</em></strong>
|
|
</p>
|
|
|
|
<p>Independently, <a href="#24" class="mim-tip-reference" title="Engin, F., Yao, Z., Yang, T., Zhou, G., Bertin, T., Jiang, M. M., Chen, Y., Wang, L., Zheng, H., Sutton, R. E., Boyce, B. F., Lee, B. <strong>Dimorphic effects of Notch signaling in bone homeostasis.</strong> Nature Med. 14: 299-305, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18297084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18297084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18297084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18297084">Engin et al. (2008)</a> and <a href="#33" class="mim-tip-reference" title="Hilton, M. J., Tu, X., Wu, X., Bai, S., Zhao, H., Kobayashi, T., Kronenberg, H. M., Teitelbaum, S. L., Ross, F. P., Kopan, R., Long, F. <strong>Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation.</strong> Nature Med. 14: 306-314, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18297083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18297083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18297083[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18297083">Hilton et al. (2008)</a> investigated the role of Notch signaling in bone homeostasis using rodent models. <a href="#24" class="mim-tip-reference" title="Engin, F., Yao, Z., Yang, T., Zhou, G., Bertin, T., Jiang, M. M., Chen, Y., Wang, L., Zheng, H., Sutton, R. E., Boyce, B. F., Lee, B. <strong>Dimorphic effects of Notch signaling in bone homeostasis.</strong> Nature Med. 14: 299-305, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18297084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18297084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18297084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18297084">Engin et al. (2008)</a> found that Notch and presenilin signaling regulated both osteoclastogenesis and osteoblastic proliferation. Gain of Notch function resulted in severe osteosclerosis, whereas loss of Notch function led to age-related osteoporosis. <a href="#33" class="mim-tip-reference" title="Hilton, M. J., Tu, X., Wu, X., Bai, S., Zhao, H., Kobayashi, T., Kronenberg, H. M., Teitelbaum, S. L., Ross, F. P., Kopan, R., Long, F. <strong>Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation.</strong> Nature Med. 14: 306-314, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18297083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18297083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18297083[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18297083">Hilton et al. (2008)</a> found that Notch signaling in bone marrow maintained a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Disruption of Notch signaling in limb skeletogenic mesenchyme increased trabecular bone mass in adolescent mice and led to severe osteopenia as they aged. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18297084+18297083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
|
|
<p><a href="#23" class="mim-tip-reference" title="Engin, F., Bertin, T., Ma, O., Jiang, M. M., Wang, L., Sutton, R. E., Donehower, L. A., Lee, B. <strong>Notch signaling contributes to the pathogenesis of human osteosarcomas.</strong> Hum. Molec. Genet. 18: 1464-1470, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19228774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19228774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19228774[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19228774">Engin et al. (2009)</a> reported that human osteosarcoma (<a href="/entry/259500">259500</a>) cell lines and primary human osteosarcoma tumor samples showed significant upregulation of Notch, its target genes, and Osterix (SP7; <a href="/entry/606633">606633</a>). Notch inhibition by gamma-secretase inhibitors or by lentiviral-mediated expression of dominant-negative MAML1 protein (<a href="/entry/605424">605424</a>) decreased osteosarcoma cell proliferation in vitro. Established human tumor xenografts in nude mice showed decreased tumor growth after chemical or genetic inhibition of Notch signaling. Transcriptional profiling of osteosarcomas from p53 (<a href="/entry/191170">191170</a>) mutant mice confirmed upregulation of Notch target genes Hes1 (<a href="/entry/139605">139605</a>), Hey1 (<a href="/entry/602953">602953</a>), and its ligand Dll4 (<a href="/entry/605185">605185</a>). <a href="#23" class="mim-tip-reference" title="Engin, F., Bertin, T., Ma, O., Jiang, M. M., Wang, L., Sutton, R. E., Donehower, L. A., Lee, B. <strong>Notch signaling contributes to the pathogenesis of human osteosarcomas.</strong> Hum. Molec. Genet. 18: 1464-1470, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19228774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19228774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19228774[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19228774">Engin et al. (2009)</a> suggested that activation of Notch signaling may contribute to the pathogenesis of human osteosarcomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19228774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimCytogeneticsFold" id="mimCytogeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCytogeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCytogeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>Chromosome 7q34-q35, which contains the locus for the beta T-cell receptor (see <a href="/entry/186930">186930</a>), is a common site for translocation in T-cell neoplasms. In t(7;9)(q34;q34.3) translocations from 3 cases of acute T-cell lymphoblastic leukemia, <a href="#21" class="mim-tip-reference" title="Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., Sklar, J. <strong>TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.</strong> Cell 66: 649-661, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1831692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1831692</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90111-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1831692">Ellisen et al. (1991)</a> found breakpoints within 100 bp of an intron in TAN1, resulting in truncation of TAN1 transcripts. They concluded that TAN1 is important for normal lymphocyte function and that alterations in TAN1 play a role in the pathogenesis of some T-cell neoplasms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1831692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="molecularGenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMolecularGeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Aortic Valve Disease</em></strong></p><p>
|
|
<a href="#26" class="mim-tip-reference" title="Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., Srivastava, D. <strong>Mutations in NOTCH1 cause aortic valve disease.</strong> Nature 437: 270-274, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025100</a>] [<a href="https://doi.org/10.1038/nature03940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16025100">Garg et al. (2005)</a> showed that mutations in the signaling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification (AOVD1; <a href="/entry/109730">109730</a>) in nonsyndromic autosomal dominant human pedigrees (see <a href="#0001">190198.0001</a>-<a href="#0002">190198.0002</a>). Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2 (<a href="/entry/600211">600211</a>), a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors, which are activated by Notch1 signaling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independently of histone deacetylase activity. <a href="#26" class="mim-tip-reference" title="Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., Srivastava, D. <strong>Mutations in NOTCH1 cause aortic valve disease.</strong> Nature 437: 270-274, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025100</a>] [<a href="https://doi.org/10.1038/nature03940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16025100">Garg et al. (2005)</a> concluded that their results suggested that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later derepression of calcium deposition that causes progressive aortic valve disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16025100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 48 sporadic German patients with bicuspid aortic valve (BAV), <a href="#63" class="mim-tip-reference" title="Mohamed, S. A., Aherrahrou, Z., Liptau, H., Erasmi, A. W., Hagemann, C., Wrobel, S., Borzym, K., Schunkert, H., Sievers, H. H., Erdmann, J. <strong>Novel missense mutations (p.T596M and p.P1797H) in MOTCH1 in patients with bicuspid aortic valve.</strong> Biochem. Biophys. Res. Commun. 345: 1460-1465, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16729972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16729972</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.05.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16729972">Mohamed et al. (2006)</a> sequenced the NOTCH1 gene and identified 2 men with BAV and thoracic aortic aneurysm (AAT) who were heterozygous for missense mutations (T596M, <a href="#0011">190198.0011</a> and P1797H, <a href="#0012">190198.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16729972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="McBride, K. L., Riley, M. F., Zender, G. A., Fitzgerald-Butt, S. M., Towbin, J. A., Belmont, J. W., Cole, S. E. <strong>NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.</strong> Hum. Molec. Genet. 17: 2886-2893, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18593716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18593716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18593716[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18593716">McBride et al. (2008)</a> analyzed the NOTCH1 gene in 91 unrelated European American patients with congenital aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta (COA; see <a href="/entry/120000">120000</a>), and/or hypoplastic left heart syndrome (see <a href="/entry/241550">241550</a>), and identified 2 heterozygous missense variants in 6 probands, respectively, that were either completely absent or significantly underrepresented in over 200 ethnically matched controls and were also shown to reduce ligand-induced NOTCH1 signaling. Four of the mutation-positive probands had aortic valve stenosis and/or bicuspid aortic valve, which in 1 patient was associated with COA, and 2 probands had HLHS. In each case, the NOTCH1 variant was also present in an unaffected parent; <a href="#59" class="mim-tip-reference" title="McBride, K. L., Riley, M. F., Zender, G. A., Fitzgerald-Butt, S. M., Towbin, J. A., Belmont, J. W., Cole, S. E. <strong>NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.</strong> Hum. Molec. Genet. 17: 2886-2893, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18593716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18593716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18593716[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18593716">McBride et al. (2008)</a> suggested that these variants represent susceptibility alleles that are not sufficient in and of themselves to perturb cardiac development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18593716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Cardiac Malformations</em></strong></p><p>
|
|
<a href="#40" class="mim-tip-reference" title="Kerstjens-Frederikse, W. S., van de Laar, I. M. B. H., Vos, Y. J., Verhagen, J. M. A., Berger, R. M. F., Lichtenbelt, K. D., Klein Wassink-Ruiter, J. S., van der Zwaag, P. A., du Marchie-Sarvaas, G. J., Bergman, K. A., Bilardo, C. M., Roos-Hesselink, J. W., Janssen, J. H. P., Frohn-Mulder, I. M., van Spaendonck-Zwarts, K. Y., van Melle, J. P., Hofstra, R. M. W., Wessels, M. W. <strong>Cardiovascular malformations caused by NOTCH mutations do not keep left: data on 428 probands with left-sided CHD and their families.</strong> Genet. Med. 18: 914-923, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26820064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26820064</a>] [<a href="https://doi.org/10.1038/gim.2015.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26820064">Kerstjens-Frederikse et al. (2016)</a> sequenced NOTCH1 in 428 probands with nonsyndromic left-sided congenital heart disease. Family history was obtained for all. When a mutation was detected, relatives were also tested. In 148 of the probands (35%), left-sided congenital heart disease was familial. Fourteen mutations (3%) (5 splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 of 148 familial cases (7%) and 3 of 280 sporadic disease cases (1%). Familial screening showed 49 additional mutation carriers among the 14 families, of whom 12 (25%) were asymptomatic. Most of the mutation carriers had left-sided heart disease, but 9 (18%) had right-sided or conotruncal heart disease. Thoracic aortic aneurysms occurred in 6 mutations carriers. Penetrance was high; cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26820064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Adams-Oliver Syndrome 5</em></strong></p><p>
|
|
In affected individuals from 5 unrelated families with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> identified heterozygosity for 5 different mutations in the NOTCH1 gene, including an 85-kb deletion spanning the NOTCH1 5-prime region (<a href="#0003">190198.0003</a>), a splice site mutation (<a href="#0004">190198.0004</a>), and 3 missense mutations (C429R, <a href="#0005">190198.0005</a>; C1496Y, <a href="#0006">190198.0006</a>; D1989N, <a href="#0007">190198.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 11 (17%) of 64 probands with AOS, <a href="#98" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. <strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong> Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25963545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25963545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25963545">Southgate et al. (2015)</a> identified mutations in the NOTCH1 gene (see, e.g., <a href="#0008">190198.0008</a> and <a href="#0010">190198.0010</a>) and concluded that NOTCH1 is the primary cause of Adams-Oliver syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25963545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>T-cell Acute Lymphoblastic Leukemia</em></strong></p><p>
|
|
Very rare cases of human T-cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T-cell development. <a href="#117" class="mim-tip-reference" title="Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. P., IV, Silverman, L. B., Sanchez-Irizarry, C., Blacklow, S. C., Look, A. T., Aster, J. C. <strong>Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.</strong> Science 306: 269-271, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472075</a>] [<a href="https://doi.org/10.1126/science.1102160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15472075">Weng et al. (2004)</a> reported that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. <a href="#117" class="mim-tip-reference" title="Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. P., IV, Silverman, L. B., Sanchez-Irizarry, C., Blacklow, S. C., Look, A. T., Aster, J. C. <strong>Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.</strong> Science 306: 269-271, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472075</a>] [<a href="https://doi.org/10.1126/science.1102160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15472075">Weng et al. (2004)</a> concluded that their findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Isolated Juvenile or Chronic Myelomonocytic Leukemia</em></strong></p><p>
|
|
<a href="#41" class="mim-tip-reference" title="Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I. <strong>A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.</strong> Nature 473: 230-233, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21562564[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21562564">Klinakis et al. (2011)</a> identified novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukemia (CMML). Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1 (<a href="/entry/139605">139605</a>). <a href="#41" class="mim-tip-reference" title="Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I. <strong>A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.</strong> Nature 473: 230-233, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21562564[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21562564">Klinakis et al. (2011)</a> concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21562564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chronic Lymphocytic Leukemia</em></strong></p><p>
|
|
<a href="#80" class="mim-tip-reference" title="Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordonez, G. R., Villamor, N., Escaramis, G., Jares, P., Bea, S., Gonzalez-Diaz, M., Bassaganyas, L., Baumann, T., and 52 others. <strong>Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.</strong> Nature 475: 101-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21642962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21642962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21642962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21642962">Puente et al. (2011)</a> identified somatic mutations in the NOTCH1 gene in 31 (12.2%) of 255 cases of chronic lymphocytic leukemia (CLL; <a href="/entry/151400">151400</a>). These mutations generated a premature stop codon, resulting in a NOTCH1 protein lacking the C-terminal domain. The mutations caused an accumulation of an active protein isoform in the mutated CLL cells, since this isoform is more stable and active. NOTCH1-mutated patients had a more advanced clinical stage at diagnosis, more adverse biological features, and an overall shorter survival than those without NOTCH1 mutations. NOTCH1-mutated CLL also underwent transformation into diffuse large B-cell lymphoma more frequently than NOTCH1-unmutated CLL (23% vs 1.3%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21642962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Quesada, V., Conde, L., Villamor, N., Ordonez, G. R., Jares, P., Bassaganyas, L., Ramsay, A. J., Bea, S., Pinyol, M., Martinez-Trillos, A., Lopez-Guerra, M., Colomer, D., and 29 others. <strong>Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.</strong> Nature Genet. 44: 47-52, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158541</a>] [<a href="https://doi.org/10.1038/ng.1032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158541">Quesada et al. (2012)</a> identified somatic mutations in the NOTCH1 gene in 25 (9.5%) of 260 cases of CLL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22158541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Head and Neck Squamous Cell Carcinoma</em></strong></p><p>
|
|
To explore the genetic origins of head and neck squamous cell carcinoma (HNSCC; <a href="/entry/275355">275355</a>), <a href="#1" class="mim-tip-reference" title="Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., Fakhry, C., Xie, T.-X., Zhang, J., Wang, J., Zhang, N., El-Naggar, A. K., and 19 others. <strong>Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.</strong> Science 333: 1154-1157, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21798897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21798897</a>] [<a href="https://doi.org/10.1126/science.1206923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21798897">Agrawal et al. (2011)</a> used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53 (<a href="/entry/191170">191170</a>), CDKN2A (<a href="/entry/600160">600160</a>), PIK3CA (<a href="/entry/171834">171834</a>), and HRAS (<a href="/entry/171834">171834</a>), <a href="#1" class="mim-tip-reference" title="Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., Fakhry, C., Xie, T.-X., Zhang, J., Wang, J., Zhang, N., El-Naggar, A. K., and 19 others. <strong>Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.</strong> Science 333: 1154-1157, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21798897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21798897</a>] [<a href="https://doi.org/10.1126/science.1206923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21798897">Agrawal et al. (2011)</a> identified mutations in FBXW7 (<a href="/entry/606278">606278</a>) and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type. Seven of 21 patients with NOTCH1 mutations had 2 independent mutations presumably on different alleles. After TP53, NOTCH1 was the most frequently mutated gene found in the combined discovery and prevalence sets, with alterations present in 15% of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21798897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#102" class="mim-tip-reference" title="Stransky, N., Egloff, A. M., Tward, A. D., Kostic, A. D., Cibulskis, K., Sivachenko, A., Kryukov, G. V., Lawrence, M. S., Sougnez, C., McKenna, A., Shefler, E., Ramos, A. H., and 27 others. <strong>The mutational landscape of head and neck squamous cell carcinoma.</strong> Science 333: 1157-1160, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21798893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21798893</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21798893[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1208130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21798893">Stransky et al. (2011)</a> independently analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying known HNSCC genes, their analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (i.e., NOTCH1; IRF6, <a href="/entry/607199">607199</a>; and TP63, <a href="/entry/603273">603273</a>), implicating its dysregulation as a major driver of HNSCC carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21798893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Mutation in Normal Esophageal Epithelium</em></strong></p><p>
|
|
By intensively sequencing 682 microscale esophageal samples, <a href="#122" class="mim-tip-reference" title="Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., Fujii, Y., Yoshida, K., and 28 others. <strong>Age-related remodelling of esophageal epithelia by mutated cancer drivers.</strong> Nature 565: 312-317, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30602793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30602793</a>] [<a href="https://doi.org/10.1038/s41586-018-0811-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30602793">Yokoyama et al. (2019)</a> showed, in physiologically normal esophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with aging, and ultimately replace almost the entire esophageal epithelium in the extremely elderly. Compared with mutations in esophageal cancer (<a href="/entry/133239">133239</a>), there is a marked overrepresentation of NOTCH1 and PPM1D (<a href="/entry/605100">605100</a>) mutations in physiologically normal esophageal epithelia; these mutations can be acquired before late adolescence and as early as early infancy, and significantly increase in number with heavy smoking and drinking. The remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal aging, which, depending on lifestyle risks, may affect cancer development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30602793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="animalModel" class="mim-anchor"></a>
|
|
<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAnimalModelToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimAnimalModelFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#36" class="mim-tip-reference" title="Huppert, S. S., Le, A., Schroeter, E. H., Mumm, J. S., Saxena, M. T., Milner, L. A., Kopan, R. <strong>Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.</strong> Nature 405: 966-970, 2000. Note: Erratum: Nature 408, 616 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10879540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10879540</a>] [<a href="https://doi.org/10.1038/35016111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10879540">Huppert et al. (2000)</a> mutated valine at position 1744 of the mouse Notch1 gene to glycine. This position is the site for proteolytic cleavage and is critical for Notch1 intracellular processing in tissue-culture cells. <a href="#36" class="mim-tip-reference" title="Huppert, S. S., Le, A., Schroeter, E. H., Mumm, J. S., Saxena, M. T., Milner, L. A., Kopan, R. <strong>Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.</strong> Nature 405: 966-970, 2000. Note: Erratum: Nature 408, 616 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10879540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10879540</a>] [<a href="https://doi.org/10.1038/35016111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10879540">Huppert et al. (2000)</a> generated homozygous animals carrying 2 germline mutations and compared these with mice who have 2 null alleles for Notch1 (<a href="#13" class="mim-tip-reference" title="Conlon, R. A., Reaume, A. G., Rossant, J. <strong>Notch1 is required for the coordinate segmentation of somites.</strong> Development 121: 1533-1545, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789282</a>] [<a href="https://doi.org/10.1242/dev.121.5.1533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7789282">Conlon et al., 1995</a>). At embryonic day 8.5 to 10.5, homozygous embryos were detected at the expected mendelian frequency. Similar to the null alleles, embryo absorption was detected between embryonic day 10 and 12, and no homozygous embryos were recovered past embryonic day 12. These results suggested that efficient Notch processing is necessary for the early embryonic developmental aspects of Notch activity. RT-PCR and immunoprecipitation showed comparable amounts of Notch mRNA and protein, respectively, in the processing-deficient embryos and their heterozygous and wildtype littermates. The phenotypes associated with the single point mutation resembled the null Notch1 phenotype, but with slightly reduced penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7789282+10879540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Krebs, L. T., Xue, Y., Norton, C. R., Shutter, J. R., Maguire, M., Sundberg, J. P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., Smith, G. H., Stark, K. L., Gridley, T. <strong>Notch signaling is essential for vascular morphogenesis in mice.</strong> Genes Dev. 14: 1343-1352, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837027[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837027">Krebs et al. (2000)</a> generated Notch4 (<a href="/entry/164951">164951</a>)-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene (<a href="#104" class="mim-tip-reference" title="Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G., Gridley, T. <strong>Notch1 is essential for postimplantation development in mice.</strong> Genes Dev. 8: 707-719, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7926761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7926761</a>] [<a href="https://doi.org/10.1101/gad.8.6.707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7926761">Swiatek et al., 1994</a>). Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 (DLL4; <a href="/entry/605185">605185</a>) gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. <a href="#44" class="mim-tip-reference" title="Krebs, L. T., Xue, Y., Norton, C. R., Shutter, J. R., Maguire, M., Sundberg, J. P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., Smith, G. H., Stark, K. L., Gridley, T. <strong>Notch signaling is essential for vascular morphogenesis in mice.</strong> Genes Dev. 14: 1343-1352, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837027[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837027">Krebs et al. (2000)</a> stated that these results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10837027+7926761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In vertebrates with mutations in the Notch cell-cell communication pathway, segmentation fails: the boundaries demarcating somites, the segments of the embryonic body axis, are absent or irregular. Somite patterning is thought to be governed by a 'clock-and-wavefront' mechanism: a biochemical oscillator (the segmentation clock) operates in the cells of the presomitic mesoderm, the immature tissue from which the somites are sequentially produced, and a wavefront of maturation sweeps back through this tissue, arresting oscillation and initiating somite differentiation. Cells arrested in different phases of their cycle express different genes, defining the spatially periodic pattern of somites and controlling the physical process of segmentation. <a href="#38" class="mim-tip-reference" title="Jiang, Y.-J., Aerne, B. L., Smithers, L., Haddon, C., Ish-Horowitz, D., Lewis, J. <strong>Notch signalling and the synchronization of the somite segmentation clock.</strong> Nature 408: 475-479, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11100729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11100729</a>] [<a href="https://doi.org/10.1038/35044091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11100729">Jiang et al. (2000)</a> analyzed a set of zebrafish mutants and determined that the essential function of Notch signaling in somite segmentation is to keep the oscillations of neighboring presomitic mesoderm cells synchronized. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11100729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H., Dotto, G. P., Radtke, F. <strong>Notch1 functions as a tumor suppressor in mouse skin.</strong> Nature Genet. 33: 416-421, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12590261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12590261</a>] [<a href="https://doi.org/10.1038/ng1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12590261">Nicolas et al. (2003)</a> studied the role of Notch signaling in mammalian skin. Conventional gene targeting was not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1 -/- embryos die during gestation. Therefore, <a href="#70" class="mim-tip-reference" title="Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H., Dotto, G. P., Radtke, F. <strong>Notch1 functions as a tumor suppressor in mouse skin.</strong> Nature Genet. 33: 416-421, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12590261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12590261</a>] [<a href="https://doi.org/10.1038/ng1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12590261">Nicolas et al. (2003)</a> used a tissue-specific inducible gene targeting approach to study the physiologic role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 resulted in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and primary keratinocytes resulted in increased and sustained expression of Gli1 (<a href="/entry/165220">165220</a>), causing the development of basal cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis resulted in derepressed beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling could be reversed by reintroduction of a dominant active form of the Notch1 receptor. The results indicated that Notch1 functions as a tumor suppressor gene in mammalian skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12590261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Kumano, K., Chiba, S., Kunisato, A., Sata, M., Saito, T., Nakagami-Yamaguchi, E., Yamaguchi, T., Masuda, S., Shimizu, K., Takahashi, T., Ogawa, S., Hamada, Y., Hirai, H. <strong>Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.</strong> Immunity 18: 699-711, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12753746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12753746</a>] [<a href="https://doi.org/10.1016/s1074-7613(03)00117-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12753746">Kumano et al. (2003)</a> found that hematopoietic stem cell development and angiogenesis were severely impaired in paraaortic splanchnopleura (P-Sp) culture of Notch1 -/-, but not Notch2 -/-, mouse embryos. Although colony-forming cell activity in the yolk sac was unimpaired in Notch1 -/- mice, hematopoietic stem cell activity was undetectable in either the yolk sac or P-Sp culture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12753746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T. <strong>Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.</strong> Genes Dev. 17: 1207-1212, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1084703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730124">Krebs et al. (2003)</a> showed that mouse embryos mutant for the Notch ligand Dll1 or doubly mutant for Notch1 and Notch2 exhibited multiple defects in left-right asymmetry. Dll1 -/- embryos did not express Nodal in the region around the node. Analysis of the enhancer regulating node-specific Nodal expression revealed binding sites for Rbpj. Mutation of these sites destroyed the ability of the enhancer to direct node-specific gene expression in transgenic mice. <a href="#43" class="mim-tip-reference" title="Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T. <strong>Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.</strong> Genes Dev. 17: 1207-1212, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1084703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730124">Krebs et al. (2003)</a> concluded that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that perinodal expression of Nodal is an essential component of left-right asymmetry determination in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using gain- and loss-of-function experiments in zebrafish and mouse, <a href="#83" class="mim-tip-reference" title="Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Buscher, D., Koth, C. M., Itoh, T., Morita, M., Raya, R. M., Dubova, I., Bessa, J. G., de la Pompa, J. L., Belmonte, J. C. I. <strong>Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos.</strong> Genes Dev. 17: 1213-1218, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1084403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730123">Raya et al. (2003)</a> showed that activity of the Notch pathway was necessary and sufficient for Nodal expression around the node and for proper left-right determination. They also identified critical Rbpj-binding sequences in the Nodal promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using inducible ablation of Notch1 in adult mouse cornea, <a href="#111" class="mim-tip-reference" title="Vauclair, S., Majo, F., Durham, A.-D., Ghyselinck, N. B., Barrandon, Y., Radtke, F. <strong>Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism.</strong> Dev. Cell 13: 242-253, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17681135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17681135</a>] [<a href="https://doi.org/10.1016/j.devcel.2007.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17681135">Vauclair et al. (2007)</a> showed that Notch1 -/- corneal progenitor cells lost the ability to repair mechanically wounded corneal epithelium. Instead of generating a new cornea after injury, Notch1 -/- corneal cells repaired the wound into a hyperproliferative epidermis-like epithelium, similar to xerophthalmia caused by vitamin A deficiency. Repair was associated with secretion of Fgf2 (<a href="/entry/134920">134920</a>) through Notch1 -/- epithelium, followed by vascularization and remodeling of the underlying stroma. <a href="#111" class="mim-tip-reference" title="Vauclair, S., Majo, F., Durham, A.-D., Ghyselinck, N. B., Barrandon, Y., Radtke, F. <strong>Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism.</strong> Dev. Cell 13: 242-253, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17681135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17681135</a>] [<a href="https://doi.org/10.1016/j.devcel.2007.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17681135">Vauclair et al. (2007)</a> identified Crbp1 (RBP1; <a href="/entry/180260">180260</a>) as a direct Notch1 target within the corneal epithelium, linking the Notch pathway to vitamin A metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17681135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Gamma-secretase inhibitors block the activation of oncogenic NOTCH1 in T-ALL, but the clinical use of these drugs in humans has been limited by antileukemic cytotoxicity and severe gastrointestinal toxicity. <a href="#85" class="mim-tip-reference" title="Real, P. J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M. L., Barnes, K., Sawai, C., Homminga, I., Meijerink, J., Aifantis, I., Basso, G., Cordon-Cardo, C., Ai, W., Ferrando, A. <strong>Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.</strong> Nature Med. 15: 50-58, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19098907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19098907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19098907[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.1900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19098907">Real et al. (2009)</a> found that treatment of several glucocorticoid-resistant T-ALL cell lines with a combination of gamma-secretase inhibitors and corticosteroids resulted in synergistic dose-related apoptotic cell death. The findings were specific to T-ALL. Microarray analysis of these cells indicated that inhibition of NOTCH1 resulted in upregulation of the glucocorticoid receptor NR3C1 (<a href="/entry/138040">138040</a>) as well as increased expression of BCL2L11 (<a href="/entry/603827">603827</a>). In mouse models of human T-ALL, this double treatment resulted in antileukemic effects and cell cycle arrest. In addition, the double treatment protected mice from developing intestinal goblet cell metaplasia that was typically induced by treatment with gamma-secretase inhibitors alone. Further studies indicated that upregulation of Klf4 (<a href="/entry/602252">602252</a>) was responsible for the metaplastic gastrointestinal effects of gamma-secretase inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19098907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a mouse model of aplastic anemia (<a href="/entry/609135">609135</a>) and conditionally deleting Notch1 or administering gamma-secretase inhibitors (GSIs), <a href="#89" class="mim-tip-reference" title="Roderick, J. E., Gonzalez-Perez, G., Kuksin, C. A., Dongre, A., Roberts, E. R., Srinivasan, J., Andrzejewski, C., Jr., Fauq, A. H., Golde, T. E., Miele, L., Minter, L. M. <strong>Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.</strong> J. Exp. Med. 210: 1311-1329, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23733784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23733784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23733784[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20112615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23733784">Roderick et al. (2013)</a> observed attenuated aplastic anemia and rescue of mice from bone marrow failure. The cleaved, active form of Notch1, which was increased in wildtype mice with aplastic anemia, bound to the Tbx21 (<a href="/entry/604895">604895</a>) promoter, and these findings were also detected in humans with untreated aplastic anemia. Extended GSI treatment had no adverse effect on engraftment or long-term hematopoiesis, and it also resulted in loss of Notch1 binding to the Tbx21 promoter. <a href="#89" class="mim-tip-reference" title="Roderick, J. E., Gonzalez-Perez, G., Kuksin, C. A., Dongre, A., Roberts, E. R., Srinivasan, J., Andrzejewski, C., Jr., Fauq, A. H., Golde, T. E., Miele, L., Minter, L. M. <strong>Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.</strong> J. Exp. Med. 210: 1311-1329, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23733784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23733784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23733784[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20112615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23733784">Roderick et al. (2013)</a> concluded that NOTCH1 is a critical mediator of Th1 pathology in aplastic anemia through its direct regulation of TBX21 and that NOTCH1 is responsive to GSIs in vitro and in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23733784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="allelicVariants" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
|
|
</span>
|
|
<strong>12 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/190198" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=190198[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
|
|
|
|
</div>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0001" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, ARG1108TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs41309764 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41309764;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs41309764?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs41309764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs41309764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013294 OR RCV001781254 OR RCV001851821" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013294, RCV001781254, RCV001851821" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013294...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-generation pedigree affected by autosomal dominant congenital heart disease and valve calcification (AOVD1; <a href="/entry/109730">109730</a>), <a href="#26" class="mim-tip-reference" title="Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., Srivastava, D. <strong>Mutations in NOTCH1 cause aortic valve disease.</strong> Nature 437: 270-274, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025100</a>] [<a href="https://doi.org/10.1038/nature03940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16025100">Garg et al. (2005)</a> identified a C-to-T transition at nucleotide 3322 of the NOTCH1 gene that resulted in an arg-to-ter substitution at codon 1108 (R1108X), in the extracellular domain. Affected family members had aortic stenosis, dysmorphic aortic valve, ventricular septal defect, tetralogy of Fallot, and mitral stenosis with or without bicuspid aortic valve and calcification. Unaffected individuals manifested no valvular or other congenital heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16025100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0002" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, 1-BP DEL, NT4515
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs41309766 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41309766;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs41309766?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs41309766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs41309766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013295" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013295" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013295</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with autosomal dominant congenital heart disease with valve calcification (AOVD1; <a href="/entry/109730">109730</a>), <a href="#26" class="mim-tip-reference" title="Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., Srivastava, D. <strong>Mutations in NOTCH1 cause aortic valve disease.</strong> Nature 437: 270-274, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025100</a>] [<a href="https://doi.org/10.1038/nature03940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16025100">Garg et al. (2005)</a> identified heterozygosity for a frameshift mutation in the NOTCH1 gene at the his1505 position. The mutation was predicted to result in a severely altered protein containing 74 incorrect amino acids at the C terminus of the extracellular domain followed by a premature stop codon. Affected individuals had severe aortic stenosis, hypoplastic left ventricle, and double-outlet right ventricle with calcification and bicuspid aortic valve. The phenotype segregated with the mutation in affected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16025100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0003" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, 85-KB DEL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144232" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144232" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144232</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old boy with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> identified heterozygosity for a de novo 85-kb deletion involving the 5-prime region of the NOTCH1 gene, including part of the promoter and all of exon 1 (chr9:139,439,620-139,524,480; GRCh37). The deletion was not found in the unaffected parents, in 2 unaffected sibs, or in more than 10,000 control genomes or exomes. The patient had occipital aplasia cutis congenita, marked cutis marmorata, hypoplastic and dystrophic toenails, and areas of focal calcinosis cutis. Mild narrowing of the pulmonary branch arteries was noted on echocardiography in infancy; at age 6 years, the branch pulmonary arteries were normal, and there was stable dilation of the main pulmonary artery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0004" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, IVS4AS, G-T, -1
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777735 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777735;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144234" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144234" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144234</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and daughter with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> identified heterozygosity for a splice site mutation in intron 4 of the NOTCH1 gene (c.743-1G-T, at chr9:139,414,018; GRCh37), disrupting the exon 5 acceptor splice site. The mutation was not found in the unaffected mother or an unaffected brother, or in more than 10,000 control genomes or exomes. The daughter had severe aplasia cutis of the scalp that was complicated by recurrent hemorrhage during a lengthy healing process. She had hypoplastic toes on the left foot and nail hypoplasia of the second and third toes. Her father was born with a cutaneous and bony defect involving two-thirds of his cranium, brachydactyly of the right hand, and terminal transverse defects of both feet, including soft-tissue syndactyly of hypoplastic toes. Bony ingrowth of the skull never fully bridged the father's cranial defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0005" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, CYS429ARG
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777736 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777736;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144235</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old boy of Portuguese ancestry with Adams-Oliver syndrome (AOS5; <a href="/entry/616028">616028</a>), originally described by <a href="#96" class="mim-tip-reference" title="Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S. <strong>Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?</strong> Am. J. Med. Genet. 158A: 648-651, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22307742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22307742</a>] [<a href="https://doi.org/10.1002/ajmg.a.34435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22307742">Silva et al. (2012)</a>, <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> identified heterozygosity for a de novo c.1285T-C transition (chr9:139,412,360; GRCh37) in the NOTCH1 gene, resulting in a cys429-to-arg (C429R) substitution at a highly conserved residue in calcium-binding EGF (<a href="/entry/131530">131530</a>)-like repeat 11. The mutation was not found in his unaffected parents or in more than 10,000 control genomes or exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22307742+25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0006" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, CYS1496TYR
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587781259 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587781259;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587781259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587781259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144236</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female proband of European and Asian ancestry with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> identified heterozygosity for a de novo c.4487G-A transition (chr9:139,399,861; GRCh37) in the NOTCH1 gene, resulting in a cys1496-to-tyr (C1496Y) substitution at a highly conserved residue within the extracellular negative regulatory region (NRR) of the second Lin-12 NOTCH repeat (LNR) domain. <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> noted that the NRR sterically inhibits processing of NOTCH1 in the absence of ligand stimulation; thus, destabilization of this domain could increase constitutive Notch signaling and result in a gain of function. The mutation was not found in the proband's unaffected parents or in more than 10,000 control genomes or exomes. The patient was born with severe aplasia cutis affecting most of the scalp superior to the ears as well as the posterior neck. She had bilateral prominent tortuous scalp vessels, truncal cutis marmorata, and bilateral toe hypoplasia with absent toenails. Neuroimaging at day 1 of life showed small focal areas of bilateral parietal and left frontal white matter acute infarction and partial superior sagittal sinus thrombosis; repeat imaging at 1 week showed evolving biparietal and left frontal lobe infarcts, near-complete sagittal sinus thrombosis, and biparietal cortical venous thromboses, with stabilization and improvement over the next several months. She also had mild mitral valve annulus hypoplasia and multiperforated patent foramen ovale with insignificant shunting; severe pulmonary hypertension on day 1 of life resolved by day 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0007" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, ASP1989ASN
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777734 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777734;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144233" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144233" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144233</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 24-year-old woman with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), originally reported by <a href="#110" class="mim-tip-reference" title="Vandersteen, A. M., Dixon, J. W. <strong>Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.</strong> Clin. Dysmorph. 20: 210-213, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21785343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21785343</a>] [<a href="https://doi.org/10.1097/MCD.0b013e32834964d1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21785343">Vandersteen and Dixon (2011)</a>, <a href="#101" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. <strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25132448">Stittrich et al. (2014)</a> identified heterozygosity for a c.5965G-A transition (chr9: 139,393,681; GRCh37) in the NOTCH1 gene, resulting in an asp1989-to-asn (D1989N) substitution at a highly conserved residue involved in a bipartite-charged hydrogen-bonding interaction with the backbone nitrogen-hydrogen atoms of asp2020. No DNA was available from the proband's deceased affected father and sister. The mutation was not found in more than 10,000 control genomes or exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25132448+21785343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0008" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, TYR550TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864622059 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622059;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864622059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864622059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000203698" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203698" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203698</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members of a 3-generation family with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), <a href="#98" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. <strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong> Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25963545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25963545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25963545">Southgate et al. (2015)</a> identified heterozygosity for a 1-bp insertion (c.1649dupA, NM_017617.3) in the NOTCH1 gene, resulting in a tyr550-to-ter (Y550X) substitution within the EGF-like repeats of the extracellular domain. The proband and his brother each exhibited a severe cutaneous and bony scalp defect and marked terminal transverse limb defects, as well as an undefined heart murmur. The mutation was also present in their clinically unaffected mother, who had no scalp or limb defects but was found to have an unexplained heart murmur. Quantitative RT-PCR analysis of patient RNA demonstrated an approximately 50% reduction in NOTCH1 transcripts compared to control, and analysis of downstream signaling factors revealed significant reductions in HEY1 (<a href="/entry/602953">602953</a>) and HES1 (<a href="/entry/139605">139605</a>) with the Y550X mutant compared to wildtype NOTCH1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25963545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0009" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, 2-BP DEL, 6049TC
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864622063 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622063;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864622063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864622063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000206353 OR RCV004767148" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000206353, RCV004767148" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000206353...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian male proband with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), originally reported by <a href="#15" class="mim-tip-reference" title="Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G. <strong>Familial aplasia cutis congenita and coarctation of the aorta.</strong> Am. J. Med. Genet. 43: 762-763, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1621771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1621771</a>] [<a href="https://doi.org/10.1002/ajmg.1320430423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1621771">Dallapiccola et al. (1992)</a>, <a href="#98" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. <strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong> Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25963545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25963545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25963545">Southgate et al. (2015)</a> identified heterozygosity for a 2-bp deletion (c.6049_6050delTC, NM_017617.3) in the NOTCH1 gene, causing a frameshift predicted to result in a premature termination codon (Ser2017ThrfsTer9) within the intracellular ANK repeat domain. DNA was unavailable from the proband's affected mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25963545+1621771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0010" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, CYS1374ARG
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864622060 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622060;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864622060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864622060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000205222" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000205222" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000205222</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old German boy with Adams-Oliver syndrome-5 (AOS5; <a href="/entry/616028">616028</a>), <a href="#98" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. <strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong> Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25963545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25963545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25963545">Southgate et al. (2015)</a> identified heterozygosity for a c.4120T-C transition (c.4120T-C, NM_017617.3) in the NOTCH1 gene, resulting in a cys1374-to-arg (C1374R) substitution at a highly conserved residue within the EGF-like repeats of the extracellular domain. The mutation was present in an affected paternal uncle but was not found in 2 clinically normal sibs or 2 unaffected paternal uncles; however, it was a detected in the proband's clinically unaffected father. Cardiovascular evaluation by echocardiography showed no abnormality, confirming the father's unaffected status and indicating reduced penetrance for the C1374R mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25963545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0011" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, THR596MET
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs61755997 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61755997;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs61755997?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61755997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61755997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000660144 OR RCV000787043 OR RCV001049180 OR RCV001575577 OR RCV002311202 OR RCV004701355" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000660144, RCV000787043, RCV001049180, RCV001575577, RCV002311202, RCV004701355" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000660144...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 49-year-old German man with a calcified bicuspid aortic valve and ascending aortic aneurysm (AOVD1; <a href="/entry/109730">109730</a>), <a href="#63" class="mim-tip-reference" title="Mohamed, S. A., Aherrahrou, Z., Liptau, H., Erasmi, A. W., Hagemann, C., Wrobel, S., Borzym, K., Schunkert, H., Sievers, H. H., Erdmann, J. <strong>Novel missense mutations (p.T596M and p.P1797H) in MOTCH1 in patients with bicuspid aortic valve.</strong> Biochem. Biophys. Res. Commun. 345: 1460-1465, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16729972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16729972</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.05.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16729972">Mohamed et al. (2006)</a> identified heterozygosity for a g.40264C-T transition in exon 11 of the NOTCH1 gene, resulting in a thr596-to-met (T596M) substitution at a highly conserved residue within an EGF-like domain in the N-terminal half of the protein. The authors stated in the text that the variant was not found in at least 327 controls or in public variant databases, but stated in table 3 that the variant had a minor allele frequency of 0.01. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16729972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0012" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
NOTCH1, PRO1797HIS
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000787044" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000787044" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000787044</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 55-year-old German man with a calcified bicuspid aortic valve and ascending aortic aneurysm (AOVD1; <a href="/entry/109730">109730</a>), <a href="#63" class="mim-tip-reference" title="Mohamed, S. A., Aherrahrou, Z., Liptau, H., Erasmi, A. W., Hagemann, C., Wrobel, S., Borzym, K., Schunkert, H., Sievers, H. H., Erdmann, J. <strong>Novel missense mutations (p.T596M and p.P1797H) in MOTCH1 in patients with bicuspid aortic valve.</strong> Biochem. Biophys. Res. Commun. 345: 1460-1465, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16729972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16729972</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.05.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16729972">Mohamed et al. (2006)</a> identified heterozygosity for a g.53777A-C transversion in exon 29 of the NOTCH1 gene, resulting in a pro1797-to-his (P1797H) substitution at a highly conserved residue in the short juxtamembrane within the intracellular domain. The authors stated in the text that the variant was not found in at least 327 controls or in public variant databases, but stated in table 3 that the variant had a minor allele frequency of 0.01. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16729972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Agrawal2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., Fakhry, C., Xie, T.-X., Zhang, J., Wang, J., Zhang, N., El-Naggar, A. K., and 19 others.
|
|
<strong>Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.</strong>
|
|
Science 333: 1154-1157, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21798897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21798897</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21798897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1206923" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Aguirre2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Aguirre, A., Rubio, M. E., Gallo, V.
|
|
<strong>Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal.</strong>
|
|
Nature 467: 323-327, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20844536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20844536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20844536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20844536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature09347" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Artavanis-Tsakonas1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Artavanis-Tsakonas, S., Matsuno, K., Fortini, M.
|
|
<strong>Notch signaling.</strong>
|
|
Science 268: 225-232, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7716513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7716513</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7716513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.7716513" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Axelrod1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Axelrod, J. D., Matsuno, K., Artavanis-Tsakonas, S., Perrimon, N.
|
|
<strong>Interaction between Wingless and Notch signaling pathways mediated by Dishevelled.</strong>
|
|
Science 271: 1826-1832, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596950</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8596950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.271.5257.1826" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Balint2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Balint, K., Xiao, M., Pinnix, C. C., Soma, A., Veres, I., Juhasz, I., Brown, E. J., Capobianco, A. J., Herlyn, M., Liu, Z.-J.
|
|
<strong>Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.</strong>
|
|
J. Clin. Invest. 115: 3166-3176, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16239965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI25001" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Benedito2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H.
|
|
<strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong>
|
|
Nature 484: 110-114, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22426001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature10908" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Boskovski2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boskovski, M. T., Yuan, S., Pedersen, N. B., Goth, C. K., Makova, S., Clausen, H., Brueckner, M., Khokha, M. K.
|
|
<strong>The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.</strong>
|
|
Nature 504: 456-459, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24226769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24226769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24226769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24226769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature12723" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Brou2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J. R., Cumano, A., Roux, P., Black, R. A., Israel, A.
|
|
<strong>A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.</strong>
|
|
Molec. Cell 5: 207-216, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1097-2765(00)80417-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Bruckner2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bruckner, K., Perez, L., Clausen, H., Cohen, S.
|
|
<strong>Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.</strong>
|
|
Nature 406: 411-415, 2000. Note: Erratum: Nature 407: 654 only, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10935637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10935637</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10935637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35019075" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Carlson2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Carlson, M. E., Hsu, M., Conboy, I. M.
|
|
<strong>Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.</strong>
|
|
Nature 454: 528-532, 2008. Note: Erratum: Nature 538: 274 only, 2016.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18552838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18552838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18552838[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18552838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature07034" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Chan1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Chan, Y.-M., Jan, Y. N.
|
|
<strong>Roles for proteolysis and trafficking in Notch maturation and signal transduction.</strong>
|
|
Cell 94: 423-426, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9727485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9727485</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9727485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0092-8674(00)81583-4" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Conboy2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Conboy, I. M., Conboy, M. J., Smythe, G. M., Rando, T. A.
|
|
<strong>Notch-mediated restoration of regenerative potential to aged muscle.</strong>
|
|
Science 302: 1575-1577, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645852</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1087573" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Conlon1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Conlon, R. A., Reaume, A. G., Rossant, J.
|
|
<strong>Notch1 is required for the coordinate segmentation of somites.</strong>
|
|
Development 121: 1533-1545, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7789282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1242/dev.121.5.1533" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Dale2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dale, J. K., Maroto, M., Dequeant, M.-L., Malapert, P., McGrew, M., Pourquie, O.
|
|
<strong>Periodic Notch inhibition by lunatic Fringe underlies the chick segmentation clock.</strong>
|
|
Nature 421: 275-278, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature01244" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Dallapiccola1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G.
|
|
<strong>Familial aplasia cutis congenita and coarctation of the aorta.</strong>
|
|
Am. J. Med. Genet. 43: 762-763, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1621771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1621771</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1621771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.1320430423" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Das2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Das, I., Craig, C., Funahashi, Y., Jung, K.-M., Kim, T.-W., Byers, R., Weng, A. P., Kutok, J. L., Aster, J. C., Kitajewski, J.
|
|
<strong>Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.</strong>
|
|
J. Biol. Chem. 279: 30771-30780, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123653</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M309252200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="De Strooper1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., Goate, A., Kopan, R.
|
|
<strong>A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.</strong>
|
|
Nature 398: 518-522, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10206645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/19083" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="del Amo1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
del Amo, F., Gendron-Maguire, M., Swiatek, P. J., Jenkins, N. A., Copeland, N. G., Gridley, T.
|
|
<strong>Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch.</strong>
|
|
Genomics 15: 259-264, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8449489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8449489</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8449489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1993.1055" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Del Monte-Nieto2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Del Monte-Nieto, G., Ramialison, M., Adam, A. A. S., Wu, B., Aharonov, A., D'Uva, G., Bourke, L. M., Pitulescu, M. E., Chen, H., de la Pompa, J. L., Shou, W., Adams, R. H., Harten, S. K., Tzahor, E., Zhou, B., Harvey, R. P.
|
|
<strong>Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation.</strong>
|
|
Nature 557: 439-445, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29743679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29743679</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29743679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41586-018-0110-6" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Dequeant2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dequeant, M.-L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O.
|
|
<strong>A complex oscillating network of signaling genes underlies the mouse segmentation clock.</strong>
|
|
Science 314: 1595-1598, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17095659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17095659</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17095659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1133141" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Ellisen1991" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., Sklar, J.
|
|
<strong>TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.</strong>
|
|
Cell 66: 649-661, 1991.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1831692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1831692</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1831692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/0092-8674(91)90111-b" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Engel2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Engel, M. E., Nguyen, H. N., Mariotti, J., Hunt, A., Hiebert, S. W.
|
|
<strong>Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification.</strong>
|
|
Molec. Cell. Biol. 30: 1852-1863, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20123979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1128/MCB.01342-09" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Engin2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Engin, F., Bertin, T., Ma, O., Jiang, M. M., Wang, L., Sutton, R. E., Donehower, L. A., Lee, B.
|
|
<strong>Notch signaling contributes to the pathogenesis of human osteosarcomas.</strong>
|
|
Hum. Molec. Genet. 18: 1464-1470, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19228774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19228774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19228774[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19228774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddp057" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Engin2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Engin, F., Yao, Z., Yang, T., Zhou, G., Bertin, T., Jiang, M. M., Chen, Y., Wang, L., Zheng, H., Sutton, R. E., Boyce, B. F., Lee, B.
|
|
<strong>Dimorphic effects of Notch signaling in bone homeostasis.</strong>
|
|
Nature Med. 14: 299-305, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18297084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18297084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18297084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18297084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm1712" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Fre2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., Artavanis-Tsakonas, S.
|
|
<strong>Notch signals control the fate of immature progenitor cells in the intestine. (Letter)</strong>
|
|
Nature 435: 964-968, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15959516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15959516</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15959516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature03589" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Garg2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., Srivastava, D.
|
|
<strong>Mutations in NOTCH1 cause aortic valve disease.</strong>
|
|
Nature 437: 270-274, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16025100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature03940" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Guarani2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Guarani, V., Deflorian, G., Franco, C. A., Kruger, M., Phng, L.-K., Bentley, K., Toussaint, L., Dequiedt, F., Mostoslavsky, R., Schmidt, M. H. H., Zimmermann, B., Brandes, R. P., Mione, M., Westphal, C. H., Braun, T., Zeiher, A. M., Gerhardt, H., Dimmeler, S., Potente, M.
|
|
<strong>Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.</strong>
|
|
Nature 473: 234-238, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21499261[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21499261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature09917" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Gustafsson2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gustafsson, M. V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J. L., Poellinger, L., Lendahl, U., Bondesson, M.
|
|
<strong>Hypoxia requires Notch signaling to maintain the undifferentiated cell state.</strong>
|
|
Dev. Cell 9: 617-628, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16256737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16256737</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16256737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.devcel.2005.09.010" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Hadland2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hadland, B. K., Manley, N. R., Su, D., Longmore, G. D., Moore, C. L., Wolfe, M. S., Schroeter, E. H., Kopan, R.
|
|
<strong>Gamma-secretase inhibitors repress thymocyte development.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 7487-7491, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11416218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11416218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11416218[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11416218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.131202798" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Han2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Han, H., Tanigaki, K., Yamamoto, N., Kuroda, K., Yoshimoto, M., Nakahata, T., Ikuta, K., Honjo, T.
|
|
<strong>Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.</strong>
|
|
Int. Immun. 14: 637-645, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12039915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12039915</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12039915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/intimm/dxf030" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Hardy1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hardy, J., Israel, A.
|
|
<strong>In search of gamma-secretase.</strong>
|
|
Nature 398: 466-467, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206639</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10206639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/18979" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Hellstrom2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C.
|
|
<strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong>
|
|
Nature 445: 776-780, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature05571" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Hilton2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hilton, M. J., Tu, X., Wu, X., Bai, S., Zhao, H., Kobayashi, T., Kronenberg, H. M., Teitelbaum, S. L., Ross, F. P., Kopan, R., Long, F.
|
|
<strong>Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation.</strong>
|
|
Nature Med. 14: 306-314, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18297083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18297083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18297083[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18297083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm1716" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Hozumi2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S.
|
|
<strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong>
|
|
J. Exp. Med. 205: 2507-2513, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824583[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20080134" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Hu2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hu, Q.-D., Ang, B.-T., Karsak, M., Hu, W.-P., Cui, X.-Y., Duka, T., Takeda, Y., Chia, W., Sankar, N., Ng, Y.-K., Ling, E.-A., Maciag, T., and 12 others.
|
|
<strong>F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.</strong>
|
|
Cell 115: 163-175, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14567914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14567914</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14567914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0092-8674(03)00810-9" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="36" class="mim-anchor"></a>
|
|
<a id="Huppert2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Huppert, S. S., Le, A., Schroeter, E. H., Mumm, J. S., Saxena, M. T., Milner, L. A., Kopan, R.
|
|
<strong>Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.</strong>
|
|
Nature 405: 966-970, 2000. Note: Erratum: Nature 408, 616 only, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10879540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10879540</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10879540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35016111" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="37" class="mim-anchor"></a>
|
|
<a id="Jarriault1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jarriault, S., Brou, C., Logeat, F., Schroeter, E. H., Kopan, R., Israel, A.
|
|
<strong>Signalling downstream of activated mammalian Notch.</strong>
|
|
Nature 377: 355-358, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7566092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7566092</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7566092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/377355a0" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="38" class="mim-anchor"></a>
|
|
<a id="Jiang2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jiang, Y.-J., Aerne, B. L., Smithers, L., Haddon, C., Ish-Horowitz, D., Lewis, J.
|
|
<strong>Notch signalling and the synchronization of the somite segmentation clock.</strong>
|
|
Nature 408: 475-479, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11100729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11100729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11100729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35044091" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="39" class="mim-anchor"></a>
|
|
<a id="Kasahara2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L.
|
|
<strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong>
|
|
Science 342: 734-737, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24091702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1241359" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="40" class="mim-anchor"></a>
|
|
<a id="Kerstjens-Frederikse2016" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kerstjens-Frederikse, W. S., van de Laar, I. M. B. H., Vos, Y. J., Verhagen, J. M. A., Berger, R. M. F., Lichtenbelt, K. D., Klein Wassink-Ruiter, J. S., van der Zwaag, P. A., du Marchie-Sarvaas, G. J., Bergman, K. A., Bilardo, C. M., Roos-Hesselink, J. W., Janssen, J. H. P., Frohn-Mulder, I. M., van Spaendonck-Zwarts, K. Y., van Melle, J. P., Hofstra, R. M. W., Wessels, M. W.
|
|
<strong>Cardiovascular malformations caused by NOTCH mutations do not keep left: data on 428 probands with left-sided CHD and their families.</strong>
|
|
Genet. Med. 18: 914-923, 2016.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26820064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26820064</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26820064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/gim.2015.193" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="41" class="mim-anchor"></a>
|
|
<a id="Klinakis2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I.
|
|
<strong>A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.</strong>
|
|
Nature 473: 230-233, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21562564[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21562564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature09999" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="42" class="mim-anchor"></a>
|
|
<a id="Koch2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F.
|
|
<strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong>
|
|
J. Exp. Med. 205: 2515-2523, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824585[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20080829" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="43" class="mim-anchor"></a>
|
|
<a id="Krebs2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T.
|
|
<strong>Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.</strong>
|
|
Genes Dev. 17: 1207-1212, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1101/gad.1084703" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="44" class="mim-anchor"></a>
|
|
<a id="Krebs2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Krebs, L. T., Xue, Y., Norton, C. R., Shutter, J. R., Maguire, M., Sundberg, J. P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., Smith, G. H., Stark, K. L., Gridley, T.
|
|
<strong>Notch signaling is essential for vascular morphogenesis in mice.</strong>
|
|
Genes Dev. 14: 1343-1352, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837027[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10837027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="45" class="mim-anchor"></a>
|
|
<a id="Kumano2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kumano, K., Chiba, S., Kunisato, A., Sata, M., Saito, T., Nakagami-Yamaguchi, E., Yamaguchi, T., Masuda, S., Shimizu, K., Takahashi, T., Ogawa, S., Hamada, Y., Hirai, H.
|
|
<strong>Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.</strong>
|
|
Immunity 18: 699-711, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12753746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12753746</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12753746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1074-7613(03)00117-1" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="46" class="mim-anchor"></a>
|
|
<a id="Larsson1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Larsson, C., Lardelli, M., White, I., Lendahl, U.
|
|
<strong>The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.</strong>
|
|
Genomics 24: 253-258, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698746</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7698746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1994.1613" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="47" class="mim-anchor"></a>
|
|
<a id="Lefort2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lefort, K., Mandinova, A., Ostano, P., Kolev, V., Calpini, V., Kolfschoten, I., Devgan, V., Lieb, J., Raffoul, W., Hohl, D., Neel, V., Garlick, J., Chiorino, G., Dotto, G. P.
|
|
<strong>Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK-alpha kinases.</strong>
|
|
Genes Dev. 21: 562-577, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17344417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17344417</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17344417[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17344417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1101/gad.1484707" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="48" class="mim-anchor"></a>
|
|
<a id="Lim2017" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lim, J. S., Ibaseta, A., Fischer, M. M., Cancilla, B., O'Young, G., Cristea, S., Luca, V. C., Yang, D., Jahchan, N. S., Hamard, C., Antoine, M., Wislez, M., Kong, C., Cain, J., Liu, Y.-W., Kapoun, A. M., Garcia, K. C., Hoey, T., Murriel, C. L., Sage, J.
|
|
<strong>Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.</strong>
|
|
Nature 545: 360-364, 2017.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489825[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28489825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature22323" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="49" class="mim-anchor"></a>
|
|
<a id="Lim2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lim, R., Sugino, T., Nolte, H., Andrade, J., Zimmermann, B., Shi, C., Doddaballapur, A., Ong, Y. T., Wilhelm, K., Fasse, J. W. D., Ernst, A., Kaulich, M., Husnjak, K., Boettger, T., Guenther, S., Braun, T., Kruger, M., Benedito, R., Dikic, I., Potente, M.
|
|
<strong>Deubiquitinase USP10 regulates Notch signaling in the endothelium.</strong>
|
|
Science 364: 188-193, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30975888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30975888</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30975888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.aat0778" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="50" class="mim-anchor"></a>
|
|
<a id="Loganathan2020" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Loganathan, S. K., Schleicher, K., Malik, A., Quevedo, R., Langille, E., Teng, K., Oh, R. H., Rathod, B., Tsai, R., Samavarchi-Tehrani, P., Pugh, T. J., Gingras, A.-C., Schramek, D.
|
|
<strong>Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.</strong>
|
|
Science 367: 1264-1269, 2020.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32165588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32165588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32165588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.aax0902" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="51" class="mim-anchor"></a>
|
|
<a id="Logeat1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Logeat, F., Bessia, C., Brou, C., LeBail, O., Jarriault, S., Seidah, N. G., Israel, A.
|
|
<strong>The Notch1 receptor is cleaved constitutively by a furin-like convertase.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 8108-8112, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.95.14.8108" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="52" class="mim-anchor"></a>
|
|
<a id="Loomes2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Loomes, K. M., Taichman, D. B., Glover, C. L., Williams, P. T., Markowitz, J. E., Piccoli, D. A., Baldwin, H. S., Oakey, R. J.
|
|
<strong>Characterization of Notch receptor expression in the developing mammalian heart and liver.</strong>
|
|
Am. J. Med. Genet. 112: 181-189, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244553</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.10592" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="53" class="mim-anchor"></a>
|
|
<a id="Loomes1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Loomes, K. M., Underkoffler, L. A., Morabito, J., Gottlieb, S., Piccoli, D. A., Spinner, N. B., Baldwin, H. S., Oakey, R. J.
|
|
<strong>The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome.</strong>
|
|
Hum. Molec. Genet. 8: 2443-2449, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556292</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10556292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/8.13.2443" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="54" class="mim-anchor"></a>
|
|
<a id="Luca2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Luca, V. C., Jude, K. M., Pierce, N. W., Nachury, M. V., Fischer, S., Garcia, K. C.
|
|
<strong>Structural basis for Notch1 engagement of delta-like 4.</strong>
|
|
Science 347: 847-853, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25700513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25700513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25700513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25700513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1261093" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="55" class="mim-anchor"></a>
|
|
<a id="Luca2017" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Luca, V. C., Kim, B. C., Ge, C., Kakuda, S., Wu, D., Roein-Peikar, M., Haltiwanger, R. S., Zhu, C., Ha, T., Garcia, K. C.
|
|
<strong>Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity.</strong>
|
|
Science 355: 1320-1324, 2017.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28254785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28254785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28254785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28254785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.aaf9739" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="56" class="mim-anchor"></a>
|
|
<a id="Maeda2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Maeda, T., Merghoub, T., Hobbs, R. M., Dong, L., Maeda, M., Zakrzewski, J., van den Brink, M. R. M., Zelent, A., Shigematsu, H., Akashi, K., Teruya-Feldstein, J., Cattoretti, G., Pandolfi, P. P.
|
|
<strong>Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF.</strong>
|
|
Science 316: 860-866, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17495164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17495164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17495164[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17495164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1140881" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="57" class="mim-anchor"></a>
|
|
<a id="Magnusson2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Magnusson, J. P., Goritz, C., Tatarishvili, J., Dias, D. O., Smith, E. M. K., Lindvall, O., Kokaia, Z., Frisen, J.
|
|
<strong>A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.</strong>
|
|
Science 346: 237-241, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25301628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25301628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25301628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.346.6206.237" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="58" class="mim-anchor"></a>
|
|
<a id="Mammucari2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mammucari, C., Tommasi di Vignano, A., Sharov, A. A., Neilson, J., Havrda, M. C., Roop, D. R., Botchkarev, V. A., Crabtree, G. R., Dotto, G. P.
|
|
<strong>Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.</strong>
|
|
Dev. Cell 8: 665-676, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15866158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15866158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15866158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.devcel.2005.02.016" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="59" class="mim-anchor"></a>
|
|
<a id="McBride2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
McBride, K. L., Riley, M. F., Zender, G. A., Fitzgerald-Butt, S. M., Towbin, J. A., Belmont, J. W., Cole, S. E.
|
|
<strong>NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.</strong>
|
|
Hum. Molec. Genet. 17: 2886-2893, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18593716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18593716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18593716[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18593716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddn187" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="60" class="mim-anchor"></a>
|
|
<a id="Milner1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Milner, L. A., Kopan, R., Martin, D. I. K., Bernstein, I. D.
|
|
<strong>A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors.</strong>
|
|
Blood 83: 2057-2062, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7512837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7512837</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7512837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="61" class="mim-anchor"></a>
|
|
<a id="Mizutani2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mizutani, K., Yoon, K., Dang, L., Tokunaga, A., Gaiano, N.
|
|
<strong>Differential Notch signalling distinguishes neural stem cells from intermediate progenitors.</strong>
|
|
Nature 449: 351-355, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721509</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17721509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature06090" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="62" class="mim-anchor"></a>
|
|
<a id="Moellering2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Moellering, R. E., Cornejo, M., Davis, T. N., Del Bianco, C., Aster, J. C., Blacklow, S. C., Kung, A. L., Gilliland, D. G., Verdine, G. L., Bradner, J. E.
|
|
<strong>Direct inhibition of the NOTCH transcription factor complex.</strong>
|
|
Nature 462: 182-188, 2009. Note: Erratum: Nature 463: 384 only, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19907488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19907488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19907488[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19907488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature08543" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="63" class="mim-anchor"></a>
|
|
<a id="Mohamed2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mohamed, S. A., Aherrahrou, Z., Liptau, H., Erasmi, A. W., Hagemann, C., Wrobel, S., Borzym, K., Schunkert, H., Sievers, H. H., Erdmann, J.
|
|
<strong>Novel missense mutations (p.T596M and p.P1797H) in MOTCH1 in patients with bicuspid aortic valve.</strong>
|
|
Biochem. Biophys. Res. Commun. 345: 1460-1465, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16729972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16729972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16729972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.bbrc.2006.05.046" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="64" class="mim-anchor"></a>
|
|
<a id="Moloney2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Moloney, D. J., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K. D., Haltiwanger, R. S., Vogt, T. F.
|
|
<strong>Fringe is a glycosyltransferase that modifies Notch.</strong>
|
|
Nature 406: 369-375, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10935626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10935626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10935626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35019000" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="65" class="mim-anchor"></a>
|
|
<a id="Morales2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Morales, A. V., Yasuda, Y., Ish-Horowicz, D.
|
|
<strong>Periodic lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling.</strong>
|
|
Dev. Cell 3: 63-74, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12110168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1534-5807(02)00211-3" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="66" class="mim-anchor"></a>
|
|
<a id="Moretti2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Moretti, J., Chastagner, P., Liang, C.-C., Cohn, M. A., Israel, A., Brou, C.
|
|
<strong>The ubiquitin-specific protease 12 (USP12) is a negative regulator of Notch signaling acting on Notch receptor trafficking toward degradation.</strong>
|
|
J. Biol. Chem. 287: 29429-29441, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22778262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22778262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22778262[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22778262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M112.366807" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="67" class="mim-anchor"></a>
|
|
<a id="Morimoto2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Morimoto, M., Takahashi, Y., Endo, M., Saga, Y.
|
|
<strong>The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity.</strong>
|
|
Nature 435: 354-359, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15902259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15902259</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15902259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature03591" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="68" class="mim-anchor"></a>
|
|
<a id="Mumm2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mumm, J. S., Schroeter, E. H., Saxena, M. T., Griesemer, A., Tian, X., Pan, D. J., Ray, W. J., Kopan, R.
|
|
<strong>A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.</strong>
|
|
Molec. Cell 5: 197-206, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882062</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1097-2765(00)80416-5" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="69" class="mim-anchor"></a>
|
|
<a id="Murtaugh2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Murtaugh, L. C., Stanger, B. Z., Kwan, K. M., Melton, D. A.
|
|
<strong>Notch signaling controls multiple steps of pancreatic differentiation.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 14920-14925, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657333</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14657333[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14657333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.2436557100" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="70" class="mim-anchor"></a>
|
|
<a id="Nicolas2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H., Dotto, G. P., Radtke, F.
|
|
<strong>Notch1 functions as a tumor suppressor in mouse skin.</strong>
|
|
Nature Genet. 33: 416-421, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12590261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12590261</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12590261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng1099" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="71" class="mim-anchor"></a>
|
|
<a id="Niranjan2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Niranjan, T., Bielesz, B., Gruenwald, A., Ponda, M. P., Kopp, J. B., Thomas, D. B., Susztak, K.
|
|
<strong>The Notch pathway in podocytes plays a role in the development of glomerular disease.</strong>
|
|
Nature Med. 14: 290-298, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18311147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm1731" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="72" class="mim-anchor"></a>
|
|
<a id="Nueda2018" class="mim-anchor"></a>
|
|
<div class="mim-changed mim-change">
|
|
<p class="mim-text-font">
|
|
Nueda, M. L., Gonzalez-Gomez, M. J., Rodriguez-Cano, M. M., Monsalve, E. M., Diaz-Guerra, M. J. M., Sanchez-Solana, B., Laborda, J., Baladron, V.
|
|
<strong>DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate.</strong>
|
|
Sci. Rep. 8: 16923, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30446682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30446682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30446682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30446682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41598-018-35252-3" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="73" class="mim-anchor"></a>
|
|
<a id="Okajima2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Okajima, T., Irvine, K. D.
|
|
<strong>Regulation of Notch signaling by O-linked fucose.</strong>
|
|
Cell 111: 893-904, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526814</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12526814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0092-8674(02)01114-5" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="74" class="mim-anchor"></a>
|
|
<a id="Okuyama2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Okuyama, R., Nguyen, B.-C., Talora, C., Ogawa, E., Tommasi di Vignano, A., Lioumi, M., Chiorino, G., Tagami, H., Woo, M., Dotto, G. P.
|
|
<strong>High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.</strong>
|
|
Dev. Cell 6: 551-562, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15068794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15068794</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15068794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1534-5807(04)00098-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="75" class="mim-anchor"></a>
|
|
<a id="Palomero2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Palomero, T., Lim, W. K., Odom, D. T., Sulis, M. L., Real, P. J., Margolin, A., Barnes, K. C., O'Neil, J., Neuberg, D., Weng, A. P., Aster, J. C., Sigaux, F., Soulier, J., Look, A. T., Young, R. A., Califano, A., Ferrando, A. A.
|
|
<strong>NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 18261-18266, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 104: 4240 only, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17114293[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17114293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.0606108103" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="76" class="mim-anchor"></a>
|
|
<a id="Palomero2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Palomero, T., Sulis, M. L., Cortina, M., Real, P. J., Barnes, K., Ciofani, M., Caparros, E., Buteau, J., Brown, K., Perkins, S. L., Bhagat, G., Agarwal, A. M., Basso, G., Castillo, M., Nagase, S., Cordon-Cardo, C., Parsons, R., Zuniga-Pflucker, J. C., Dominguez, M., Ferrando, A. A.
|
|
<strong>Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.</strong>
|
|
Nature Med. 13: 1203-1210, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17873882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17873882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17873882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17873882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm1636" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="77" class="mim-anchor"></a>
|
|
<a id="Pilz1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Pilz, A., Prohaska, R., Peters, J., Abbott, C.
|
|
<strong>Genetic linkage analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notch1 genes in the region of mouse chromosome 2 homologous to human chromosome 9q.</strong>
|
|
Genomics 21: 104-109, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1994.1230" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="78" class="mim-anchor"></a>
|
|
<a id="Polacheck2017" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Polacheck, W. J., Kutys, M. L., Yang, J., Eyckmans, J., Wu, Y., Vasavada, H., Hirschi, K. K., Chen, C. S.
|
|
<strong>A non-canonical Notch complex regulates adherens junctions and vascular barrier function.</strong>
|
|
Nature 552: 258-262, 2017.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160307[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29160307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature24998" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="79" class="mim-anchor"></a>
|
|
<a id="Puca2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Puca, L., Chastagner, P., Meas-Yedid, V., Israel, A., Brou, C.
|
|
<strong>Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals.</strong>
|
|
J. Cell Sci. 126: 4457-4468, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23886940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23886940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23886940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1242/jcs.130500" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="80" class="mim-anchor"></a>
|
|
<a id="Puente2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordonez, G. R., Villamor, N., Escaramis, G., Jares, P., Bea, S., Gonzalez-Diaz, M., Bassaganyas, L., Baumann, T., and 52 others.
|
|
<strong>Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.</strong>
|
|
Nature 475: 101-105, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21642962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21642962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21642962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21642962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature10113" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="81" class="mim-anchor"></a>
|
|
<a id="Quesada2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Quesada, V., Conde, L., Villamor, N., Ordonez, G. R., Jares, P., Bassaganyas, L., Ramsay, A. J., Bea, S., Pinyol, M., Martinez-Trillos, A., Lopez-Guerra, M., Colomer, D., and 29 others.
|
|
<strong>Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.</strong>
|
|
Nature Genet. 44: 47-52, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22158541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng.1032" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="82" class="mim-anchor"></a>
|
|
<a id="Rangarajan2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rangarajan, A., Talora, C., Okuvama, R., Nicolas, M., Mammucari, C., Oh, H., Aster, J. C., Krishna, S., Metzger, D., Chambon, P., Miele, L., Aguet, M., Radtke, F., Dotto, G. P.
|
|
<strong>Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.</strong>
|
|
EMBO J. 20: 3427-3436, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11432830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11432830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11432830[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11432830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/emboj/20.13.3427" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="83" class="mim-anchor"></a>
|
|
<a id="Raya2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Buscher, D., Koth, C. M., Itoh, T., Morita, M., Raya, R. M., Dubova, I., Bessa, J. G., de la Pompa, J. L., Belmonte, J. C. I.
|
|
<strong>Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos.</strong>
|
|
Genes Dev. 17: 1213-1218, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1101/gad.1084403" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="84" class="mim-anchor"></a>
|
|
<a id="Raya2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I.
|
|
<strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong>
|
|
Nature 427: 121-128, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14712268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14712268</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14712268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature02190" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="85" class="mim-anchor"></a>
|
|
<a id="Real2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Real, P. J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M. L., Barnes, K., Sawai, C., Homminga, I., Meijerink, J., Aifantis, I., Basso, G., Cordon-Cardo, C., Ai, W., Ferrando, A.
|
|
<strong>Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.</strong>
|
|
Nature Med. 15: 50-58, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19098907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19098907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19098907[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19098907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm.1900" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="86" class="mim-anchor"></a>
|
|
<a id="Reya2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L.
|
|
<strong>A role for Wnt signalling in self-renewal of haematopoietic stem cells.</strong>
|
|
Nature 423: 409-414, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature01593" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="87" class="mim-anchor"></a>
|
|
<a id="Riccio2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Riccio, O., van Gijn, M. E., Bezdek, A. C., Pellegrinet, L., van Es, J. H., Zimber-Strobl, U., Strobl, L. J., Honjo, T., Clevers, H., Radtke, F.
|
|
<strong>Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27(Kip1) and p57(Kip2).</strong>
|
|
EMBO Rep. 9: 377-383, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18274550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18274550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18274550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18274550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/embor.2008.7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="88" class="mim-anchor"></a>
|
|
<a id="Rios2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C.
|
|
<strong>Neural crest regulates myogenesis through the transient activation of NOTCH.</strong>
|
|
Nature 473: 532-535, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21572437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21572437</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21572437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature09970" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="89" class="mim-anchor"></a>
|
|
<a id="Roderick2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Roderick, J. E., Gonzalez-Perez, G., Kuksin, C. A., Dongre, A., Roberts, E. R., Srinivasan, J., Andrzejewski, C., Jr., Fauq, A. H., Golde, T. E., Miele, L., Minter, L. M.
|
|
<strong>Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.</strong>
|
|
J. Exp. Med. 210: 1311-1329, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23733784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23733784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23733784[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23733784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20112615" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="90" class="mim-anchor"></a>
|
|
<a id="Rustighi2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., Kaplan, F., Capobianco, A., Pece, S., De Fiore, P. P., Del Sal, G.
|
|
<strong>The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.</strong>
|
|
Nature Cell Biol. 11: 133-142, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19151708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19151708</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19151708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ncb1822" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="91" class="mim-anchor"></a>
|
|
<a id="Sanchez-Solana2011" class="mim-anchor"></a>
|
|
<div class="mim-changed mim-change">
|
|
<p class="mim-text-font">
|
|
Sanchez-Solana, B., Nueda, M. L., Ruvira, M. D., Ruiz-Hidalgo, M. J., Monsalve, E. M., Rivero, S., Garcia-Ramirez, J. J., Diaz-Guerra, M. J., Baladron, V., Laborda, J.
|
|
<strong>The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.</strong>
|
|
Biochim. Biophys. Acta 1813: 1153-1164, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419176</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.bbamcr.2011.03.004" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="92" class="mim-anchor"></a>
|
|
<a id="Schroeter1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schroeter, E. H., Kisslinger, J. A., Kopan, R.
|
|
<strong>Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.</strong>
|
|
Nature 393: 382-386, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620803</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/30756" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="93" class="mim-anchor"></a>
|
|
<a id="Sestan1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sestan, N., Artavanis-Tsakonas, S., Rakic, P.
|
|
<strong>Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling.</strong>
|
|
Science 286: 741-746, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531053</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10531053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.286.5440.741" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="94" class="mim-anchor"></a>
|
|
<a id="Shen2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., Temple, S.
|
|
<strong>Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells.</strong>
|
|
Science 304: 1338-1340, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060285</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15060285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1095505" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="95" class="mim-anchor"></a>
|
|
<a id="Siekmann2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Siekmann, A. F., Lawson, N. D.
|
|
<strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong>
|
|
Nature 445: 781-784, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature05577" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="96" class="mim-anchor"></a>
|
|
<a id="Silva2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S.
|
|
<strong>Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?</strong>
|
|
Am. J. Med. Genet. 158A: 648-651, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22307742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22307742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22307742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.34435" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="97" class="mim-anchor"></a>
|
|
<a id="Sjolund2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sjolund, J., Johansson, M., Manna, S., Norin, C., Pietras, A., Beckman, S., Nilsson, E., Ljungberg, B., Axelson, H.
|
|
<strong>Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo.</strong>
|
|
J. Clin. Invest. 118: 217-228, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18079963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18079963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18079963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18079963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI32086" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="98" class="mim-anchor"></a>
|
|
<a id="Southgate2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C.
|
|
<strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong>
|
|
Circ. Cardiovasc. Genet. 8: 572-581, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25963545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25963545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25963545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/CIRCGENETICS.115.001086" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="99" class="mim-anchor"></a>
|
|
<a id="Sprinzak2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B.
|
|
<strong>Cis-interactions between Notch and Delta generate mutually exclusive signalling states.</strong>
|
|
Nature 465: 86-91, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418862[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20418862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature08959" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="100" class="mim-anchor"></a>
|
|
<a id="Stanger2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stanger, B. Z., Datar, R., Murtaugh, L. C., Melton, D. A.
|
|
<strong>Direct regulation of intestinal fate by Notch.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 12443-12448, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16107537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16107537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16107537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16107537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.0505690102" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="101" class="mim-anchor"></a>
|
|
<a id="Stittrich2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S.
|
|
<strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong>
|
|
Am. J. Hum. Genet. 95: 275-284, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="102" class="mim-anchor"></a>
|
|
<a id="Stransky2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stransky, N., Egloff, A. M., Tward, A. D., Kostic, A. D., Cibulskis, K., Sivachenko, A., Kryukov, G. V., Lawrence, M. S., Sougnez, C., McKenna, A., Shefler, E., Ramos, A. H., and 27 others.
|
|
<strong>The mutational landscape of head and neck squamous cell carcinoma.</strong>
|
|
Science 333: 1157-1160, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21798893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21798893</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21798893[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21798893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1208130" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="103" class="mim-anchor"></a>
|
|
<a id="Struhl1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Struhl, G., Greenwald, I.
|
|
<strong>Presenilin is required for activity and nuclear access of Notch in Drosophila.</strong>
|
|
Nature 398: 522-525, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206646</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10206646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/19091" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="104" class="mim-anchor"></a>
|
|
<a id="Swiatek1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G., Gridley, T.
|
|
<strong>Notch1 is essential for postimplantation development in mice.</strong>
|
|
Genes Dev. 8: 707-719, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7926761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7926761</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7926761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1101/gad.8.6.707" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="105" class="mim-anchor"></a>
|
|
<a id="Takahashi2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Takahashi, Y., Koizumi, K., Takagi, A., Kitajima, S., Inoue, T., Koseki, H., Saga, Y.
|
|
<strong>Mesp2 initiates somite segmentation through the Notch signalling pathway.</strong>
|
|
Nature Genet. 25: 390-396, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932180</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/78062" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="106" class="mim-anchor"></a>
|
|
<a id="Tanigaki2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T.
|
|
<strong>Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.</strong>
|
|
Neuron 29: 45-55, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0896-6273(01)00179-9" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="107" class="mim-anchor"></a>
|
|
<a id="Tanigaki2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tanigaki, K., Tsuji, M., Yamamoto, N., Han, H., Tsukada, J., Inoue, H., Kubo, M., Honjo, T.
|
|
<strong>Regulation of alpha-beta/gamma-delta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling.</strong>
|
|
Immunity 20: 611-622, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15142529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15142529</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15142529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1074-7613(04)00109-8" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="108" class="mim-anchor"></a>
|
|
<a id="Taniguchi2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M.
|
|
<strong>A gp130-Src-YAP module links inflammation to epithelial regeneration.</strong>
|
|
Nature 519: 57-62, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25731159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25731159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25731159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25731159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature14228" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="109" class="mim-anchor"></a>
|
|
<a id="van Es2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van Es, J. H., van Gijn, M. E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D. J., Radtke, F., Clevers, H.
|
|
<strong>Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. (Letter)</strong>
|
|
Nature 435: 959-963, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15959515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15959515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15959515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature03659" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="110" class="mim-anchor"></a>
|
|
<a id="Vandersteen2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vandersteen, A. M., Dixon, J. W.
|
|
<strong>Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.</strong>
|
|
Clin. Dysmorph. 20: 210-213, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21785343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21785343</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21785343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1097/MCD.0b013e32834964d1" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="111" class="mim-anchor"></a>
|
|
<a id="Vauclair2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vauclair, S., Majo, F., Durham, A.-D., Ghyselinck, N. B., Barrandon, Y., Radtke, F.
|
|
<strong>Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism.</strong>
|
|
Dev. Cell 13: 242-253, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17681135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17681135</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17681135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.devcel.2007.06.012" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="112" class="mim-anchor"></a>
|
|
<a id="Vilimas2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vilimas, T., Mascarenhas, J., Palomero, T., Mandal, M., Buonamici, S., Meng, F., Thompson, B., Spaulding, C., Macaroun, S., Alegre, M.-L., Kee, B. L., Ferrando, A., Miele, L., Aifantis, I.
|
|
<strong>Targeting the NF-kappa-B signaling pathway in Notch1-induced T-cell leukemia.</strong>
|
|
Nature Med. 13: 70-77, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173050</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17173050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm1524" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="113" class="mim-anchor"></a>
|
|
<a id="Visan2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Visan, I., Tan, J. B., Yuan, J. S., Harper, J. A., Koch, U., Guidos, C. J.
|
|
<strong>Regulation of T lymphopoiesis by Notch1 and lunatic fringe-mediated competition for intrathymic niches.</strong>
|
|
Nature Immun. 7: 634-643, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16699526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16699526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16699526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ni1345" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="114" class="mim-anchor"></a>
|
|
<a id="Wang2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, J., Shelly, L., Miele, L., Boykins, R., Norcross, M. A., Guan, E.
|
|
<strong>Human Notch-1 inhibits NF-kappa-B activity in the nucleus through a direct interaction involving a novel domain.</strong>
|
|
J. Immun. 167: 289-295, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11418662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11418662</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11418662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.4049/jimmunol.167.1.289" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="115" class="mim-anchor"></a>
|
|
<a id="Weaver2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Weaver, K. L., Alves-Guerra, M.-C., Jin, K., Wang, Z., Han, X., Ranganathan, P., Zhu, X., DaSilva, T., Liu, W., Ratti, F., Demarest, R. M., Tzimas, C., Rice, M., Vasquez-Del Carpio, R., Dahmane, N., Robbins, D. J., Capobianco, A. J.
|
|
<strong>NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.</strong>
|
|
Cancer Res. 74: 4741-4751, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25038227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1158/0008-5472.CAN-14-1547" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="116" class="mim-anchor"></a>
|
|
<a id="Weijzen2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C., Hahn, W. C., Rudolf, M., Siziopikou, K., Kast, W. M., Miele, L.
|
|
<strong>Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.</strong>
|
|
Nature Med. 8: 979-986, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12185362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12185362</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12185362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm754" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="117" class="mim-anchor"></a>
|
|
<a id="Weng2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. P., IV, Silverman, L. B., Sanchez-Irizarry, C., Blacklow, S. C., Look, A. T., Aster, J. C.
|
|
<strong>Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.</strong>
|
|
Science 306: 269-271, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1102160" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="118" class="mim-anchor"></a>
|
|
<a id="Wu2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others.
|
|
<strong>Therapeutic antibody targeting of individual Notch receptors.</strong>
|
|
Nature 464: 1052-1057, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393564</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20393564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature08878" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="119" class="mim-anchor"></a>
|
|
<a id="Yamamoto2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yamamoto, S., Charng, W.-L., Rana, N. A., Kakuda, S., Jaiswal, M., Bayat, V., Xiong, B., Zhang, K., Sandoval, H., David, G., Wang, H., Haltiwanger, R. S., Bellen, H. J.
|
|
<strong>A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.</strong>
|
|
Science 338: 1229-1232, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23197537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23197537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23197537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23197537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1228745" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="120" class="mim-anchor"></a>
|
|
<a id="Yang2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yang, G., Zhou, R., Zhou, Q., Guo, X., Yan, C., Ke, M., Lei, J., Shi, Y.
|
|
<strong>Structural basis of Notch recognition by human gamma-secretase.</strong>
|
|
Nature 565: 192-197, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30598546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30598546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30598546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41586-018-0813-8" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="121" class="mim-anchor"></a>
|
|
<a id="Ye1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ye, Y., Lukinova, N., Fortini, M. E.
|
|
<strong>Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants.</strong>
|
|
Nature 398: 525-529, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206647</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10206647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/19096" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="122" class="mim-anchor"></a>
|
|
<a id="Yokoyama2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., Fujii, Y., Yoshida, K., and 28 others.
|
|
<strong>Age-related remodelling of esophageal epithelia by mutated cancer drivers.</strong>
|
|
Nature 565: 312-317, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30602793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30602793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30602793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41586-018-0811-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="123" class="mim-anchor"></a>
|
|
<a id="Yu2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yu, H., Saura, C. A., Choi, S.-Y., Sun, L. D., Yang, X., Handler, M., Kawarabayashi, T., Younkin, L., Fedeles, B., Wilson, M. A., Younkin, S., Kandel, E. R., Kirkwood, A., Shen, J.
|
|
<strong>APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.</strong>
|
|
Neuron 31: 713-726, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11567612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11567612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11567612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0896-6273(01)00417-2" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="contributors" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="mim-text-font">
|
|
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Bao Lige - updated : 03/06/2025
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Bao Lige - updated : 03/01/2022<br>Ada Hamosh - updated : 01/25/2021<br>Ada Hamosh - updated : 09/16/2020<br>Ada Hamosh - updated : 09/27/2019<br>Ada Hamosh - updated : 08/12/2019<br>Marla J. F. O'Neill - updated : 07/08/2019<br>Ada Hamosh - updated : 03/07/2019<br>Ada Hamosh - updated : 10/19/2018<br>Ada Hamosh - updated : 09/06/2018<br>Ada Hamosh - updated : 02/12/2018<br>Ada Hamosh - updated : 08/11/2017<br>Patricia A. Hartz - updated : 04/27/2017<br>Sarah M. Robbins - updated : 02/10/2017<br>Marla J. F. O'Neill - updated : 1/30/2016<br>Ada Hamosh - updated : 6/3/2015<br>Ada Hamosh - updated : 3/11/2015<br>Ada Hamosh - updated : 11/10/2014<br>Marla J. F. O'Neill - updated : 9/24/2014<br>Paul J. Converse - updated : 7/2/2014<br>Ada Hamosh - updated : 1/31/2014<br>Ada Hamosh - updated : 1/15/2014<br>Ada Hamosh - updated : 1/14/2013<br>Paul J. Converse - updated : 7/16/2012<br>Patricia A. Hartz - updated : 6/8/2012<br>Marla J. F. O'Neill - updated : 2/14/2012<br>Cassandra L. Kniffin - updated : 1/25/2012<br>Ada Hamosh - updated : 9/21/2011<br>Ada Hamosh - updated : 6/22/2011<br>Ada Hamosh - updated : 5/23/2011<br>Ada Hamosh - updated : 9/29/2010<br>Ada Hamosh - updated : 6/8/2010<br>Ada Hamosh - updated : 5/27/2010<br>Ada Hamosh - updated : 2/18/2010<br>Patricia A. Hartz - updated : 1/20/2010<br>Ada Hamosh - updated : 12/29/2009<br>George E. Tiller - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 2/12/2009<br>Ada Hamosh - updated : 8/13/2008<br>Patricia A. Hartz - updated : 5/29/2008<br>Patricia A. Hartz - updated : 3/13/2008<br>Ada Hamosh - updated : 1/10/2008<br>Cassandra L. Kniffin - updated : 10/25/2007<br>Patricia A. Hartz - updated : 9/21/2007<br>Patricia A. Hartz - updated : 7/10/2007<br>Ada Hamosh - updated : 7/5/2007<br>Ada Hamosh - updated : 6/26/2007<br>Paul J. Converse - updated : 6/7/2007<br>Patricia A. Hartz - updated : 5/7/2007<br>Marla J. F. O'Neill - updated : 2/26/2007<br>Patricia A. Hartz - updated : 1/26/2007<br>Ada Hamosh - updated : 1/23/2007<br>Paul J. Converse - updated : 12/20/2006<br>Paul J. Converse - updated : 6/20/2006<br>Patricia A. Hartz - updated : 1/26/2006<br>Marla J. F. O'Neill - updated : 12/16/2005<br>Patricia A. Hartz - updated : 12/13/2005<br>Paul J. Converse - updated : 10/20/2005<br>Matthew B. Gross - reorganized : 10/3/2005<br>Joanna S. Amberger - updated : 10/3/2005<br>Patricia A. Hartz - updated : 9/20/2005<br>Ada Hamosh - updated : 9/7/2005<br>Patricia A. Hartz - updated : 6/30/2005<br>Ada Hamosh - updated : 6/3/2005<br>Ada Hamosh - updated : 2/2/2005<br>Ada Hamosh - updated : 6/8/2004<br>Patricia A. Hartz - updated : 5/12/2004<br>Ada Hamosh - updated : 1/22/2004<br>Ada Hamosh - updated : 12/3/2003<br>Cassandra L. Kniffin - updated : 5/16/2003<br>Ada Hamosh - updated : 5/6/2003<br>Deborah L. Stone - updated : 3/26/2003<br>Dawn Watkins-Chow - updated : 2/27/2003<br>Victor A. McKusick - updated : 2/20/2003<br>Stylianos E. Antonarakis - updated : 1/17/2003<br>Ada Hamosh - updated : 1/17/2003<br>Ada Hamosh - updated : 9/30/2002<br>Dawn Watkins-Chow - updated : 2/14/2002<br>Paul J. Converse - updated : 11/26/2001<br>Victor A. McKusick - updated : 7/6/2001<br>Ada Hamosh - updated : 4/26/2001<br>Ada Hamosh - updated : 11/30/2000<br>Ada Hamosh - updated : 8/2/2000<br>Ada Hamosh - updated : 7/27/2000<br>Patti M. Sherman - updated : 7/13/2000<br>Ada Hamosh - updated : 6/20/2000<br>Stylianos E. Antonarakis - updated : 3/27/2000<br>Ada Hamosh - updated : 10/20/1999<br>Victor A. McKusick - updated : 4/6/1999<br>Moyra Smith - updated : 3/28/1996
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 10/28/1991
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
mgross : 03/06/2025
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
alopez : 08/04/2022<br>carol : 03/02/2022<br>mgross : 03/01/2022<br>mgross : 02/09/2021<br>mgross : 01/25/2021<br>alopez : 09/16/2020<br>carol : 02/05/2020<br>alopez : 09/27/2019<br>alopez : 08/12/2019<br>alopez : 08/12/2019<br>carol : 08/07/2019<br>carol : 07/24/2019<br>carol : 07/08/2019<br>alopez : 03/07/2019<br>alopez : 12/21/2018<br>carol : 11/26/2018<br>alopez : 10/19/2018<br>alopez : 09/06/2018<br>carol : 02/13/2018<br>alopez : 02/12/2018<br>carol : 10/05/2017<br>alopez : 08/11/2017<br>carol : 04/27/2017<br>carol : 04/19/2017<br>mgross : 02/10/2017<br>alopez : 12/19/2016<br>carol : 09/06/2016<br>carol : 03/16/2016<br>carol : 1/30/2016<br>alopez : 6/3/2015<br>alopez : 3/11/2015<br>alopez : 11/10/2014<br>carol : 9/29/2014<br>carol : 9/25/2014<br>mcolton : 9/24/2014<br>mgross : 7/2/2014<br>mcolton : 7/2/2014<br>alopez : 1/31/2014<br>alopez : 1/15/2014<br>mgross : 10/7/2013<br>alopez : 1/16/2013<br>terry : 1/14/2013<br>terry : 12/20/2012<br>terry : 12/19/2012<br>carol : 9/17/2012<br>carol : 9/17/2012<br>mgross : 7/20/2012<br>terry : 7/16/2012<br>mgross : 6/8/2012<br>terry : 6/7/2012<br>alopez : 4/25/2012<br>alopez : 4/11/2012<br>alopez : 3/7/2012<br>carol : 2/15/2012<br>terry : 2/14/2012<br>carol : 2/1/2012<br>ckniffin : 1/25/2012<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>terry : 9/21/2011<br>alopez : 6/27/2011<br>terry : 6/22/2011<br>alopez : 5/24/2011<br>terry : 5/23/2011<br>alopez : 10/4/2010<br>terry : 9/29/2010<br>terry : 9/9/2010<br>alopez : 6/8/2010<br>terry : 6/8/2010<br>alopez : 6/1/2010<br>terry : 5/27/2010<br>terry : 5/27/2010<br>terry : 2/18/2010<br>mgross : 1/20/2010<br>alopez : 1/5/2010<br>terry : 12/29/2009<br>wwang : 10/20/2009<br>terry : 10/15/2009<br>wwang : 3/4/2009<br>ckniffin : 2/12/2009<br>alopez : 8/20/2008<br>terry : 8/13/2008<br>mgross : 6/3/2008<br>terry : 5/29/2008<br>mgross : 3/18/2008<br>terry : 3/13/2008<br>ckniffin : 2/5/2008<br>alopez : 1/28/2008<br>terry : 1/10/2008<br>wwang : 11/5/2007<br>ckniffin : 10/25/2007<br>mgross : 9/27/2007<br>terry : 9/21/2007<br>terry : 7/10/2007<br>alopez : 7/5/2007<br>alopez : 7/2/2007<br>terry : 6/26/2007<br>mgross : 6/7/2007<br>mgross : 6/7/2007<br>wwang : 5/7/2007<br>wwang : 2/26/2007<br>mgross : 1/26/2007<br>mgross : 1/26/2007<br>alopez : 1/25/2007<br>terry : 1/23/2007<br>mgross : 12/20/2006<br>carol : 8/16/2006<br>alopez : 8/3/2006<br>terry : 8/1/2006<br>mgross : 6/20/2006<br>mgross : 2/2/2006<br>terry : 1/26/2006<br>wwang : 12/16/2005<br>wwang : 12/13/2005<br>mgross : 10/20/2005<br>mgross : 10/20/2005<br>mgross : 10/4/2005<br>mgross : 10/3/2005<br>mgross : 10/3/2005<br>mgross : 10/3/2005<br>joanna : 10/3/2005<br>wwang : 9/21/2005<br>wwang : 9/20/2005<br>alopez : 9/14/2005<br>alopez : 9/14/2005<br>terry : 9/7/2005<br>wwang : 6/30/2005<br>wwang : 6/7/2005<br>wwang : 6/3/2005<br>alopez : 2/23/2005<br>terry : 2/2/2005<br>terry : 7/1/2004<br>alopez : 6/9/2004<br>terry : 6/8/2004<br>mgross : 5/13/2004<br>terry : 5/12/2004<br>alopez : 1/22/2004<br>terry : 1/22/2004<br>alopez : 12/8/2003<br>terry : 12/3/2003<br>alopez : 5/28/2003<br>cwells : 5/22/2003<br>ckniffin : 5/16/2003<br>alopez : 5/6/2003<br>alopez : 5/6/2003<br>terry : 5/6/2003<br>carol : 3/26/2003<br>carol : 3/26/2003<br>carol : 3/26/2003<br>tkritzer : 3/24/2003<br>tkritzer : 3/24/2003<br>alopez : 3/12/2003<br>carol : 3/4/2003<br>tkritzer : 2/27/2003<br>tkritzer : 2/27/2003<br>alopez : 2/21/2003<br>terry : 2/20/2003<br>mgross : 1/17/2003<br>alopez : 1/17/2003<br>terry : 1/17/2003<br>terry : 1/17/2003<br>alopez : 10/1/2002<br>tkritzer : 9/30/2002<br>carol : 3/1/2002<br>terry : 2/14/2002<br>mgross : 12/5/2001<br>terry : 11/26/2001<br>alopez : 7/16/2001<br>mcapotos : 7/6/2001<br>mcapotos : 5/7/2001<br>mcapotos : 5/3/2001<br>terry : 4/26/2001<br>mcapotos : 2/13/2001<br>carol : 12/1/2000<br>terry : 11/30/2000<br>terry : 10/6/2000<br>mgross : 9/15/2000<br>mcapotos : 8/7/2000<br>alopez : 8/2/2000<br>alopez : 7/27/2000<br>alopez : 7/27/2000<br>mcapotos : 7/21/2000<br>psherman : 7/13/2000<br>alopez : 6/21/2000<br>carol : 6/20/2000<br>mgross : 3/27/2000<br>alopez : 10/23/1999<br>terry : 10/20/1999<br>alopez : 4/7/1999<br>carol : 4/6/1999<br>mark : 1/19/1998<br>mark : 8/5/1996<br>mark : 4/25/1996<br>mark : 3/28/1996<br>mark : 3/28/1996<br>mark : 2/7/1996<br>mimadm : 6/7/1995<br>carol : 1/5/1995<br>davew : 6/9/1994<br>jason : 6/7/1994<br>carol : 7/1/1993<br>supermim : 3/16/1992
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 190198
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
NOTCH RECEPTOR 1; NOTCH1
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
NOTCH, DROSOPHILA, HOMOLOG OF, 1<br />
|
|
TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: NOTCH1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 9q34.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 9:136,494,433-136,546,048 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
9q34.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Adams-Oliver syndrome 5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616028
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Aortic valve disease 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
109730
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Notch proteins are single-pass transmembrane receptors that regulate cell fate decisions during development. The Notch family includes 4 receptors, NOTCH1, NOTCH2 (600275), NOTCH3 (600276), and NOTCH4 (164951), whose ligands include JAG1 (601920), JAG2 (602570), DLL1 (606582), DLL3 (602768), and DLL4 (605185). All of the receptors have an extracellular domain containing multiple epidermal growth factor (EGF; 131530)-like repeats and an intracellular region containing the RAM domain, ankyrin repeats, and a C-terminal PEST domain (Das et al., 2004). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In a translocation t(7;9)(q34;q34.3) found in a case of acute T-cell lymphoblastic leukemia, Ellisen et al. (1991) found that the locus on chromosome 9 contains a gene, NOTCH1, highly homologous to the Drosophila gene Notch. Transcripts of the human NOTCH1 gene, which Ellisen et al. (1991) called TAN1, and its murine counterpart were demonstrated in many normal human fetal and adult mouse tissues, but were most abundant in lymphoid tissues. </p><p>Milner et al. (1994) found that at least 1 Notch homolog was expressed in human bone marrow CD34 (142230)-positive cells, a population enriched for hematopoietic precursors. On the basis of these findings, they suggested that members of the Notch family, including TAN1, may be involved in mediating cell-fate decisions during hematopoiesis. </p><p>In addition to the EGF-like repeats in the extracellular region of Notch, known motifs in the intracellular region of Notch include a nuclear localization signal (NLS) and a RAM motif, 6 ankyrin/CDC10 repeats, a second NLS, PEST sequences, and a glutamine-rich domain. By luciferase and Western blot analysis, Wang et al. (2001) determined that a highly conserved 109-amino acid region (residues 1773-1881) N-terminal of the 6 ankyrin repeats of intracellular NOTCH1 inhibits NFKB (164011) DNA binding and gene expression. They termed this protein-protein interaction domain, which includes an NLS, the NFKB-binding domain. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Luca et al. (2015) determined the crystal structure of the interacting regions of the NOTCH1-DLL4 complex at 2.3-angstrom resolution. The complex reveals a 2-site, antiparallel binding orientation assisted by NOTCH1 O-linked glycosylation. NOTCH1 EGF-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag2 (DSL) domain and module at the N terminus of Notch ligand (MNNL) domains, respectively. Threonine and serine residues on NOTCH1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific and essential contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in NOTCH1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways. </p><p>Luca et al. (2017) determined the 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jag1. The structure revealed a binding interface that extends approximately 120 angstroms along 5 consecutive domains of each protein. O-Linked fucose modifications on Notch1 EGF domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Dll4 ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. This mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
Yang et al. (2019) reported the cryoelectron microscopy structure of human gamma-secretase (see PS1, 104311) in complex with a Notch fragment at a resolution of 2.7 angstroms. The transmembrane helix of Notch is surrounded by 3 transmembrane domains of PS1, and the carboxyl-terminal beta-strand of the Notch fragment forms a beta-sheet with 2 substrate-induced beta-strands of PS1 on the intracellular side. Formation of the hybrid beta-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. Yang et al. (2019) concluded that these features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by gamma-secretase. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By analysis of somatic cell hybrids and FISH, Larsson et al. (1994) mapped the NOTCH1 gene to chromosome 9q34. They mapped the NOTCH2 and NOTCH3 genes to chromosomes 1p13-p11 and 19p13.2-p13.1, respectively. </p><p>Del Amo et al. (1993) and Pilz et al. (1994) demonstrated that the mouse Notch1 gene maps to chromosome 2. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Notch Ligand Selectivity</em></strong></p><p>
|
|
To identify the specific domains in the Notch receptor responsible for ligand selectivity, Yamamoto et al. (2012) performed genetic screens in Drosophila and isolated a mutation, Notch(Jigsaw), that affects Serrate- but not Delta-dependent signaling. Notch(Jigsaw) carries a missense mutation in epidermal growth factor repeat-8 (Egfr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 (600275) results in defects in signaling of a mammalian Serrate homolog, Jagged1 (601920). Yamamoto et al. (2012) concluded that an evolutionarily conserved valine in Egfr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events. </p><p><strong><em>Processing of Notch</em></strong></p><p>
|
|
There is proteolytic processing in maturation and activation of NOTCH1 (Chan and Jan, 1998). Maturation of the NOTCH1 protein is mediated by a furin (136950)-like convertase within the secretory pathway; cleavage occurs at an extracellular site, called site 1 (S1), after the recognition sequence RQRR (Logeat et al., 1998). The resultant polypeptides associate as an intramolecular heterodimer thought to be the only form of the NOTCH1 receptor found on the cell surface (Logeat et al., 1998). Activation of NOTCH1 involves cleavage between gly1743 and val1744 (termed site 3, or S3) (Schroeter et al., 1998). S3 cleavage serves to release the NOTCH1 intracellular domain (NICD) from the membrane. NICD then translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL family members (RBPSUH (147183), 'suppressor of hairless,' and LAG1) (Jarriault et al., 1995). S3 processing occurs only in response to ligand binding. Mumm et al. (2000) demonstrated that ligand binding facilitates cleavage at another site, which they named S2, within the extracellular juxtamembrane region. This serves to release ectodomain repression of NICD production. S2 cleavage occurs between ala1710 and val1711, approximately 12 amino acids outside the transmembrane domain. Cleavage at S2 generates a transient intermediate peptide termed NEXT (Notch extracellular truncation). NEXT accumulates when NICD production is blocked by point mutations or gamma-secretase inhibitors, or by loss of presenilin-1 (PSEN1; 104311), and inhibition of NEXT eliminates NICD production. These data demonstrated that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to NOTCH1 activation. </p><p>Brou et al. (2000) purified the gamma-secretase-like activity that accounts for the S2 cleavage in vitro and showed that it is due to tumor necrosis factor-converting enzyme, or TACE (ADAM17; 603639), a member of the ADAM family of metalloproteases. Furthermore, experiments on TACE -/- bone marrow-derived monocytic precursor cells suggested that TACE plays a prominent role in the activation of the Notch pathway. </p><p><strong><em>Role of Presenilins in Notch Processing</em></strong></p><p>
|
|
The connection between Notch and the presenilins (PSEN1, 104311; PSEN2, 600759) was indicated by the work of De Strooper et al. (1999), Struhl and Greenwald (1999), and Ye et al. (1999). Struhl and Greenwald (1999) and Ye et al. (1999) showed that loss-of-function mutations in the Drosophila presenilin gene exhibited a lethal Notch-like phenotype. De Strooper et al. (1999) investigated the effect of presenilin on Notch processing by introducing a constitutively active form of murine Notch1 into fibroblasts derived from presenilin-1 knockout mice. This construct had previously been used to identify a proteolytic cleavage site located in or near the transmembrane region of Notch. All 3 groups concluded that presenilin is required for release of the intracellular domain of Notch from the plasma membrane. The significance of this work was discussed by Hardy and Israel (1999). By analyzing a Psen1 conditional knockout mouse, Yu et al. (2001) concluded that inactivation of Psen1 function in the adult cerebral cortex does not affect expression of Notch downstream target genes. </p><p>A major therapeutic target in the search for a cure for Alzheimer disease (104300) is gamma-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of A-beta-42 peptides, precipitates of which are thought to cause Alzheimer disease. Presenilins are thought to contain the active site for gamma-secretase. Gamma-secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This fact led to concern that therapeutic inhibition of gamma-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Hadland et al. (2001) showed that application of gamma-secretase inhibitors to fetal thymus organ cultures interfered with T-cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8- state to an intermediate CD4+/CD8+ double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ single-positive cells. These results demonstrated that pharmacologic gamma-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and presented a system in which rapid evaluation of gamma-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed. </p><p><strong><em>Modulation of Notch Signaling by Fringe Proteins</em></strong></p><p>
|
|
Notch receptors function in highly conserved intercellular signaling pathways that direct cell-fate decisions, proliferation, and apoptosis in metazoans. Fringe proteins, such as 'lunatic fringe' (LFNG; 602576), can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Moloney et al. (2000) established the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta-1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor (EGF; 131530)-like sequence repeats of Notch. Moloney et al. (2000) obtained biologic evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signaling by using coculture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The authors stated that the posttranslational modification of Notch by Fringe represents a striking example of modulation of a signaling event by differential receptor glycosylation and identifies a mechanism they considered likely to be relevant to other signaling pathways. </p><p>Studying Drosophila, Bruckner et al. (2000) showed that Fringe acts in the Golgi as a glycosyltransferase enzyme that modifies the EGF modules of Notch and alters the ability of Notch to bind its ligand Delta (602768). The authors demonstrated that Fringe catalyzes the addition of N-acetylglucosamine to fucose, which is consistent with a role in the elongation of O-linked fucose O-glycosylation that is associated with EGF repeats. They suggested that cell type-specific modification of glycosylation may provide a general mechanism to regulate ligand-receptor interactions in vivo. </p><p>Visan et al. (2006) found that developmental stage-specific expression of Lfng was required for coordinating access of mouse T-cell progenitors to intrathymic niches supporting Notch1-dependent phases of T-cell development. Progenitors lacking Lfng generated few thymocytes in competitive assays, whereas overexpression of Lfng resulted in 'supercompetitive' thymocytes that showed enhanced binding to delta-like ligands (e.g., DLL1) and blocked T lymphopoiesis by normal progenitors. Visan et al. (2006) proposed that LFNG and NOTCH1 control of progenitor competition for cortical niches that suppress the B-cell potential of progenitors is important in regulation of thymus size. </p><p><strong><em>Modulation of Notch Signaling by POFUT1</em></strong></p><p>
|
|
Notch and its ligands are modified by POFUT1 (607491), which attaches fucose to a serine or threonine within EGF domains. Using RNA interference to decrease Pofut1 expression in Drosophila, Okajima and Irvine (2002) demonstrated that O-linked fucose is positively required for Notch signaling, including both fringe-dependent and fringe-independent processes. The requirement for Pofut1 was found to be cell autonomous, in the signal-receiving cell, and upstream of Notch activation. The transcription of Pofut1 was developmentally regulated, and overexpression of Pofut1 inhibited Notch signaling. The authors concluded that POFUT1 is a core component of the Notch pathway that is required for the activation of Notch by its ligands and whose regulation may contribute to the pattern of Notch activation during development. </p><p><strong><em>Modulation of Notch Signaling by PIN1</em></strong></p><p>
|
|
Rustighi et al. (2009) showed that PIN1 (601052) enhanced NOTCH1 signaling in human cancer cell lines through its prolyl-isomerase activity. PIN1 interacted directly with phosphorylated NOTCH1 and enhanced NOTCH1 cleavage by gamma-secretase. Accordingly, PIN1 contributed to NOTCH1 transforming properties both in vitro and in vivo. NOTCH1 in turn upregulated PIN1, thus establishing a positive feedback loop that amplified NOTCH1 signaling. </p><p><strong><em>Modulation of Notch Signaling by USP10</em></strong></p><p>
|
|
Lim et al. (2019) found that human USP10 (609818) interacted with NICD to slow ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Inactivation of USP10 reduced NICD abundance and stability and diminished Notch-induced target gene expression in human endothelial cells. In mice, loss of endothelial Usp10 increased vessel sprouting and partially restored patterning defects caused by ectopic expression of NICD. The authors concluded that USP10 functions as an NICD deubiquitinase that modulates endothelial Notch responses during angiogenic sprouting. </p><p><strong><em>Notch Signaling Pathway</em></strong></p><p>
|
|
Artavanis-Tsakonas et al. (1995) reviewed the Notch signaling pathway. </p><p>Axelrod et al. (1996) reported that the Drosophila Dishevelled gene (601225), which encodes a component of the Wingless (164820) signaling pathway, interacts antagonistically with Notch and one of its ligands, Delta. A direct physical interaction between Dishevelled and the Notch C terminus suggested to the authors that Dishevelled blocks Notch signaling directly and provides a molecular mechanism for the inhibitory crosstalk observed between the Notch and Wingless signaling pathways. </p><p>Rangarajan et al. (2001) found that Notch1 activation induced p21 (CDKN1A; 116899) in differentiating mouse keratinocytes, and the induction was associated with the targeting of Rbpjk (RBPSUH; 147183) to the p21 promoter. Mammucari et al. (2005) showed that Notch1 also activated p21 through a calcineurin (see 114105)-dependent mechanism acting on the p21 TATA box-proximal region. Notch signaling through the calcineurin/NFAT (see 600490) pathway also involved calcipressin (see 602917) and Hes1. </p><p>Weijzen et al. (2002) demonstrated that oncogenic Ras (190020) activates Notch signaling and that wildtype Notch1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch1, and upregulates Notch1 ligand Delta1 (606582) and also presenilin-1 (104311), a protein involved in Notch processing, through a p38 (600289)-mediated pathway. Weijzen et al. (2002) concluded that their observations placed Notch signaling among key downstream effectors of oncogenic Ras. </p><p>Balint et al. (2005) demonstrated that the NOTCH1 pathway was activated in melanoma (see 155600) specimens compared to nevus specimens. Blocking NOTCH signaling suppressed primary melanoma cell growth, whereas constitutive activation of the NOTCH1 pathway enhanced primary melanoma cell growth both in vitro and in vivo, but NOTCH1 had little effect on metastatic melanoma cells. Activation of NOTCH1 signaling enabled primary melanoma cells to gain metastatic capability. The oncogenic effect of NOTCH1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following NOTCH1 activation; inhibiting beta-catenin expression reversed NOTCH1-enhanced tumor growth and metastasis. Balint et al. (2005) suggested that there is a beta-catenin-dependent, stage-specific role for NOTCH1 signaling in promoting the progression of primary melanoma. </p><p>Using microarray studies of the mouse presomitic mesoderm transcriptome, Dequeant et al. (2006) demonstrated that the oscillator associated with this process, the segmentation clock, drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the Notch-fibroblast growth factor (FGF) and Wnt (see 164820) pathways during each cycle suggested that coordinated regulation of these 3 pathways underlies the clock oscillator. Dequeant et al. (2006) collected presomitic mesoderm samples from 40 mouse embryos ranging from 19 to 23 somites and used their Lfng (602576) expression patterns as a proxy to select 17 samples covering an entire oscillation cycle. Six of the 8 known mouse cyclic genes, Hes1 (139605), Hes5 (607348), Hey1 (602953), Lfng, Axin2 (604025), and Nkd1 (607851), were identified with periods of 94, 102, 112, 81, 102, and 112 minutes, respectively. Two clusters were identified. One cluster contains the known cyclic genes of the Notch pathway: Hes1, Hes5, and Hey1, as well as Id1 (600349). This cluster also contains Nrarp (619987), a direct target of Notch signaling. In the same cluster as the Notch pathway were members of the FGF-MAPK pathway, including Spry2 (602466) and Dusp6 (602748). The second cluster of periodic genes contained genes cycling in opposite phase to the Notch-FGF cluster; in this cluster were a majority of the cyclic genes associated with Wnt signaling, including Dkk1 (605189), cMyc (190080), Axin2, Sp5 (609391), and Tnfrsf19 (606122). </p><p>By examining gene expression profiles, Palomero et al. (2006) found that NOTCH and MYC (190080) regulate 2 interconnected transcriptional programs containing common target genes that regulate cell growth in primary human T-cell lymphoblastic leukemias. </p><p>In studies involving bone marrow progenitor cells and T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Vilimas et al. (2007) found that constitutively active NOTCH1 activated the NFKB pathway transcriptionally and via the IKK complex (see 600664), thereby causing increased expression of NFKB target genes. The NFKB pathway was highly active in establishing human T-ALL, and inhibition of the pathway efficiently restricted tumor growth both in vitro and in vivo. Vilimas et al. (2007) concluded that NFKB is one of the major mediators of NOTCH1-induced transformation. </p><p>Lefort et al. (2007) found that NOTCH1 protein and mRNA were reduced in a panel of skin and oral squamous cell carcinoma (SCC) cell lines and in a panel of skin SCCs relative to normal epidermis controls. They found that inhibition of Notch signaling in human primary keratinocytes suppressed keratinocyte commitment to differentiation, expanded a cell population with stem cell potential, and promoted aggressive SCC formation. Expression of NOTCH1 in human keratinocytes was under the control of P53 (TP53; 191170), and NOTCH1 suppressed tumor formation through negative regulation of ROCK1 (601702)/ROCK2 (604002) and MRCK-alpha (CDC42BPA; 603412), which are effectors of small RHO GTPases (see ARHA; 165390) implicated in neoplastic progression. </p><p>Some T-ALL cells show resistance to gamma-secretase inhibitors, which act by blocking NOTCH1 activation. Using microarray analysis, Palomero et al. (2007) identified PTEN (601728) as the gene most consistently downregulated in gamma-secretase inhibitor-resistant T-cell lines. Further analysis showed that these resistant cell lines had truncating mutations in the PTEN gene. Loss of PTEN function resulted in aberrant activation of the PI3-kinase (171834)-AKT (164730) signaling pathway, which induced resistance to gamma-secretase inhibitors. Studies in normal mouse thymocytes indicated that Notch1 regulated Pten expression downstream. Notch signaling and the PI3-kinase-AKT pathway acted synergistically in a Drosophila model of Notch-induced tumorigenesis. The findings demonstrated that NOTCH1 controls a transcriptional network that regulates PTEN expression and PI3-kinase-AKT signaling activity in normal thymocytes and leukemic T cells. </p><p>Mizutani et al. (2007) showed that both neural stem cells and intermediate neural progenitors respond to Notch receptor activation, but that neural stem cells signal through the canonic Notch effector C-promoter binding factor (CBF1; 147183), whereas intermediate neural progenitors have attenuated CBF1 signaling. Furthermore, whereas knockdown of CBF1 promotes the conversion of neural stem cells to intermediate neural progenitors, activation of CBF1 is insufficient to convert intermediate neural progenitors back to neural stem cells. Using both transgenic and transient in vivo reporter assays, Mizutani et al. (2007) showed that neural stem cells and intermediate neural progenitors coexist in the telencephalic ventricular zone of mice and that they can be prospectively separated on the basis of CBF1 activity. Furthermore, using in vivo transplantation, they showed that whereas neural stem cells generate neurons, astrocytes, and oligodendrocytes at similar frequencies, intermediate neural progenitors are predominantly neurogenic. Mizutani et al. (2007) concluded that their study, together with previous work on hematopoietic stem cells, suggested the use or blockade of the CBF1 cascade downstream of Notch as a general feature distinguishing stem cells from more limited progenitors in a variety of tissues. </p><p>Sjolund et al. (2008) found that Notch signaling was constitutively active in human clear cell renal cell carcinoma (CCRCC) cell lines. Blocking Notch signaling attenuated proliferation and restrained anchorage-independent growth of CCRCC cell lines and inhibited growth of xenotransplanted CCRCC cells in nude mice. Small interfering RNA against various Notch receptors showed that growth promotion was due to Notch1 activation, and Notch1 knockdown was accompanied by elevated levels of the negative cell cycle regulators p21(Cip1) and/or p27(Kip1) (CDKN1B; 600778). Moreover, Notch1 and the Notch ligand Jagged1 were expressed at significantly higher levels in CCRCC tumors than in normal human renal tissue, and growth of primary CCRCC cells was attenuated upon inhibition of Notch signaling. </p><p>Niranjan et al. (2008) showed that genes in the Notch pathway were expressed in mature podocytes in humans and in rodent models of diabetic nephropathy and focal segmental glomerulosclerosis. In vitro and in vivo studies showed that the Notch intracellular domain induced apoptosis of podocytes, and genetic or pharmacologic inhibition of the Notch pathway protected rats with proteinuric kidney diseases. </p><p>Moellering et al. (2009) reported the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. The authors demonstrated that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 (stapled alpha-helical peptide derived from MAML1, 605424) prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-ALL. The treatment of leukemic cells with SAHM1 resulted in genomewide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program caused potent, NOTCH-specific antiproliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL. </p><p>Ligand binding in Notch receptors triggers a conformational change in the receptor-negative regulatory region (NRR) that enables ADAM (see 601533) protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalyzed by the gamma-secretase complex liberates the intracellular domain to initiate downstream Notch transcriptional program. Aberrant signaling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for drugs (summary by Wu et al., 2010). Although gamma-secretase inhibitors (GSIs) had progressed into the clinic, GSIs failed to distinguish individual Notch receptors, inhibited other signaling pathways, and caused intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (Riccio et al., 2008). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, Wu et al. (2010) used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralog and yet crossreact with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. The cocrystal structure showed that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibited tumor growth in preclinical models through 2 mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. </p><p>Engel et al. (2010) found that Mtg16 (CBFA2T3; 603870) -/- mouse hematopoietic progenitor cells showed elevated expression of Notch targets, in addition to impaired differentiation, in response to Notch signaling. The defect was reversed by restoration of Mtg16 expression. Using mouse and human cells, Engel et al. (2010) showed that all MTG family proteins bound CSL and that MTG16 bound the ICDs of all Notch receptor proteins. Binding of MTG16 to Notch ICD disrupted MTG16-CSL and MTG16-NCOR (see 600849) interactions and permitted Notch signaling. Mutation and coprecipitation analysis revealed that the N-terminal PST region of MTG16 interacted directly with Notch ICD and that binding was independent of the MTG16 NTR domains required for DNA, CSL, and histone deacetylase binding. The PST region of Mtg16 was also essential for Mtg16-dependent lineage specification in mouse hematopoietic progenitor cells. Engel et al. (2010) concluded that MTG16 is an integral component of Notch signaling that contributes to basal repression of canonical Notch target genes. </p><p>Guarani et al. (2011) reported that the NAD(+)-dependent deacetylase SIRT1 (604479) acts as an intrinsic negative modulator of Notch signaling in endothelial cells. They showed that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with the NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signaling, resulting in impaired growth, sprout elongation, and enhanced Notch target gene expression in response to DLL4 (605185) stimulation, thereby promoting a nonsprouting, stalk cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signaling. Guarani et al. (2011) concluded that their findings identified reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signaling, and indicated that SIRT1 acts as rheostat to fine-tune endothelial Notch responses. </p><p>Rios et al. (2011) characterized the signaling events taking place during morphogenesis of chick skeletal muscle and showed that muscle progenitors present in somites require the transient activation of NOTCH signaling to undergo terminal differentiation. The NOTCH ligand Delta1 (606582) is expressed in a mosaic pattern in neural crest cells that migrate past the somites. Gain and loss of Delta1 function in neural crest modifies NOTCH signaling in somites, which results in delayed or premature myogenesis. Rios et al. (2011) concluded that the neural crest regulates early muscle formation by a unique mechanism that relies on the migration of Delta1-expressing neural crest cells to trigger the transient activation of NOTCH signaling in selected muscle progenitors. This dynamic signaling guarantees a balanced and progressive differentiation of the muscle progenitor pool. </p><p>Using yeast 2-hybrid and immunoprecipitation assays, Sanchez-Solana et al. (2011) showed that DLK1 (176290) and DLK2 (621120) interacted with themselves and with each other through their extracellular EGF-like regions to form homodimers and heterodimers. DLK1 and DLK2 also interacted with NOTCH1 through their extracellular regions. By interacting with NOTCH1, DLK1 and DLK2 inhibited NOTCH activation and signaling by competing with the NOTCH1-activating ligands DLL4 and JAGGED1 for NOTCH1 binding. </p><p>Nueda et al. (2018) found that overexpression of any of the 4 Notch receptors enhanced adipogenesis of 3T3-L1 preadipocytes. Further analysis showed that Dlk1 and Dlk2 inhibited activity of all 4 Notch receptors to different degrees. Overexpression of Notch1 stimulated differentiation of 3T3-L1 cells towards a brown-like adipocyte phenotype, whereas overexpression of Notch2 (600275), Notch3 (600276), or Notch4 (164951), or of Dlk1 or Dlk2, promoted differentiation towards a white-like adipocyte phenotype. The authors observed a complex feedback mechanism involving the Notch and Dlk genes in regulation of their expression. </p><p>Moretti et al. (2012) stated that ITCH (606409) polyubiquitinates nonactivated membrane-anchored Notch receptor and targets Notch for lysosomal degradation. Using an inhibitor of lysosomal proteases, Moretti et al. (2012) confirmed that nonactivated Notch is degraded via the lysosome. Using mouse and human cells and constructs, they found that the deubiquitinating enzyme USP12 (603091) interacted with ITCH and with UAF1 (WDR48; 612167). The USP12-UAF1 complex deubiquitinated nonactivated Notch and was required for Notch degradation in lysosomes. Knockdown of USP12 or UAF1, or overexpression of inactive USP12, resulted in accumulation of Notch receptor in endosomes. Moretti et al. (2012) proposed a model whereby USP12-UAF1 is recruited to Notch-Itch, resulting in proper trafficking of Notch receptor to lysosomes. </p><p>Using immunoprecipitation analysis, Puca et al. (2013) showed that human ARRDC1 (619768) interacted directly with ITCH. Simultaneously, ARRDC1 interacted directly with beta-arrestin-1 (ARRB1; 107940) and beta-arrestin-2 (ARRB2; 107941) to form a complex that recruited ITCH to NOTCH. Through these interactions, ARRDC1 was involved in ITCH-mediated NOTCH ubiquitylation and lysosomal degradation at the same step, but not redundantly, with the beta-arrestins. Moreover, ARRDC1 and the beta-arrestins acted as negative regulators of NOTCH signaling as members of the same complex. </p><p>Kasahara et al. (2013) found that interruption of mitochondrial fusion disrupts the calcium/calcineurin (see 114105) pathway that regulates the central cardiac development factor Notch1, interrupting cardiomyocyte proliferation and blocking fetal cardiac development. Ablation of mitochondrial fusion proteins mitofusin-1 (Mfn1; 608506) and -2 (Mfn2; 608507) in the embryonic mouse heart, or gene trapping of Mfn2 or optic atrophy-1 (Opa1; 605290) in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (190180)/Bmp (see 112264), serum response factor (SRF; 600589), Gata4 (600576), and myocyte enhancer factor-2 (see 600660), linked to increased calcium-dependent calcineurin activity and Notch1 signaling that impaired embryonic stem cell differentiation. Kasahara et al. (2013) concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling. </p><p>Magnusson et al. (2014) reported that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 +/- 210 (mean +/- SEM) new neurons in a mouse striatum. Magnusson et al. (2014) concluded that under Notch signaling regulation, astrocytes in adult mouse parenchyma carry a latent neurogenic program that could be useful for neuronal replacement strategies. </p><p>By purifying NOTCH complexes from NOTCH-induced human T-cell lymphomas, followed by coimmunoprecipitation analysis, Weaver et al. (2014) identified PRAG1 (617344), which they called NACK, as a NOTCH-interacting protein. Fractionation experiments showed colocalization of PRAG1 and NOTCH1 in nucleus. Beta-galactosidase staining of transgenic knockin mice revealed coexpression of Prag1 and Notch1 in central nervous system of embryonic day-12.5 (E12.5) and E16.5 mouse embryos. Pull-down experiments showed that binding of PRAG1 to the NOTCH complex on DNA depended on binding of the complex to CSL and MAML1. Mutations in NOTCH1 or MAML1 that inhibited NOTCH complex transcriptional activity inhibited binding of PRAG1 to the complex on DNA. Cotransfection of PRAG1 with the NOTCH1 ICD in H1299 human lung carcinoma cells increased CSL-directed transcription, similar to the effect of cotransfection of MAML1 with the NOTCH1 ICD. Chromatin immunoprecipitation analysis of OE33 human esophageal adenocarcinoma cells, which are dependent on NOTCH activity, showed that PRAG1-NOTCH complexes specifically localized to the promoter region of the NOTCH target HES1. Knockdown of PRAG1 using short hairpin RNA resulted in decreased HES1 expression in OE33 cells and attenuation of NOTCH-induced Hes1 expression in HC11 mouse mammary epithelial cells. Expression of Prag1 was upregulated following expression of the ICD of any NOTCH family member in mouse embryonic fibroblasts, which lack endogenous NOTCH activity. Chromatin immunoprecipitation analysis showed binding of NOTCH to the PRAG1 promoter. Immunohistochemical and quantitative RT-PCR analyses of clinical samples of surgically resected pancreatic ductal adenocarcinoma and esophageal adenocarcinoma showed higher levels of PRAG1 and NOTCH compared with normal tissue, and this increased expression was also seen in pancreatic ductal adenocarcinoma by immunohistochemical analysis. Knockdown of Prag1 reduced anchorage-independent growth on soft agar in HC11 cells infected with NOTCH1 ICD. Furthermore, knockdown of PRAG1 in human esophageal adenocarcinoma cells prior to injection of cells into nude mice resulted in decreased tumor growth. Weaver et al. (2014) concluded that PRAG1 is an essential component of the NOTCH complex that regulates NOTCH-mediated tumorigenesis and development. </p><p>Taniguchi et al. (2015) showed in mice and human cells that GP130 (600694), a coreceptor for IL6 (147620) cytokines, triggers activation of YAP (606608) and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the GP130 effector STAT3 (102582). Through YAP and Notch, intestinal GP130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation, and confers resistance to mucosal erosion. GP130 associates with the related tyrosine kinases SRC (190090) and YES (164880), which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. </p><p>Using an engineered organotypic model of perfused microvessels, Polacheck et al. (2017) showed that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a noncanonical, transcription-independent signaling mechanism that drives assembly of adherens junctions. They confirmed these findings in mouse models. Shear stress triggers DLL4 (605185)-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1. The transmembrane domain restores barrier function by catalyzing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin (CDH5; 601120), the transmembrane protein tyrosine phosphatase LAR (PTPRF; 179590), and the RAC1 guanidine-exchange factor TRIO (601893). This complex activates RAC1 (602048) to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signaling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial-venous differentiation, angiogenesis, and remodeling. Polacheck et al. (2017) concluded that they established the existence of a noncanonical cortical NOTCH1 signaling pathway that regulates vascular barrier function, and thus provided a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling. </p><p>Lim et al. (2017) showed that Notch signaling can be both tumor suppressive and protumorigenic in small cell lung cancer (see 182280). Endogenous activation of the Notch pathway results in a neuroendocrine to nonneuroendocrine fate switch in 10 to 50% of tumor cells in a mouse model of small cell lung cancer and in human tumors. This switch is mediated in part by Rest (600571), a transcriptional repressor that inhibits neuroendocrine gene expression. Nonneuroendocrine Notch-active small cell lung cancer cells are slow growing, consistent with a tumor-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumor cells, consistent with a protumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumor growth and delays relapse in preclinical models. Lim et al. (2017) concluded that thus, small cell lung cancer tumors generate their own microenvironment via activation of Notch signaling in a subset of tumor cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small cell lung cancer. </p><p>Loganathan et al. (2020) focused on 484 genes harboring recurrent but rare mutations ('long tail' genes) in head and neck squamous cell carcinoma (HNSCC; 275355) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 (602192) and AJUBA (609066) suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occurred in 28% of human HNSCC cases and were mutually exclusive with NOTCH receptor mutations. Loganathan et al. (2020) concluded that their results showed that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of this cancer. </p><p><strong><em>Role of Notch in Early Embryonic Development</em></strong></p><p>
|
|
Takahashi et al. (2000) found that Mesp2 (605195) initiates the establishment of rostro-caudal polarity by controlling 2 Notch signaling pathways. Initially, Mesp2 activates a Ps1-independent Notch signaling cascade to suppress Dll1 (see 602768) expression and specify the rostral half of the somite. Ps1-mediated Notch signaling is required to induce Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and Ps1-dependent activation of Notch signaling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites. </p><p>Using mouse embryos with deficient Notch signaling, Morales et al. (2002) showed that dynamic expression of the mouse Lfng gene in the cycling presomitic mesoderm (PSM) is lost in the absence of Notch signaling. They concluded that periodic Lfng expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling. </p><p>Dale et al. (2003) demonstrated that the protein product of Lfng, which encodes a glycosyltransferase that can modify Notch activity, oscillates in the chick presomitic mesoderm. Overexpressing Lfng in the paraxial mesoderm abolishes the expression of cyclic genes including endogenous Lfng and leads to defects in segmentation. This effect on cyclic genes phenocopies inhibition of Notch signaling in the presomitic mesoderm. Dale et al. (2003) therefore proposed that Lfng establishes a negative feedback loop that implements periodic inhibition of Notch, which in turn controls rhythmic expression of cyclic genes in the chick presomitic mesoderm. This feedback loop provides a molecular basis for the oscillator underlying the avian segmentation clock. </p><p>Raya et al. (2004) first investigated whether Notch activity is necessary for establishing proper left-right asymmetry during chick embryo development. Blocking the Notch signaling pathway by overexpressing a dominant-negative form of the Notch pathway effector RBPSUH resulted in laterality defects at both the morphologic and molecular levels similar to those described for mouse embryos. Raya et al. (2004) found that before the appearance of the left-sided perinodal expression domain of Nodal (601265), the Notch ligands Dll1 and Serrate1 showed complementary patterns of expression that form a sharp anterior/posterior interface across the Hensen node. During HH3 to HH7 stages of chick embryo development, Lfng is expressed in a complex, dynamic pattern of waves that sweep the AP axis of the embryo. Raya et al. (2004) noticed that the fifth wave of Lfng is clearly asymmetric when it reaches the node at HH6: the medial-most part of the left stripe is anteriorly displaced with respect to the right. Raya et al. (2004) developed a mathematical model which described the dynamics of the Notch signaling pathway during chick embryo gastrulation, which revealed a complex and highly robust genetic network that locally activates Notch on the left side of the Hensen node. Raya et al. (2004) identified the source of the asymmetric activation of Notch as a transient accumulation of extracellular calcium, which in turn depends on left-right differences in hydrogen/potassium-ATPase activity. Raya et al. (2004) concluded that their results uncovered a mechanism by which the Notch signaling pathway translates asymmetry in epigenetic factors into asymmetric gene expression around the node. </p><p>Morimoto et al. (2005) visualized endogenous levels of Notch1 activity in mice, showing that it oscillates in the posterior presomitic mesoderm but is arrested in the anterior presomitic mesoderm. Somite boundaries formed at the interface between Notch1-activated and -repressed domains. Genetic and biochemical studies indicated that this interface is generated by suppression of Notch activity by Mesp2 through induction of the Lfng gene. Morimoto et al. (2005) proposed that the oscillation of Notch activity is arrested and translated in the wavefront by Mesp2. </p><p>Boskovski et al. (2013) showed, in Xenopus tropicalis, that GALNT11 (615130) activates Notch signaling. GALNT11 O-glycosylated human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either by increasing ADAM17 (603639)-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats. Boskovski et al. (2013) developed a quantitative live imaging technique for Xenopus left-right organizer cilia and showed that GALNT11-mediated NOTCH1 signaling modulates the spatial distribution and ratio of motile and immotile cilia at the left-right organizer. GALNT11 or NOTCH1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor PKD2 (173910). By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia-1 (CILD1; 244400). Boskovski et al. (2013) concluded that their data demonstrated that GALNT11 modifies Notch, establishing an essential balance between motile and immotile cilia at the left-right organizer to determine laterality, and revealed a novel mechanism for human heterotaxy. </p><p>Del Monte-Nieto et al. (2018) presented a model of trabeculation in mice that integrated dynamic endocardial and myocardial cell behaviors and extracellular matrix (ECM) remodeling, and revealed epistatic relationships between the involved signaling pathways. Notch1 signaling promotes extracellular matrix degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas Nrg1 (142445) promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through Nrg1 control of Vegfa (192240), but act antagonistically to establish trabecular architecture. Del Monte-Nieto et al. (2018) concluded that their findings enabled the prediction of persistent extracellular matrix and cardiomyocyte growth in a mouse noncompaction cardiomyopathy model, providing insights into the pathophysiology of congenital heart disease. </p><p><strong><em>Role of Notch in Cell Fate Determination</em></strong></p><p>
|
|
Tanigaki et al. (2001) presented evidence that activated NOTCH1 and NOTCH3 promote the differentiation of astroglia from rat adult hippocampus-derived multipotent progenitors. Transient activation of Notch can direct commitment of adult hippocampal-derived progenitors irreversibly to astroglia. Astroglial induction by Notch signaling was shown to be independent of STAT3 (102582), which is a key regulatory transcriptional factor when ciliary neurotrophic factor (CNTF; 118945) induces astroglia. Tanigaki et al. (2001) suggested that Notch provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells. </p><p>Shen et al. (2004) demonstrated that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulated neuroepithelial cell contact, activating Notch and HES1 (139605) to promote self-renewal. These findings identified endothelial cells as a critical component of the neural stem cell niche. </p><p>Loomes et al. (2002) characterized Notch receptor expression in the developing mouse heart and liver, 2 organs significantly affected in Alagille syndrome (see 118450). In the developing mouse heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, and in specific cell populations previously shown to express Jag1 (Loomes et al., 1999). These cells are destined to undergo transformation from epithelial to mesenchymal cells. In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development. Jag1 is also expressed in cells adjacent to those expressing Notch2, suggesting a possible ligand-receptor interaction. </p><p>Hematopoietic stem cells (HSCs) have the ability to renew themselves and to give rise to all lineages of the blood. Reya et al. (2003) showed that the WNT signaling pathway has an important role in this process. Overexpression of activated beta-catenin (116806) expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF1/TCF (153245) reporter, which indicates that HSCs respond to WNT signaling in vivo. To demonstrate the physiologic significance of this pathway for HSC proliferation, Reya et al. (2003) showed that the ectopic expression of axin (603816) or a frizzled (603408) ligand-binding domain, inhibitors of the WNT signaling pathway, led to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs induced increased expression of HOXB4 (142965) and NOTCH1, genes previously implicated in self-renewal of HSCs. Reya et al. (2003) concluded that the WNT signaling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development. </p><p>Murtaugh et al. (2003) found that misexpression of activated Notch in Pdx1 (IPF1; 600733)-expressing mouse pancreatic progenitor cells prevented the differentiation of both exocrine and endocrine cell lineages. Progenitors remained trapped in an undifferentiated state even if Notch activation occurred after the pancreatic fate had been specified. Endocrine differentiation was associated with escape from Notch activity. </p><p>Using immunoprecipitation and fluorescence microscopy, Hu et al. (2003) identified mouse F3 (CNTN1; 600016) as a physiologic ligand and activator of Notch. Upon activation by F3, Notch signals through Dtx1 (602582), which leads to oligodendrocyte maturation via upregulation of certain myelin-related proteins. Thus, Hu et al. (2003) concluded that Notch does not solely function to inhibit oligodendrocyte precursor differentiation to mature cells, and they suggested that it may be useful in promoting remyelination in degenerative diseases. </p><p>Okuyama et al. (2004) found that pure keratinocytes cultured from embryonic day-15.5 mouse embryos committed irreversibly to differentiation much earlier than those cultured from newborn mice. Notch signaling, which promotes keratinocyte differentiation, was upregulated in embryonic keratinocytes and epidermis, and elevated caspase-3 (600636) expression, which the authors identified as a target for Notch1 transcriptional activation, accounted in part for the high commitment of embryonic keratinocytes to terminal differentiation. </p><p>Van Es et al. (2005) showed a rapid, massive conversion of proliferative crypt cells into postmitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (147183). The authors obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumor suppressor gene (611731). Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. </p><p>By modulating Notch activity in the mouse intestine, Fre et al. (2005) directly implicated Notch signals in intestinal cell lineage specification. Fre et al. (2005) also showed that Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. The authors concluded that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium. </p><p>Stanger et al. (2005) found that ectopic expression of Notch in adult mouse intestinal progenitor cells biased differentiation against secretory fates, whereas ectopic Notch activation in the embryonic foregut resulted in reversible defects in villus morphogenesis and loss of proliferative progenitor compartment. Stanger et al. (2005) concluded that Notch regulates adult intestinal development by controlling the balance between secretory and absorptive cell types. </p><p>RBPJ functions immediately downstream of Notch signaling. Han et al. (2002) used a conditional gene knockout strategy to inactivate the DNA-binding domain of Rbpj in mouse bone marrow and found that Rbpj was required for T-cell development. In the absence of Rbpj, there was an increase in thymic B-cell development. Han et al. (2002) proposed that RBPJ-mediated Notch signaling controls T- versus B-cell fate decisions in lymphoid progenitors. </p><p>Thymocytes can be divided into 4 subsets based on CD4 (186940) and CD8 (see 186910) expression, with double-negative (DN) cells being the least mature. The DN population can be further subdivided into 4 subsets, DN1 through DN4. Tanigaki et al. (2004) used a conditional knockout strategy to inactivate Rbpj at the DN2 and DN4 stages in mice. Inactivation at DN2 resulted in severe developmental arrest of alpha-beta T cells at the DN3 stage and enhanced generation of gamma-delta T cells. Inactivation at DN4 caused no abnormalities in CD4/CD8 lineage commitment, but it resulted in enhanced Th1 responses and reduced T-cell proliferation. Tanigaki et al. (2004) concluded that Notch/RBPJ signaling regulates not only the T-cell developmental process, but also the direction and magnitude of immune responses via regulation of peripheral T cells. </p><p>Using Lrf (ZBTB7; 605878) -/- mice and Lrf conditional knockout mice, Maeda et al. (2007) showed that LRF acts as a master regulator in determination of B versus T lymphoid fate by negatively regulating T-lineage commitment by opposing NOTCH function. Thus, loss of LRF results in aberrant activation of the NOTCH pathway, with upregulation of NOTCH target genes in hematopoietic stem cells and common lymphoid progenitors. </p><p>Gustafsson et al. (2005) found that hypoxia blocked differentiation of mammalian neuronal and myogenic progenitor cells in culture through a Notch signaling pathway. Hypoxia led to recruitment of Hif1a (603348) to Notch-responsive promoters and elevated expression of Notch downstream genes. </p><p>Hellstrom et al. (2007) presented evidence that Dll4 (605185)-Notch1 signaling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in mouse retina. They showed that inhibition of Notch signaling using gamma-secretase inhibitors, genetic inactivation of 1 allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1 all promoted increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 (601920) peptide led to fewer tip cells and vessel branches. Dll4 and reporters of Notch signaling were distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assumed tip cell characteristics. Hellstrom et al. (2007) concluded that DLL4 (605185)-Notch1 signaling between the endothelial cells within the angiogenic sprout restricts tip cell formation in response to VEGF (192240), thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. The authors further concluded that their model offered an explanation for the dose-dependency and haploinsufficiency of the DLL4 gene, and indicated that modulators of DLL4 or Notch signaling, such as gamma-secretase inhibitors developed for Alzheimer disease (104300), might find usage as pharmacologic regulators of angiogenesis. </p><p>Siekmann and Lawson (2007) demonstrated that Notch signaling is necessary to restrict angiogenic cell behavior to tip cells in developing segmental arteries in the zebrafish embryo. In the absence of the Notch signaling component Rbpsuh (147183), The authors observed excessive sprouting of segmental arteries, whereas Notch activation suppressed angiogenesis. Through mosaic analysis Siekmann and Lawson (2007) found that cells lacking Rbpsuh preferentially localized to the terminal position in developing sprouts. In contrast, cells in which Notch signaling had been activated were excluded from the tip cell position. In vivo time-lapse analysis revealed that endothelial tip cells undergo a stereotypical pattern of proliferation and migration during sprouting. In the absence of Notch, nearly all sprouting endothelial cells exhibited tip cell behavior, leading to excessive numbers of cells within segmental arteries. Furthermore, Siekmann and Lawson (2007) found that Flt4 (136352) was expressed in segmental artery tip cells and became ectopically expressed throughout the sprout in the absence of Notch. Loss of Flt4 partially restored normal endothelial cell number in Rbpsuh-deficient segmental arteries. Finally, loss of the Notch ligand Dll4 also led to an increased number of endothelial cells within segmental arteries. Siekmann and Lawson (2007) concluded that their studies taken together indicated that proper specification of cell identity, position, and behavior in a developing blood vessel sprout is required for normal angiogenesis, and implicated the Notch signaling pathway in this process. </p><p>Hozumi et al. (2008) found that mice lacking Dll4 expression in thymic epithelial cells (TECs) exhibited a marked reduction of Notch1 in hematopoietic cells and a lack of Cd4 and Cd8 double- or single-positive T cells in thymus. The double-negative cell fraction also showed an absence of T-cell progenitors and an aberrant accumulation of B-lineage cells. Enforced expression of the intracellular fragment of Notch1 restored thymic T-cell differentiation. Hozumi et al. (2008) concluded that the thymus-specific environment for T-cell fate determination requires DLL4 expression to induce NOTCH signaling in cells immigrating into thymus. </p><p>Using immunohistochemical analysis, Koch et al. (2008) demonstrated expression of Dll4, but not Dll1 (606582), on TECs in mice. Inactivation of Dll4 in TECs or hematopoietic progenitors in mice resulted in loss of T-cell development with no loss of thymus development, as well as ectopic appearance of immature B cells in thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional Notch1-deficient mice. Koch et al. (2008) concluded that DLL4 is the essential and nonredundant Notch1 ligand responsible for T-cell fate specification. They proposed that NOTCH1-expressing thymic progenitors interact with DLL4-expressing TECs to suppress B-lineage potential and to induce the first steps of intrathymic T-cell development. </p><p>To investigate how Delta (see 606582) both transactivates Notch neighboring cells and cis-inhibits Notch in its own cell, Sprinzak et al. (2010) developed a quantitative time-lapse microscopy platform for analyzing Notch-Delta signaling dynamics in individual mammalian cells. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, Sprinzak et al. (2010) measured the combined cis-trans input-output relationship in the Notch-Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. Sprinzak et al. (2010) developed a simple mathematical model that shows how these behaviors emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signaling states. At the multicellular level, this switch can amplify small differences between neighboring cells even without transcription-mediated feedback. Sprinzak et al. (2010) concluded that this Notch-Delta signaling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviors. </p><p>Aguirre et al. (2010) demonstrated that functional cell-cell interaction between neural progenitor cells (NPCs) and neural stem cells (NSCs) through EGFR (131550) and Notch signaling has a crucial role in maintaining the balance between these cell populations in the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. Enhanced EGFR signaling in vivo results in the expansion of the NPC pool and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signaling. Aguirre et al. (2010) concluded that their findings defined a novel interaction between EGFR and Notch pathways in the adult subventricular zone, and thus provided a mechanism for NSC and NPC pool maintenance. </p><p>Benedito et al. (2012) used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 (191306) signaling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3 (136352), the main receptor for VEGFC (601528), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. Benedito et al. (2012) concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling. </p><p><strong><em>Role of Notch in Neural Development</em></strong></p><p>
|
|
The exuberant growth of neurites during development becomes markedly reduced as cortical neurons mature. Using in vitro studies of neurons from mouse cerebral cortex, Sestan et al. (1999) demonstrated that contact-mediated Notch signaling regulates the capacity of neurons to extend and elaborate neurites. Upregulation of Notch activity was concomitant with an increase in the number of interneuronal contacts and cessation of neurite growth. In neurons with low Notch activity, which readily extend neurites, upregulation of Notch activity either inhibited extension or caused retraction of neurites. Conversely, in more mature neurons that had ceased their growth after establishing numerous connections and displayed high Notch activity, inhibition of Notch signaling promoted neurite extension. Thus, Sestan et al. (1999) concluded that the formation of neuronal contacts results in activation of Notch receptors, leading to restriction of neuronal growth and a subsequent arrest in maturity. </p><p><strong><em>Role of Notch in Muscle Regeneration</em></strong></p><p>
|
|
Conboy et al. (2003) analyzed injured muscle and observed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient upregulation of the Notch ligand Delta and thus diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Conboy et al. (2003) concluded that Notch signaling is a key determinant of muscle regenerative potential that declines with age. </p><p>In experiments using mouse muscle, Carlson et al. (2008) found that, in addition to the loss of Notch activation, old muscle produces excessive TGF-beta (190180) (but not myostatin, 601788), which induces unusually high levels of Smad3 (603109) in resident satellite cells and interfered with the regenerative capacity. Importantly, endogenous Notch and Smad3 antagonize each other in the control of satellite cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15 (600431), p16 (600160), p21 (116899), and p27 (600778), whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determined the binding of Smad3 to the promoters of these negative regulators of cell cycle progression. Attenuation of TGF-beta/Smad3 in old, injured muscle restored regeneration to satellite cells in vivo. Thus, a balance between endogenous Smad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration. </p><p><strong><em>Role of Notch in Bone Homeostasis</em></strong></p><p>
|
|
Independently, Engin et al. (2008) and Hilton et al. (2008) investigated the role of Notch signaling in bone homeostasis using rodent models. Engin et al. (2008) found that Notch and presenilin signaling regulated both osteoclastogenesis and osteoblastic proliferation. Gain of Notch function resulted in severe osteosclerosis, whereas loss of Notch function led to age-related osteoporosis. Hilton et al. (2008) found that Notch signaling in bone marrow maintained a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Disruption of Notch signaling in limb skeletogenic mesenchyme increased trabecular bone mass in adolescent mice and led to severe osteopenia as they aged. </p><p>Engin et al. (2009) reported that human osteosarcoma (259500) cell lines and primary human osteosarcoma tumor samples showed significant upregulation of Notch, its target genes, and Osterix (SP7; 606633). Notch inhibition by gamma-secretase inhibitors or by lentiviral-mediated expression of dominant-negative MAML1 protein (605424) decreased osteosarcoma cell proliferation in vitro. Established human tumor xenografts in nude mice showed decreased tumor growth after chemical or genetic inhibition of Notch signaling. Transcriptional profiling of osteosarcomas from p53 (191170) mutant mice confirmed upregulation of Notch target genes Hes1 (139605), Hey1 (602953), and its ligand Dll4 (605185). Engin et al. (2009) suggested that activation of Notch signaling may contribute to the pathogenesis of human osteosarcomas. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Chromosome 7q34-q35, which contains the locus for the beta T-cell receptor (see 186930), is a common site for translocation in T-cell neoplasms. In t(7;9)(q34;q34.3) translocations from 3 cases of acute T-cell lymphoblastic leukemia, Ellisen et al. (1991) found breakpoints within 100 bp of an intron in TAN1, resulting in truncation of TAN1 transcripts. They concluded that TAN1 is important for normal lymphocyte function and that alterations in TAN1 play a role in the pathogenesis of some T-cell neoplasms. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Aortic Valve Disease</em></strong></p><p>
|
|
Garg et al. (2005) showed that mutations in the signaling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification (AOVD1; 109730) in nonsyndromic autosomal dominant human pedigrees (see 190198.0001-190198.0002). Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2 (600211), a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors, which are activated by Notch1 signaling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independently of histone deacetylase activity. Garg et al. (2005) concluded that their results suggested that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later derepression of calcium deposition that causes progressive aortic valve disease. </p><p>In a cohort of 48 sporadic German patients with bicuspid aortic valve (BAV), Mohamed et al. (2006) sequenced the NOTCH1 gene and identified 2 men with BAV and thoracic aortic aneurysm (AAT) who were heterozygous for missense mutations (T596M, 190198.0011 and P1797H, 190198.0012). </p><p>McBride et al. (2008) analyzed the NOTCH1 gene in 91 unrelated European American patients with congenital aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta (COA; see 120000), and/or hypoplastic left heart syndrome (see 241550), and identified 2 heterozygous missense variants in 6 probands, respectively, that were either completely absent or significantly underrepresented in over 200 ethnically matched controls and were also shown to reduce ligand-induced NOTCH1 signaling. Four of the mutation-positive probands had aortic valve stenosis and/or bicuspid aortic valve, which in 1 patient was associated with COA, and 2 probands had HLHS. In each case, the NOTCH1 variant was also present in an unaffected parent; McBride et al. (2008) suggested that these variants represent susceptibility alleles that are not sufficient in and of themselves to perturb cardiac development. </p><p><strong><em>Other Cardiac Malformations</em></strong></p><p>
|
|
Kerstjens-Frederikse et al. (2016) sequenced NOTCH1 in 428 probands with nonsyndromic left-sided congenital heart disease. Family history was obtained for all. When a mutation was detected, relatives were also tested. In 148 of the probands (35%), left-sided congenital heart disease was familial. Fourteen mutations (3%) (5 splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 of 148 familial cases (7%) and 3 of 280 sporadic disease cases (1%). Familial screening showed 49 additional mutation carriers among the 14 families, of whom 12 (25%) were asymptomatic. Most of the mutation carriers had left-sided heart disease, but 9 (18%) had right-sided or conotruncal heart disease. Thoracic aortic aneurysms occurred in 6 mutations carriers. Penetrance was high; cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. </p><p><strong><em>Adams-Oliver Syndrome 5</em></strong></p><p>
|
|
In affected individuals from 5 unrelated families with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for 5 different mutations in the NOTCH1 gene, including an 85-kb deletion spanning the NOTCH1 5-prime region (190198.0003), a splice site mutation (190198.0004), and 3 missense mutations (C429R, 190198.0005; C1496Y, 190198.0006; D1989N, 190198.0007). </p><p>In 11 (17%) of 64 probands with AOS, Southgate et al. (2015) identified mutations in the NOTCH1 gene (see, e.g., 190198.0008 and 190198.0010) and concluded that NOTCH1 is the primary cause of Adams-Oliver syndrome. </p><p><strong><em>T-cell Acute Lymphoblastic Leukemia</em></strong></p><p>
|
|
Very rare cases of human T-cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T-cell development. Weng et al. (2004) reported that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. Weng et al. (2004) concluded that their findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling. </p><p><strong><em>Isolated Juvenile or Chronic Myelomonocytic Leukemia</em></strong></p><p>
|
|
Klinakis et al. (2011) identified novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukemia (CMML). Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1 (139605). Klinakis et al. (2011) concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue. </p><p><strong><em>Chronic Lymphocytic Leukemia</em></strong></p><p>
|
|
Puente et al. (2011) identified somatic mutations in the NOTCH1 gene in 31 (12.2%) of 255 cases of chronic lymphocytic leukemia (CLL; 151400). These mutations generated a premature stop codon, resulting in a NOTCH1 protein lacking the C-terminal domain. The mutations caused an accumulation of an active protein isoform in the mutated CLL cells, since this isoform is more stable and active. NOTCH1-mutated patients had a more advanced clinical stage at diagnosis, more adverse biological features, and an overall shorter survival than those without NOTCH1 mutations. NOTCH1-mutated CLL also underwent transformation into diffuse large B-cell lymphoma more frequently than NOTCH1-unmutated CLL (23% vs 1.3%). </p><p>Quesada et al. (2012) identified somatic mutations in the NOTCH1 gene in 25 (9.5%) of 260 cases of CLL. </p><p><strong><em>Head and Neck Squamous Cell Carcinoma</em></strong></p><p>
|
|
To explore the genetic origins of head and neck squamous cell carcinoma (HNSCC; 275355), Agrawal et al. (2011) used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53 (191170), CDKN2A (600160), PIK3CA (171834), and HRAS (171834), Agrawal et al. (2011) identified mutations in FBXW7 (606278) and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type. Seven of 21 patients with NOTCH1 mutations had 2 independent mutations presumably on different alleles. After TP53, NOTCH1 was the most frequently mutated gene found in the combined discovery and prevalence sets, with alterations present in 15% of patients. </p><p>Stransky et al. (2011) independently analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying known HNSCC genes, their analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (i.e., NOTCH1; IRF6, 607199; and TP63, 603273), implicating its dysregulation as a major driver of HNSCC carcinogenesis. </p><p><strong><em>Mutation in Normal Esophageal Epithelium</em></strong></p><p>
|
|
By intensively sequencing 682 microscale esophageal samples, Yokoyama et al. (2019) showed, in physiologically normal esophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with aging, and ultimately replace almost the entire esophageal epithelium in the extremely elderly. Compared with mutations in esophageal cancer (133239), there is a marked overrepresentation of NOTCH1 and PPM1D (605100) mutations in physiologically normal esophageal epithelia; these mutations can be acquired before late adolescence and as early as early infancy, and significantly increase in number with heavy smoking and drinking. The remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal aging, which, depending on lifestyle risks, may affect cancer development. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Huppert et al. (2000) mutated valine at position 1744 of the mouse Notch1 gene to glycine. This position is the site for proteolytic cleavage and is critical for Notch1 intracellular processing in tissue-culture cells. Huppert et al. (2000) generated homozygous animals carrying 2 germline mutations and compared these with mice who have 2 null alleles for Notch1 (Conlon et al., 1995). At embryonic day 8.5 to 10.5, homozygous embryos were detected at the expected mendelian frequency. Similar to the null alleles, embryo absorption was detected between embryonic day 10 and 12, and no homozygous embryos were recovered past embryonic day 12. These results suggested that efficient Notch processing is necessary for the early embryonic developmental aspects of Notch activity. RT-PCR and immunoprecipitation showed comparable amounts of Notch mRNA and protein, respectively, in the processing-deficient embryos and their heterozygous and wildtype littermates. The phenotypes associated with the single point mutation resembled the null Notch1 phenotype, but with slightly reduced penetrance. </p><p>Krebs et al. (2000) generated Notch4 (164951)-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene (Swiatek et al., 1994). Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 (DLL4; 605185) gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. Krebs et al. (2000) stated that these results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice. </p><p>In vertebrates with mutations in the Notch cell-cell communication pathway, segmentation fails: the boundaries demarcating somites, the segments of the embryonic body axis, are absent or irregular. Somite patterning is thought to be governed by a 'clock-and-wavefront' mechanism: a biochemical oscillator (the segmentation clock) operates in the cells of the presomitic mesoderm, the immature tissue from which the somites are sequentially produced, and a wavefront of maturation sweeps back through this tissue, arresting oscillation and initiating somite differentiation. Cells arrested in different phases of their cycle express different genes, defining the spatially periodic pattern of somites and controlling the physical process of segmentation. Jiang et al. (2000) analyzed a set of zebrafish mutants and determined that the essential function of Notch signaling in somite segmentation is to keep the oscillations of neighboring presomitic mesoderm cells synchronized. </p><p>Nicolas et al. (2003) studied the role of Notch signaling in mammalian skin. Conventional gene targeting was not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1 -/- embryos die during gestation. Therefore, Nicolas et al. (2003) used a tissue-specific inducible gene targeting approach to study the physiologic role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 resulted in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and primary keratinocytes resulted in increased and sustained expression of Gli1 (165220), causing the development of basal cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis resulted in derepressed beta-catenin (CTNNB1; 116806) signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling could be reversed by reintroduction of a dominant active form of the Notch1 receptor. The results indicated that Notch1 functions as a tumor suppressor gene in mammalian skin. </p><p>Kumano et al. (2003) found that hematopoietic stem cell development and angiogenesis were severely impaired in paraaortic splanchnopleura (P-Sp) culture of Notch1 -/-, but not Notch2 -/-, mouse embryos. Although colony-forming cell activity in the yolk sac was unimpaired in Notch1 -/- mice, hematopoietic stem cell activity was undetectable in either the yolk sac or P-Sp culture. </p><p>Krebs et al. (2003) showed that mouse embryos mutant for the Notch ligand Dll1 or doubly mutant for Notch1 and Notch2 exhibited multiple defects in left-right asymmetry. Dll1 -/- embryos did not express Nodal in the region around the node. Analysis of the enhancer regulating node-specific Nodal expression revealed binding sites for Rbpj. Mutation of these sites destroyed the ability of the enhancer to direct node-specific gene expression in transgenic mice. Krebs et al. (2003) concluded that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that perinodal expression of Nodal is an essential component of left-right asymmetry determination in mice. </p><p>Using gain- and loss-of-function experiments in zebrafish and mouse, Raya et al. (2003) showed that activity of the Notch pathway was necessary and sufficient for Nodal expression around the node and for proper left-right determination. They also identified critical Rbpj-binding sequences in the Nodal promoter. </p><p>Using inducible ablation of Notch1 in adult mouse cornea, Vauclair et al. (2007) showed that Notch1 -/- corneal progenitor cells lost the ability to repair mechanically wounded corneal epithelium. Instead of generating a new cornea after injury, Notch1 -/- corneal cells repaired the wound into a hyperproliferative epidermis-like epithelium, similar to xerophthalmia caused by vitamin A deficiency. Repair was associated with secretion of Fgf2 (134920) through Notch1 -/- epithelium, followed by vascularization and remodeling of the underlying stroma. Vauclair et al. (2007) identified Crbp1 (RBP1; 180260) as a direct Notch1 target within the corneal epithelium, linking the Notch pathway to vitamin A metabolism. </p><p>Gamma-secretase inhibitors block the activation of oncogenic NOTCH1 in T-ALL, but the clinical use of these drugs in humans has been limited by antileukemic cytotoxicity and severe gastrointestinal toxicity. Real et al. (2009) found that treatment of several glucocorticoid-resistant T-ALL cell lines with a combination of gamma-secretase inhibitors and corticosteroids resulted in synergistic dose-related apoptotic cell death. The findings were specific to T-ALL. Microarray analysis of these cells indicated that inhibition of NOTCH1 resulted in upregulation of the glucocorticoid receptor NR3C1 (138040) as well as increased expression of BCL2L11 (603827). In mouse models of human T-ALL, this double treatment resulted in antileukemic effects and cell cycle arrest. In addition, the double treatment protected mice from developing intestinal goblet cell metaplasia that was typically induced by treatment with gamma-secretase inhibitors alone. Further studies indicated that upregulation of Klf4 (602252) was responsible for the metaplastic gastrointestinal effects of gamma-secretase inhibitors. </p><p>Using a mouse model of aplastic anemia (609135) and conditionally deleting Notch1 or administering gamma-secretase inhibitors (GSIs), Roderick et al. (2013) observed attenuated aplastic anemia and rescue of mice from bone marrow failure. The cleaved, active form of Notch1, which was increased in wildtype mice with aplastic anemia, bound to the Tbx21 (604895) promoter, and these findings were also detected in humans with untreated aplastic anemia. Extended GSI treatment had no adverse effect on engraftment or long-term hematopoiesis, and it also resulted in loss of Notch1 binding to the Tbx21 promoter. Roderick et al. (2013) concluded that NOTCH1 is a critical mediator of Th1 pathology in aplastic anemia through its direct regulation of TBX21 and that NOTCH1 is responsive to GSIs in vitro and in vivo. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>12 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, ARG1108TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41309764,
|
|
|
|
|
|
gnomAD: rs41309764,
|
|
|
|
|
|
ClinVar: RCV000013294, RCV001781254, RCV001851821
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-generation pedigree affected by autosomal dominant congenital heart disease and valve calcification (AOVD1; 109730), Garg et al. (2005) identified a C-to-T transition at nucleotide 3322 of the NOTCH1 gene that resulted in an arg-to-ter substitution at codon 1108 (R1108X), in the extracellular domain. Affected family members had aortic stenosis, dysmorphic aortic valve, ventricular septal defect, tetralogy of Fallot, and mitral stenosis with or without bicuspid aortic valve and calcification. Unaffected individuals manifested no valvular or other congenital heart disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, 1-BP DEL, NT4515
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41309766,
|
|
|
|
|
|
gnomAD: rs41309766,
|
|
|
|
|
|
ClinVar: RCV000013295
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with autosomal dominant congenital heart disease with valve calcification (AOVD1; 109730), Garg et al. (2005) identified heterozygosity for a frameshift mutation in the NOTCH1 gene at the his1505 position. The mutation was predicted to result in a severely altered protein containing 74 incorrect amino acids at the C terminus of the extracellular domain followed by a premature stop codon. Affected individuals had severe aortic stenosis, hypoplastic left ventricle, and double-outlet right ventricle with calcification and bicuspid aortic valve. The phenotype segregated with the mutation in affected family members. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, 85-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000144232
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old boy with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a de novo 85-kb deletion involving the 5-prime region of the NOTCH1 gene, including part of the promoter and all of exon 1 (chr9:139,439,620-139,524,480; GRCh37). The deletion was not found in the unaffected parents, in 2 unaffected sibs, or in more than 10,000 control genomes or exomes. The patient had occipital aplasia cutis congenita, marked cutis marmorata, hypoplastic and dystrophic toenails, and areas of focal calcinosis cutis. Mild narrowing of the pulmonary branch arteries was noted on echocardiography in infancy; at age 6 years, the branch pulmonary arteries were normal, and there was stable dilation of the main pulmonary artery. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, IVS4AS, G-T, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777735,
|
|
|
|
|
|
|
|
ClinVar: RCV000144234
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and daughter with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a splice site mutation in intron 4 of the NOTCH1 gene (c.743-1G-T, at chr9:139,414,018; GRCh37), disrupting the exon 5 acceptor splice site. The mutation was not found in the unaffected mother or an unaffected brother, or in more than 10,000 control genomes or exomes. The daughter had severe aplasia cutis of the scalp that was complicated by recurrent hemorrhage during a lengthy healing process. She had hypoplastic toes on the left foot and nail hypoplasia of the second and third toes. Her father was born with a cutaneous and bony defect involving two-thirds of his cranium, brachydactyly of the right hand, and terminal transverse defects of both feet, including soft-tissue syndactyly of hypoplastic toes. Bony ingrowth of the skull never fully bridged the father's cranial defect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, CYS429ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777736,
|
|
|
|
|
|
|
|
ClinVar: RCV000144235
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old boy of Portuguese ancestry with Adams-Oliver syndrome (AOS5; 616028), originally described by Silva et al. (2012), Stittrich et al. (2014) identified heterozygosity for a de novo c.1285T-C transition (chr9:139,412,360; GRCh37) in the NOTCH1 gene, resulting in a cys429-to-arg (C429R) substitution at a highly conserved residue in calcium-binding EGF (131530)-like repeat 11. The mutation was not found in his unaffected parents or in more than 10,000 control genomes or exomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, CYS1496TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587781259,
|
|
|
|
|
|
|
|
ClinVar: RCV000144236
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female proband of European and Asian ancestry with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a de novo c.4487G-A transition (chr9:139,399,861; GRCh37) in the NOTCH1 gene, resulting in a cys1496-to-tyr (C1496Y) substitution at a highly conserved residue within the extracellular negative regulatory region (NRR) of the second Lin-12 NOTCH repeat (LNR) domain. Stittrich et al. (2014) noted that the NRR sterically inhibits processing of NOTCH1 in the absence of ligand stimulation; thus, destabilization of this domain could increase constitutive Notch signaling and result in a gain of function. The mutation was not found in the proband's unaffected parents or in more than 10,000 control genomes or exomes. The patient was born with severe aplasia cutis affecting most of the scalp superior to the ears as well as the posterior neck. She had bilateral prominent tortuous scalp vessels, truncal cutis marmorata, and bilateral toe hypoplasia with absent toenails. Neuroimaging at day 1 of life showed small focal areas of bilateral parietal and left frontal white matter acute infarction and partial superior sagittal sinus thrombosis; repeat imaging at 1 week showed evolving biparietal and left frontal lobe infarcts, near-complete sagittal sinus thrombosis, and biparietal cortical venous thromboses, with stabilization and improvement over the next several months. She also had mild mitral valve annulus hypoplasia and multiperforated patent foramen ovale with insignificant shunting; severe pulmonary hypertension on day 1 of life resolved by day 10. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, ASP1989ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777734,
|
|
|
|
|
|
|
|
ClinVar: RCV000144233
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 24-year-old woman with Adams-Oliver syndrome-5 (AOS5; 616028), originally reported by Vandersteen and Dixon (2011), Stittrich et al. (2014) identified heterozygosity for a c.5965G-A transition (chr9: 139,393,681; GRCh37) in the NOTCH1 gene, resulting in an asp1989-to-asn (D1989N) substitution at a highly conserved residue involved in a bipartite-charged hydrogen-bonding interaction with the backbone nitrogen-hydrogen atoms of asp2020. No DNA was available from the proband's deceased affected father and sister. The mutation was not found in more than 10,000 control genomes or exomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, TYR550TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864622059,
|
|
|
|
|
|
|
|
ClinVar: RCV000203698
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members of a 3-generation family with Adams-Oliver syndrome-5 (AOS5; 616028), Southgate et al. (2015) identified heterozygosity for a 1-bp insertion (c.1649dupA, NM_017617.3) in the NOTCH1 gene, resulting in a tyr550-to-ter (Y550X) substitution within the EGF-like repeats of the extracellular domain. The proband and his brother each exhibited a severe cutaneous and bony scalp defect and marked terminal transverse limb defects, as well as an undefined heart murmur. The mutation was also present in their clinically unaffected mother, who had no scalp or limb defects but was found to have an unexplained heart murmur. Quantitative RT-PCR analysis of patient RNA demonstrated an approximately 50% reduction in NOTCH1 transcripts compared to control, and analysis of downstream signaling factors revealed significant reductions in HEY1 (602953) and HES1 (139605) with the Y550X mutant compared to wildtype NOTCH1. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, 2-BP DEL, 6049TC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864622063,
|
|
|
|
|
|
|
|
ClinVar: RCV000206353, RCV004767148
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian male proband with Adams-Oliver syndrome-5 (AOS5; 616028), originally reported by Dallapiccola et al. (1992), Southgate et al. (2015) identified heterozygosity for a 2-bp deletion (c.6049_6050delTC, NM_017617.3) in the NOTCH1 gene, causing a frameshift predicted to result in a premature termination codon (Ser2017ThrfsTer9) within the intracellular ANK repeat domain. DNA was unavailable from the proband's affected mother. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ADAMS-OLIVER SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, CYS1374ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864622060,
|
|
|
|
|
|
|
|
ClinVar: RCV000205222
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old German boy with Adams-Oliver syndrome-5 (AOS5; 616028), Southgate et al. (2015) identified heterozygosity for a c.4120T-C transition (c.4120T-C, NM_017617.3) in the NOTCH1 gene, resulting in a cys1374-to-arg (C1374R) substitution at a highly conserved residue within the EGF-like repeats of the extracellular domain. The mutation was present in an affected paternal uncle but was not found in 2 clinically normal sibs or 2 unaffected paternal uncles; however, it was a detected in the proband's clinically unaffected father. Cardiovascular evaluation by echocardiography showed no abnormality, confirming the father's unaffected status and indicating reduced penetrance for the C1374R mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, THR596MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61755997,
|
|
|
|
|
|
gnomAD: rs61755997,
|
|
|
|
|
|
ClinVar: RCV000660144, RCV000787043, RCV001049180, RCV001575577, RCV002311202, RCV004701355
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 49-year-old German man with a calcified bicuspid aortic valve and ascending aortic aneurysm (AOVD1; 109730), Mohamed et al. (2006) identified heterozygosity for a g.40264C-T transition in exon 11 of the NOTCH1 gene, resulting in a thr596-to-met (T596M) substitution at a highly conserved residue within an EGF-like domain in the N-terminal half of the protein. The authors stated in the text that the variant was not found in at least 327 controls or in public variant databases, but stated in table 3 that the variant had a minor allele frequency of 0.01. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 AORTIC VALVE DISEASE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH1, PRO1797HIS
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000787044
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 55-year-old German man with a calcified bicuspid aortic valve and ascending aortic aneurysm (AOVD1; 109730), Mohamed et al. (2006) identified heterozygosity for a g.53777A-C transversion in exon 29 of the NOTCH1 gene, resulting in a pro1797-to-his (P1797H) substitution at a highly conserved residue in the short juxtamembrane within the intracellular domain. The authors stated in the text that the variant was not found in at least 327 controls or in public variant databases, but stated in table 3 that the variant had a minor allele frequency of 0.01. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., Fakhry, C., Xie, T.-X., Zhang, J., Wang, J., Zhang, N., El-Naggar, A. K., and 19 others.
|
|
<strong>Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.</strong>
|
|
Science 333: 1154-1157, 2011.
|
|
|
|
|
|
[PubMed: 21798897]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1206923]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aguirre, A., Rubio, M. E., Gallo, V.
|
|
<strong>Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal.</strong>
|
|
Nature 467: 323-327, 2010.
|
|
|
|
|
|
[PubMed: 20844536]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature09347]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Artavanis-Tsakonas, S., Matsuno, K., Fortini, M.
|
|
<strong>Notch signaling.</strong>
|
|
Science 268: 225-232, 1995.
|
|
|
|
|
|
[PubMed: 7716513]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.7716513]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Axelrod, J. D., Matsuno, K., Artavanis-Tsakonas, S., Perrimon, N.
|
|
<strong>Interaction between Wingless and Notch signaling pathways mediated by Dishevelled.</strong>
|
|
Science 271: 1826-1832, 1996.
|
|
|
|
|
|
[PubMed: 8596950]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.271.5257.1826]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Balint, K., Xiao, M., Pinnix, C. C., Soma, A., Veres, I., Juhasz, I., Brown, E. J., Capobianco, A. J., Herlyn, M., Liu, Z.-J.
|
|
<strong>Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.</strong>
|
|
J. Clin. Invest. 115: 3166-3176, 2005.
|
|
|
|
|
|
[PubMed: 16239965]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI25001]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H.
|
|
<strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong>
|
|
Nature 484: 110-114, 2012.
|
|
|
|
|
|
[PubMed: 22426001]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature10908]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boskovski, M. T., Yuan, S., Pedersen, N. B., Goth, C. K., Makova, S., Clausen, H., Brueckner, M., Khokha, M. K.
|
|
<strong>The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.</strong>
|
|
Nature 504: 456-459, 2013.
|
|
|
|
|
|
[PubMed: 24226769]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature12723]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J. R., Cumano, A., Roux, P., Black, R. A., Israel, A.
|
|
<strong>A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.</strong>
|
|
Molec. Cell 5: 207-216, 2000.
|
|
|
|
|
|
[PubMed: 10882063]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1097-2765(00)80417-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bruckner, K., Perez, L., Clausen, H., Cohen, S.
|
|
<strong>Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.</strong>
|
|
Nature 406: 411-415, 2000. Note: Erratum: Nature 407: 654 only, 2000.
|
|
|
|
|
|
[PubMed: 10935637]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35019075]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Carlson, M. E., Hsu, M., Conboy, I. M.
|
|
<strong>Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.</strong>
|
|
Nature 454: 528-532, 2008. Note: Erratum: Nature 538: 274 only, 2016.
|
|
|
|
|
|
[PubMed: 18552838]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature07034]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chan, Y.-M., Jan, Y. N.
|
|
<strong>Roles for proteolysis and trafficking in Notch maturation and signal transduction.</strong>
|
|
Cell 94: 423-426, 1998.
|
|
|
|
|
|
[PubMed: 9727485]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(00)81583-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Conboy, I. M., Conboy, M. J., Smythe, G. M., Rando, T. A.
|
|
<strong>Notch-mediated restoration of regenerative potential to aged muscle.</strong>
|
|
Science 302: 1575-1577, 2003.
|
|
|
|
|
|
[PubMed: 14645852]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1087573]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Conlon, R. A., Reaume, A. G., Rossant, J.
|
|
<strong>Notch1 is required for the coordinate segmentation of somites.</strong>
|
|
Development 121: 1533-1545, 1995.
|
|
|
|
|
|
[PubMed: 7789282]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1242/dev.121.5.1533]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dale, J. K., Maroto, M., Dequeant, M.-L., Malapert, P., McGrew, M., Pourquie, O.
|
|
<strong>Periodic Notch inhibition by lunatic Fringe underlies the chick segmentation clock.</strong>
|
|
Nature 421: 275-278, 2003.
|
|
|
|
|
|
[PubMed: 12529645]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature01244]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G.
|
|
<strong>Familial aplasia cutis congenita and coarctation of the aorta.</strong>
|
|
Am. J. Med. Genet. 43: 762-763, 1992.
|
|
|
|
|
|
[PubMed: 1621771]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.1320430423]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Das, I., Craig, C., Funahashi, Y., Jung, K.-M., Kim, T.-W., Byers, R., Weng, A. P., Kutok, J. L., Aster, J. C., Kitajewski, J.
|
|
<strong>Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.</strong>
|
|
J. Biol. Chem. 279: 30771-30780, 2004.
|
|
|
|
|
|
[PubMed: 15123653]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M309252200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., Goate, A., Kopan, R.
|
|
<strong>A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.</strong>
|
|
Nature 398: 518-522, 1999.
|
|
|
|
|
|
[PubMed: 10206645]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/19083]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
del Amo, F., Gendron-Maguire, M., Swiatek, P. J., Jenkins, N. A., Copeland, N. G., Gridley, T.
|
|
<strong>Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch.</strong>
|
|
Genomics 15: 259-264, 1993.
|
|
|
|
|
|
[PubMed: 8449489]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1993.1055]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Del Monte-Nieto, G., Ramialison, M., Adam, A. A. S., Wu, B., Aharonov, A., D'Uva, G., Bourke, L. M., Pitulescu, M. E., Chen, H., de la Pompa, J. L., Shou, W., Adams, R. H., Harten, S. K., Tzahor, E., Zhou, B., Harvey, R. P.
|
|
<strong>Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation.</strong>
|
|
Nature 557: 439-445, 2018.
|
|
|
|
|
|
[PubMed: 29743679]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41586-018-0110-6]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dequeant, M.-L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O.
|
|
<strong>A complex oscillating network of signaling genes underlies the mouse segmentation clock.</strong>
|
|
Science 314: 1595-1598, 2006.
|
|
|
|
|
|
[PubMed: 17095659]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1133141]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., Sklar, J.
|
|
<strong>TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.</strong>
|
|
Cell 66: 649-661, 1991.
|
|
|
|
|
|
[PubMed: 1831692]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0092-8674(91)90111-b]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Engel, M. E., Nguyen, H. N., Mariotti, J., Hunt, A., Hiebert, S. W.
|
|
<strong>Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification.</strong>
|
|
Molec. Cell. Biol. 30: 1852-1863, 2010.
|
|
|
|
|
|
[PubMed: 20123979]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/MCB.01342-09]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Engin, F., Bertin, T., Ma, O., Jiang, M. M., Wang, L., Sutton, R. E., Donehower, L. A., Lee, B.
|
|
<strong>Notch signaling contributes to the pathogenesis of human osteosarcomas.</strong>
|
|
Hum. Molec. Genet. 18: 1464-1470, 2009.
|
|
|
|
|
|
[PubMed: 19228774]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp057]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Engin, F., Yao, Z., Yang, T., Zhou, G., Bertin, T., Jiang, M. M., Chen, Y., Wang, L., Zheng, H., Sutton, R. E., Boyce, B. F., Lee, B.
|
|
<strong>Dimorphic effects of Notch signaling in bone homeostasis.</strong>
|
|
Nature Med. 14: 299-305, 2008.
|
|
|
|
|
|
[PubMed: 18297084]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm1712]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., Artavanis-Tsakonas, S.
|
|
<strong>Notch signals control the fate of immature progenitor cells in the intestine. (Letter)</strong>
|
|
Nature 435: 964-968, 2005.
|
|
|
|
|
|
[PubMed: 15959516]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature03589]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., Srivastava, D.
|
|
<strong>Mutations in NOTCH1 cause aortic valve disease.</strong>
|
|
Nature 437: 270-274, 2005.
|
|
|
|
|
|
[PubMed: 16025100]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature03940]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Guarani, V., Deflorian, G., Franco, C. A., Kruger, M., Phng, L.-K., Bentley, K., Toussaint, L., Dequiedt, F., Mostoslavsky, R., Schmidt, M. H. H., Zimmermann, B., Brandes, R. P., Mione, M., Westphal, C. H., Braun, T., Zeiher, A. M., Gerhardt, H., Dimmeler, S., Potente, M.
|
|
<strong>Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.</strong>
|
|
Nature 473: 234-238, 2011.
|
|
|
|
|
|
[PubMed: 21499261]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature09917]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gustafsson, M. V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J. L., Poellinger, L., Lendahl, U., Bondesson, M.
|
|
<strong>Hypoxia requires Notch signaling to maintain the undifferentiated cell state.</strong>
|
|
Dev. Cell 9: 617-628, 2005.
|
|
|
|
|
|
[PubMed: 16256737]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.devcel.2005.09.010]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hadland, B. K., Manley, N. R., Su, D., Longmore, G. D., Moore, C. L., Wolfe, M. S., Schroeter, E. H., Kopan, R.
|
|
<strong>Gamma-secretase inhibitors repress thymocyte development.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 7487-7491, 2001.
|
|
|
|
|
|
[PubMed: 11416218]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.131202798]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Han, H., Tanigaki, K., Yamamoto, N., Kuroda, K., Yoshimoto, M., Nakahata, T., Ikuta, K., Honjo, T.
|
|
<strong>Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.</strong>
|
|
Int. Immun. 14: 637-645, 2002.
|
|
|
|
|
|
[PubMed: 12039915]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/intimm/dxf030]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hardy, J., Israel, A.
|
|
<strong>In search of gamma-secretase.</strong>
|
|
Nature 398: 466-467, 1999.
|
|
|
|
|
|
[PubMed: 10206639]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/18979]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C.
|
|
<strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong>
|
|
Nature 445: 776-780, 2007.
|
|
|
|
|
|
[PubMed: 17259973]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature05571]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hilton, M. J., Tu, X., Wu, X., Bai, S., Zhao, H., Kobayashi, T., Kronenberg, H. M., Teitelbaum, S. L., Ross, F. P., Kopan, R., Long, F.
|
|
<strong>Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation.</strong>
|
|
Nature Med. 14: 306-314, 2008.
|
|
|
|
|
|
[PubMed: 18297083]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm1716]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S.
|
|
<strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong>
|
|
J. Exp. Med. 205: 2507-2513, 2008.
|
|
|
|
|
|
[PubMed: 18824583]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20080134]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hu, Q.-D., Ang, B.-T., Karsak, M., Hu, W.-P., Cui, X.-Y., Duka, T., Takeda, Y., Chia, W., Sankar, N., Ng, Y.-K., Ling, E.-A., Maciag, T., and 12 others.
|
|
<strong>F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.</strong>
|
|
Cell 115: 163-175, 2003.
|
|
|
|
|
|
[PubMed: 14567914]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(03)00810-9]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Huppert, S. S., Le, A., Schroeter, E. H., Mumm, J. S., Saxena, M. T., Milner, L. A., Kopan, R.
|
|
<strong>Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.</strong>
|
|
Nature 405: 966-970, 2000. Note: Erratum: Nature 408, 616 only, 2000.
|
|
|
|
|
|
[PubMed: 10879540]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35016111]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Jarriault, S., Brou, C., Logeat, F., Schroeter, E. H., Kopan, R., Israel, A.
|
|
<strong>Signalling downstream of activated mammalian Notch.</strong>
|
|
Nature 377: 355-358, 1995.
|
|
|
|
|
|
[PubMed: 7566092]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/377355a0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Jiang, Y.-J., Aerne, B. L., Smithers, L., Haddon, C., Ish-Horowitz, D., Lewis, J.
|
|
<strong>Notch signalling and the synchronization of the somite segmentation clock.</strong>
|
|
Nature 408: 475-479, 2000.
|
|
|
|
|
|
[PubMed: 11100729]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35044091]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L.
|
|
<strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong>
|
|
Science 342: 734-737, 2013.
|
|
|
|
|
|
[PubMed: 24091702]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1241359]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kerstjens-Frederikse, W. S., van de Laar, I. M. B. H., Vos, Y. J., Verhagen, J. M. A., Berger, R. M. F., Lichtenbelt, K. D., Klein Wassink-Ruiter, J. S., van der Zwaag, P. A., du Marchie-Sarvaas, G. J., Bergman, K. A., Bilardo, C. M., Roos-Hesselink, J. W., Janssen, J. H. P., Frohn-Mulder, I. M., van Spaendonck-Zwarts, K. Y., van Melle, J. P., Hofstra, R. M. W., Wessels, M. W.
|
|
<strong>Cardiovascular malformations caused by NOTCH mutations do not keep left: data on 428 probands with left-sided CHD and their families.</strong>
|
|
Genet. Med. 18: 914-923, 2016.
|
|
|
|
|
|
[PubMed: 26820064]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/gim.2015.193]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I.
|
|
<strong>A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.</strong>
|
|
Nature 473: 230-233, 2011.
|
|
|
|
|
|
[PubMed: 21562564]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature09999]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F.
|
|
<strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong>
|
|
J. Exp. Med. 205: 2515-2523, 2008.
|
|
|
|
|
|
[PubMed: 18824585]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20080829]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T.
|
|
<strong>Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.</strong>
|
|
Genes Dev. 17: 1207-1212, 2003.
|
|
|
|
|
|
[PubMed: 12730124]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.1084703]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Krebs, L. T., Xue, Y., Norton, C. R., Shutter, J. R., Maguire, M., Sundberg, J. P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., Smith, G. H., Stark, K. L., Gridley, T.
|
|
<strong>Notch signaling is essential for vascular morphogenesis in mice.</strong>
|
|
Genes Dev. 14: 1343-1352, 2000.
|
|
|
|
|
|
[PubMed: 10837027]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kumano, K., Chiba, S., Kunisato, A., Sata, M., Saito, T., Nakagami-Yamaguchi, E., Yamaguchi, T., Masuda, S., Shimizu, K., Takahashi, T., Ogawa, S., Hamada, Y., Hirai, H.
|
|
<strong>Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.</strong>
|
|
Immunity 18: 699-711, 2003.
|
|
|
|
|
|
[PubMed: 12753746]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1074-7613(03)00117-1]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Larsson, C., Lardelli, M., White, I., Lendahl, U.
|
|
<strong>The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.</strong>
|
|
Genomics 24: 253-258, 1994.
|
|
|
|
|
|
[PubMed: 7698746]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1994.1613]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lefort, K., Mandinova, A., Ostano, P., Kolev, V., Calpini, V., Kolfschoten, I., Devgan, V., Lieb, J., Raffoul, W., Hohl, D., Neel, V., Garlick, J., Chiorino, G., Dotto, G. P.
|
|
<strong>Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK-alpha kinases.</strong>
|
|
Genes Dev. 21: 562-577, 2007.
|
|
|
|
|
|
[PubMed: 17344417]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.1484707]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lim, J. S., Ibaseta, A., Fischer, M. M., Cancilla, B., O'Young, G., Cristea, S., Luca, V. C., Yang, D., Jahchan, N. S., Hamard, C., Antoine, M., Wislez, M., Kong, C., Cain, J., Liu, Y.-W., Kapoun, A. M., Garcia, K. C., Hoey, T., Murriel, C. L., Sage, J.
|
|
<strong>Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.</strong>
|
|
Nature 545: 360-364, 2017.
|
|
|
|
|
|
[PubMed: 28489825]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature22323]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lim, R., Sugino, T., Nolte, H., Andrade, J., Zimmermann, B., Shi, C., Doddaballapur, A., Ong, Y. T., Wilhelm, K., Fasse, J. W. D., Ernst, A., Kaulich, M., Husnjak, K., Boettger, T., Guenther, S., Braun, T., Kruger, M., Benedito, R., Dikic, I., Potente, M.
|
|
<strong>Deubiquitinase USP10 regulates Notch signaling in the endothelium.</strong>
|
|
Science 364: 188-193, 2019.
|
|
|
|
|
|
[PubMed: 30975888]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.aat0778]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Loganathan, S. K., Schleicher, K., Malik, A., Quevedo, R., Langille, E., Teng, K., Oh, R. H., Rathod, B., Tsai, R., Samavarchi-Tehrani, P., Pugh, T. J., Gingras, A.-C., Schramek, D.
|
|
<strong>Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.</strong>
|
|
Science 367: 1264-1269, 2020.
|
|
|
|
|
|
[PubMed: 32165588]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.aax0902]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Logeat, F., Bessia, C., Brou, C., LeBail, O., Jarriault, S., Seidah, N. G., Israel, A.
|
|
<strong>The Notch1 receptor is cleaved constitutively by a furin-like convertase.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 8108-8112, 1998.
|
|
|
|
|
|
[PubMed: 9653148]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.95.14.8108]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Loomes, K. M., Taichman, D. B., Glover, C. L., Williams, P. T., Markowitz, J. E., Piccoli, D. A., Baldwin, H. S., Oakey, R. J.
|
|
<strong>Characterization of Notch receptor expression in the developing mammalian heart and liver.</strong>
|
|
Am. J. Med. Genet. 112: 181-189, 2002.
|
|
|
|
|
|
[PubMed: 12244553]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.10592]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Loomes, K. M., Underkoffler, L. A., Morabito, J., Gottlieb, S., Piccoli, D. A., Spinner, N. B., Baldwin, H. S., Oakey, R. J.
|
|
<strong>The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome.</strong>
|
|
Hum. Molec. Genet. 8: 2443-2449, 1999.
|
|
|
|
|
|
[PubMed: 10556292]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.13.2443]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Luca, V. C., Jude, K. M., Pierce, N. W., Nachury, M. V., Fischer, S., Garcia, K. C.
|
|
<strong>Structural basis for Notch1 engagement of delta-like 4.</strong>
|
|
Science 347: 847-853, 2015.
|
|
|
|
|
|
[PubMed: 25700513]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1261093]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Luca, V. C., Kim, B. C., Ge, C., Kakuda, S., Wu, D., Roein-Peikar, M., Haltiwanger, R. S., Zhu, C., Ha, T., Garcia, K. C.
|
|
<strong>Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity.</strong>
|
|
Science 355: 1320-1324, 2017.
|
|
|
|
|
|
[PubMed: 28254785]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.aaf9739]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Maeda, T., Merghoub, T., Hobbs, R. M., Dong, L., Maeda, M., Zakrzewski, J., van den Brink, M. R. M., Zelent, A., Shigematsu, H., Akashi, K., Teruya-Feldstein, J., Cattoretti, G., Pandolfi, P. P.
|
|
<strong>Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF.</strong>
|
|
Science 316: 860-866, 2007.
|
|
|
|
|
|
[PubMed: 17495164]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1140881]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Magnusson, J. P., Goritz, C., Tatarishvili, J., Dias, D. O., Smith, E. M. K., Lindvall, O., Kokaia, Z., Frisen, J.
|
|
<strong>A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.</strong>
|
|
Science 346: 237-241, 2014.
|
|
|
|
|
|
[PubMed: 25301628]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.346.6206.237]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mammucari, C., Tommasi di Vignano, A., Sharov, A. A., Neilson, J., Havrda, M. C., Roop, D. R., Botchkarev, V. A., Crabtree, G. R., Dotto, G. P.
|
|
<strong>Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.</strong>
|
|
Dev. Cell 8: 665-676, 2005.
|
|
|
|
|
|
[PubMed: 15866158]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.devcel.2005.02.016]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
McBride, K. L., Riley, M. F., Zender, G. A., Fitzgerald-Butt, S. M., Towbin, J. A., Belmont, J. W., Cole, S. E.
|
|
<strong>NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.</strong>
|
|
Hum. Molec. Genet. 17: 2886-2893, 2008.
|
|
|
|
|
|
[PubMed: 18593716]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn187]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Milner, L. A., Kopan, R., Martin, D. I. K., Bernstein, I. D.
|
|
<strong>A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors.</strong>
|
|
Blood 83: 2057-2062, 1994.
|
|
|
|
|
|
[PubMed: 7512837]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mizutani, K., Yoon, K., Dang, L., Tokunaga, A., Gaiano, N.
|
|
<strong>Differential Notch signalling distinguishes neural stem cells from intermediate progenitors.</strong>
|
|
Nature 449: 351-355, 2007.
|
|
|
|
|
|
[PubMed: 17721509]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature06090]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Moellering, R. E., Cornejo, M., Davis, T. N., Del Bianco, C., Aster, J. C., Blacklow, S. C., Kung, A. L., Gilliland, D. G., Verdine, G. L., Bradner, J. E.
|
|
<strong>Direct inhibition of the NOTCH transcription factor complex.</strong>
|
|
Nature 462: 182-188, 2009. Note: Erratum: Nature 463: 384 only, 2010.
|
|
|
|
|
|
[PubMed: 19907488]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature08543]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mohamed, S. A., Aherrahrou, Z., Liptau, H., Erasmi, A. W., Hagemann, C., Wrobel, S., Borzym, K., Schunkert, H., Sievers, H. H., Erdmann, J.
|
|
<strong>Novel missense mutations (p.T596M and p.P1797H) in MOTCH1 in patients with bicuspid aortic valve.</strong>
|
|
Biochem. Biophys. Res. Commun. 345: 1460-1465, 2006.
|
|
|
|
|
|
[PubMed: 16729972]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.bbrc.2006.05.046]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Moloney, D. J., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K. D., Haltiwanger, R. S., Vogt, T. F.
|
|
<strong>Fringe is a glycosyltransferase that modifies Notch.</strong>
|
|
Nature 406: 369-375, 2000.
|
|
|
|
|
|
[PubMed: 10935626]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35019000]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Morales, A. V., Yasuda, Y., Ish-Horowicz, D.
|
|
<strong>Periodic lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling.</strong>
|
|
Dev. Cell 3: 63-74, 2002.
|
|
|
|
|
|
[PubMed: 12110168]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1534-5807(02)00211-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Moretti, J., Chastagner, P., Liang, C.-C., Cohn, M. A., Israel, A., Brou, C.
|
|
<strong>The ubiquitin-specific protease 12 (USP12) is a negative regulator of Notch signaling acting on Notch receptor trafficking toward degradation.</strong>
|
|
J. Biol. Chem. 287: 29429-29441, 2012.
|
|
|
|
|
|
[PubMed: 22778262]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M112.366807]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Morimoto, M., Takahashi, Y., Endo, M., Saga, Y.
|
|
<strong>The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity.</strong>
|
|
Nature 435: 354-359, 2005.
|
|
|
|
|
|
[PubMed: 15902259]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature03591]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mumm, J. S., Schroeter, E. H., Saxena, M. T., Griesemer, A., Tian, X., Pan, D. J., Ray, W. J., Kopan, R.
|
|
<strong>A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.</strong>
|
|
Molec. Cell 5: 197-206, 2000.
|
|
|
|
|
|
[PubMed: 10882062]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1097-2765(00)80416-5]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Murtaugh, L. C., Stanger, B. Z., Kwan, K. M., Melton, D. A.
|
|
<strong>Notch signaling controls multiple steps of pancreatic differentiation.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 14920-14925, 2003.
|
|
|
|
|
|
[PubMed: 14657333]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.2436557100]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H., Dotto, G. P., Radtke, F.
|
|
<strong>Notch1 functions as a tumor suppressor in mouse skin.</strong>
|
|
Nature Genet. 33: 416-421, 2003.
|
|
|
|
|
|
[PubMed: 12590261]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1099]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Niranjan, T., Bielesz, B., Gruenwald, A., Ponda, M. P., Kopp, J. B., Thomas, D. B., Susztak, K.
|
|
<strong>The Notch pathway in podocytes plays a role in the development of glomerular disease.</strong>
|
|
Nature Med. 14: 290-298, 2008.
|
|
|
|
|
|
[PubMed: 18311147]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm1731]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nueda, M. L., Gonzalez-Gomez, M. J., Rodriguez-Cano, M. M., Monsalve, E. M., Diaz-Guerra, M. J. M., Sanchez-Solana, B., Laborda, J., Baladron, V.
|
|
<strong>DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate.</strong>
|
|
Sci. Rep. 8: 16923, 2018.
|
|
|
|
|
|
[PubMed: 30446682]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41598-018-35252-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Okajima, T., Irvine, K. D.
|
|
<strong>Regulation of Notch signaling by O-linked fucose.</strong>
|
|
Cell 111: 893-904, 2002.
|
|
|
|
|
|
[PubMed: 12526814]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(02)01114-5]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Okuyama, R., Nguyen, B.-C., Talora, C., Ogawa, E., Tommasi di Vignano, A., Lioumi, M., Chiorino, G., Tagami, H., Woo, M., Dotto, G. P.
|
|
<strong>High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.</strong>
|
|
Dev. Cell 6: 551-562, 2004.
|
|
|
|
|
|
[PubMed: 15068794]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1534-5807(04)00098-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Palomero, T., Lim, W. K., Odom, D. T., Sulis, M. L., Real, P. J., Margolin, A., Barnes, K. C., O'Neil, J., Neuberg, D., Weng, A. P., Aster, J. C., Sigaux, F., Soulier, J., Look, A. T., Young, R. A., Califano, A., Ferrando, A. A.
|
|
<strong>NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 18261-18266, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 104: 4240 only, 2007.
|
|
|
|
|
|
[PubMed: 17114293]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0606108103]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Palomero, T., Sulis, M. L., Cortina, M., Real, P. J., Barnes, K., Ciofani, M., Caparros, E., Buteau, J., Brown, K., Perkins, S. L., Bhagat, G., Agarwal, A. M., Basso, G., Castillo, M., Nagase, S., Cordon-Cardo, C., Parsons, R., Zuniga-Pflucker, J. C., Dominguez, M., Ferrando, A. A.
|
|
<strong>Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.</strong>
|
|
Nature Med. 13: 1203-1210, 2007.
|
|
|
|
|
|
[PubMed: 17873882]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm1636]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Pilz, A., Prohaska, R., Peters, J., Abbott, C.
|
|
<strong>Genetic linkage analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notch1 genes in the region of mouse chromosome 2 homologous to human chromosome 9q.</strong>
|
|
Genomics 21: 104-109, 1994.
|
|
|
|
|
|
[PubMed: 8088777]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1994.1230]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Polacheck, W. J., Kutys, M. L., Yang, J., Eyckmans, J., Wu, Y., Vasavada, H., Hirschi, K. K., Chen, C. S.
|
|
<strong>A non-canonical Notch complex regulates adherens junctions and vascular barrier function.</strong>
|
|
Nature 552: 258-262, 2017.
|
|
|
|
|
|
[PubMed: 29160307]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature24998]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Puca, L., Chastagner, P., Meas-Yedid, V., Israel, A., Brou, C.
|
|
<strong>Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals.</strong>
|
|
J. Cell Sci. 126: 4457-4468, 2013.
|
|
|
|
|
|
[PubMed: 23886940]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1242/jcs.130500]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordonez, G. R., Villamor, N., Escaramis, G., Jares, P., Bea, S., Gonzalez-Diaz, M., Bassaganyas, L., Baumann, T., and 52 others.
|
|
<strong>Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.</strong>
|
|
Nature 475: 101-105, 2011.
|
|
|
|
|
|
[PubMed: 21642962]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature10113]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Quesada, V., Conde, L., Villamor, N., Ordonez, G. R., Jares, P., Bassaganyas, L., Ramsay, A. J., Bea, S., Pinyol, M., Martinez-Trillos, A., Lopez-Guerra, M., Colomer, D., and 29 others.
|
|
<strong>Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.</strong>
|
|
Nature Genet. 44: 47-52, 2012.
|
|
|
|
|
|
[PubMed: 22158541]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.1032]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rangarajan, A., Talora, C., Okuvama, R., Nicolas, M., Mammucari, C., Oh, H., Aster, J. C., Krishna, S., Metzger, D., Chambon, P., Miele, L., Aguet, M., Radtke, F., Dotto, G. P.
|
|
<strong>Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.</strong>
|
|
EMBO J. 20: 3427-3436, 2001.
|
|
|
|
|
|
[PubMed: 11432830]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/emboj/20.13.3427]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Buscher, D., Koth, C. M., Itoh, T., Morita, M., Raya, R. M., Dubova, I., Bessa, J. G., de la Pompa, J. L., Belmonte, J. C. I.
|
|
<strong>Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos.</strong>
|
|
Genes Dev. 17: 1213-1218, 2003.
|
|
|
|
|
|
[PubMed: 12730123]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.1084403]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M., Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A., Belmonte, J. C. I.
|
|
<strong>Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.</strong>
|
|
Nature 427: 121-128, 2004.
|
|
|
|
|
|
[PubMed: 14712268]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature02190]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Real, P. J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M. L., Barnes, K., Sawai, C., Homminga, I., Meijerink, J., Aifantis, I., Basso, G., Cordon-Cardo, C., Ai, W., Ferrando, A.
|
|
<strong>Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.</strong>
|
|
Nature Med. 15: 50-58, 2009.
|
|
|
|
|
|
[PubMed: 19098907]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm.1900]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L.
|
|
<strong>A role for Wnt signalling in self-renewal of haematopoietic stem cells.</strong>
|
|
Nature 423: 409-414, 2003.
|
|
|
|
|
|
[PubMed: 12717450]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature01593]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Riccio, O., van Gijn, M. E., Bezdek, A. C., Pellegrinet, L., van Es, J. H., Zimber-Strobl, U., Strobl, L. J., Honjo, T., Clevers, H., Radtke, F.
|
|
<strong>Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27(Kip1) and p57(Kip2).</strong>
|
|
EMBO Rep. 9: 377-383, 2008.
|
|
|
|
|
|
[PubMed: 18274550]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/embor.2008.7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C.
|
|
<strong>Neural crest regulates myogenesis through the transient activation of NOTCH.</strong>
|
|
Nature 473: 532-535, 2011.
|
|
|
|
|
|
[PubMed: 21572437]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature09970]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Roderick, J. E., Gonzalez-Perez, G., Kuksin, C. A., Dongre, A., Roberts, E. R., Srinivasan, J., Andrzejewski, C., Jr., Fauq, A. H., Golde, T. E., Miele, L., Minter, L. M.
|
|
<strong>Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.</strong>
|
|
J. Exp. Med. 210: 1311-1329, 2013.
|
|
|
|
|
|
[PubMed: 23733784]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20112615]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., Kaplan, F., Capobianco, A., Pece, S., De Fiore, P. P., Del Sal, G.
|
|
<strong>The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.</strong>
|
|
Nature Cell Biol. 11: 133-142, 2009.
|
|
|
|
|
|
[PubMed: 19151708]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ncb1822]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sanchez-Solana, B., Nueda, M. L., Ruvira, M. D., Ruiz-Hidalgo, M. J., Monsalve, E. M., Rivero, S., Garcia-Ramirez, J. J., Diaz-Guerra, M. J., Baladron, V., Laborda, J.
|
|
<strong>The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.</strong>
|
|
Biochim. Biophys. Acta 1813: 1153-1164, 2011.
|
|
|
|
|
|
[PubMed: 21419176]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.bbamcr.2011.03.004]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schroeter, E. H., Kisslinger, J. A., Kopan, R.
|
|
<strong>Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.</strong>
|
|
Nature 393: 382-386, 1998.
|
|
|
|
|
|
[PubMed: 9620803]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/30756]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sestan, N., Artavanis-Tsakonas, S., Rakic, P.
|
|
<strong>Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling.</strong>
|
|
Science 286: 741-746, 1999.
|
|
|
|
|
|
[PubMed: 10531053]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.286.5440.741]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., Temple, S.
|
|
<strong>Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells.</strong>
|
|
Science 304: 1338-1340, 2004.
|
|
|
|
|
|
[PubMed: 15060285]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1095505]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Siekmann, A. F., Lawson, N. D.
|
|
<strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong>
|
|
Nature 445: 781-784, 2007.
|
|
|
|
|
|
[PubMed: 17259972]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature05577]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S.
|
|
<strong>Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?</strong>
|
|
Am. J. Med. Genet. 158A: 648-651, 2012.
|
|
|
|
|
|
[PubMed: 22307742]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.34435]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sjolund, J., Johansson, M., Manna, S., Norin, C., Pietras, A., Beckman, S., Nilsson, E., Ljungberg, B., Axelson, H.
|
|
<strong>Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo.</strong>
|
|
J. Clin. Invest. 118: 217-228, 2008.
|
|
|
|
|
|
[PubMed: 18079963]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI32086]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C.
|
|
<strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong>
|
|
Circ. Cardiovasc. Genet. 8: 572-581, 2015.
|
|
|
|
|
|
[PubMed: 25963545]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/CIRCGENETICS.115.001086]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B.
|
|
<strong>Cis-interactions between Notch and Delta generate mutually exclusive signalling states.</strong>
|
|
Nature 465: 86-91, 2010.
|
|
|
|
|
|
[PubMed: 20418862]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature08959]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stanger, B. Z., Datar, R., Murtaugh, L. C., Melton, D. A.
|
|
<strong>Direct regulation of intestinal fate by Notch.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 12443-12448, 2005.
|
|
|
|
|
|
[PubMed: 16107537]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0505690102]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S.
|
|
<strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong>
|
|
Am. J. Hum. Genet. 95: 275-284, 2014.
|
|
|
|
|
|
[PubMed: 25132448]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2014.07.011]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stransky, N., Egloff, A. M., Tward, A. D., Kostic, A. D., Cibulskis, K., Sivachenko, A., Kryukov, G. V., Lawrence, M. S., Sougnez, C., McKenna, A., Shefler, E., Ramos, A. H., and 27 others.
|
|
<strong>The mutational landscape of head and neck squamous cell carcinoma.</strong>
|
|
Science 333: 1157-1160, 2011.
|
|
|
|
|
|
[PubMed: 21798893]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1208130]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Struhl, G., Greenwald, I.
|
|
<strong>Presenilin is required for activity and nuclear access of Notch in Drosophila.</strong>
|
|
Nature 398: 522-525, 1999.
|
|
|
|
|
|
[PubMed: 10206646]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/19091]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G., Gridley, T.
|
|
<strong>Notch1 is essential for postimplantation development in mice.</strong>
|
|
Genes Dev. 8: 707-719, 1994.
|
|
|
|
|
|
[PubMed: 7926761]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.8.6.707]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Takahashi, Y., Koizumi, K., Takagi, A., Kitajima, S., Inoue, T., Koseki, H., Saga, Y.
|
|
<strong>Mesp2 initiates somite segmentation through the Notch signalling pathway.</strong>
|
|
Nature Genet. 25: 390-396, 2000.
|
|
|
|
|
|
[PubMed: 10932180]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/78062]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T.
|
|
<strong>Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.</strong>
|
|
Neuron 29: 45-55, 2001.
|
|
|
|
|
|
[PubMed: 11182080]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0896-6273(01)00179-9]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tanigaki, K., Tsuji, M., Yamamoto, N., Han, H., Tsukada, J., Inoue, H., Kubo, M., Honjo, T.
|
|
<strong>Regulation of alpha-beta/gamma-delta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling.</strong>
|
|
Immunity 20: 611-622, 2004.
|
|
|
|
|
|
[PubMed: 15142529]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1074-7613(04)00109-8]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M.
|
|
<strong>A gp130-Src-YAP module links inflammation to epithelial regeneration.</strong>
|
|
Nature 519: 57-62, 2015.
|
|
|
|
|
|
[PubMed: 25731159]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature14228]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van Es, J. H., van Gijn, M. E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D. J., Radtke, F., Clevers, H.
|
|
<strong>Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. (Letter)</strong>
|
|
Nature 435: 959-963, 2005.
|
|
|
|
|
|
[PubMed: 15959515]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature03659]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vandersteen, A. M., Dixon, J. W.
|
|
<strong>Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.</strong>
|
|
Clin. Dysmorph. 20: 210-213, 2011.
|
|
|
|
|
|
[PubMed: 21785343]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1097/MCD.0b013e32834964d1]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vauclair, S., Majo, F., Durham, A.-D., Ghyselinck, N. B., Barrandon, Y., Radtke, F.
|
|
<strong>Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism.</strong>
|
|
Dev. Cell 13: 242-253, 2007.
|
|
|
|
|
|
[PubMed: 17681135]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.devcel.2007.06.012]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vilimas, T., Mascarenhas, J., Palomero, T., Mandal, M., Buonamici, S., Meng, F., Thompson, B., Spaulding, C., Macaroun, S., Alegre, M.-L., Kee, B. L., Ferrando, A., Miele, L., Aifantis, I.
|
|
<strong>Targeting the NF-kappa-B signaling pathway in Notch1-induced T-cell leukemia.</strong>
|
|
Nature Med. 13: 70-77, 2007.
|
|
|
|
|
|
[PubMed: 17173050]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm1524]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Visan, I., Tan, J. B., Yuan, J. S., Harper, J. A., Koch, U., Guidos, C. J.
|
|
<strong>Regulation of T lymphopoiesis by Notch1 and lunatic fringe-mediated competition for intrathymic niches.</strong>
|
|
Nature Immun. 7: 634-643, 2006.
|
|
|
|
|
|
[PubMed: 16699526]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ni1345]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, J., Shelly, L., Miele, L., Boykins, R., Norcross, M. A., Guan, E.
|
|
<strong>Human Notch-1 inhibits NF-kappa-B activity in the nucleus through a direct interaction involving a novel domain.</strong>
|
|
J. Immun. 167: 289-295, 2001.
|
|
|
|
|
|
[PubMed: 11418662]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.167.1.289]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Weaver, K. L., Alves-Guerra, M.-C., Jin, K., Wang, Z., Han, X., Ranganathan, P., Zhu, X., DaSilva, T., Liu, W., Ratti, F., Demarest, R. M., Tzimas, C., Rice, M., Vasquez-Del Carpio, R., Dahmane, N., Robbins, D. J., Capobianco, A. J.
|
|
<strong>NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.</strong>
|
|
Cancer Res. 74: 4741-4751, 2014.
|
|
|
|
|
|
[PubMed: 25038227]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1158/0008-5472.CAN-14-1547]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C., Hahn, W. C., Rudolf, M., Siziopikou, K., Kast, W. M., Miele, L.
|
|
<strong>Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.</strong>
|
|
Nature Med. 8: 979-986, 2002.
|
|
|
|
|
|
[PubMed: 12185362]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm754]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. P., IV, Silverman, L. B., Sanchez-Irizarry, C., Blacklow, S. C., Look, A. T., Aster, J. C.
|
|
<strong>Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.</strong>
|
|
Science 306: 269-271, 2004.
|
|
|
|
|
|
[PubMed: 15472075]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1102160]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others.
|
|
<strong>Therapeutic antibody targeting of individual Notch receptors.</strong>
|
|
Nature 464: 1052-1057, 2010.
|
|
|
|
|
|
[PubMed: 20393564]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature08878]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yamamoto, S., Charng, W.-L., Rana, N. A., Kakuda, S., Jaiswal, M., Bayat, V., Xiong, B., Zhang, K., Sandoval, H., David, G., Wang, H., Haltiwanger, R. S., Bellen, H. J.
|
|
<strong>A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.</strong>
|
|
Science 338: 1229-1232, 2012.
|
|
|
|
|
|
[PubMed: 23197537]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1228745]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yang, G., Zhou, R., Zhou, Q., Guo, X., Yan, C., Ke, M., Lei, J., Shi, Y.
|
|
<strong>Structural basis of Notch recognition by human gamma-secretase.</strong>
|
|
Nature 565: 192-197, 2019.
|
|
|
|
|
|
[PubMed: 30598546]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41586-018-0813-8]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ye, Y., Lukinova, N., Fortini, M. E.
|
|
<strong>Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants.</strong>
|
|
Nature 398: 525-529, 1999.
|
|
|
|
|
|
[PubMed: 10206647]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/19096]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., Fujii, Y., Yoshida, K., and 28 others.
|
|
<strong>Age-related remodelling of esophageal epithelia by mutated cancer drivers.</strong>
|
|
Nature 565: 312-317, 2019.
|
|
|
|
|
|
[PubMed: 30602793]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41586-018-0811-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yu, H., Saura, C. A., Choi, S.-Y., Sun, L. D., Yang, X., Handler, M., Kawarabayashi, T., Younkin, L., Fedeles, B., Wilson, M. A., Younkin, S., Kandel, E. R., Kirkwood, A., Shen, J.
|
|
<strong>APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.</strong>
|
|
Neuron 31: 713-726, 2001.
|
|
|
|
|
|
[PubMed: 11567612]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0896-6273(01)00417-2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Bao Lige - updated : 03/06/2025<br>Bao Lige - updated : 03/01/2022<br>Ada Hamosh - updated : 01/25/2021<br>Ada Hamosh - updated : 09/16/2020<br>Ada Hamosh - updated : 09/27/2019<br>Ada Hamosh - updated : 08/12/2019<br>Marla J. F. O'Neill - updated : 07/08/2019<br>Ada Hamosh - updated : 03/07/2019<br>Ada Hamosh - updated : 10/19/2018<br>Ada Hamosh - updated : 09/06/2018<br>Ada Hamosh - updated : 02/12/2018<br>Ada Hamosh - updated : 08/11/2017<br>Patricia A. Hartz - updated : 04/27/2017<br>Sarah M. Robbins - updated : 02/10/2017<br>Marla J. F. O'Neill - updated : 1/30/2016<br>Ada Hamosh - updated : 6/3/2015<br>Ada Hamosh - updated : 3/11/2015<br>Ada Hamosh - updated : 11/10/2014<br>Marla J. F. O'Neill - updated : 9/24/2014<br>Paul J. Converse - updated : 7/2/2014<br>Ada Hamosh - updated : 1/31/2014<br>Ada Hamosh - updated : 1/15/2014<br>Ada Hamosh - updated : 1/14/2013<br>Paul J. Converse - updated : 7/16/2012<br>Patricia A. Hartz - updated : 6/8/2012<br>Marla J. F. O'Neill - updated : 2/14/2012<br>Cassandra L. Kniffin - updated : 1/25/2012<br>Ada Hamosh - updated : 9/21/2011<br>Ada Hamosh - updated : 6/22/2011<br>Ada Hamosh - updated : 5/23/2011<br>Ada Hamosh - updated : 9/29/2010<br>Ada Hamosh - updated : 6/8/2010<br>Ada Hamosh - updated : 5/27/2010<br>Ada Hamosh - updated : 2/18/2010<br>Patricia A. Hartz - updated : 1/20/2010<br>Ada Hamosh - updated : 12/29/2009<br>George E. Tiller - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 2/12/2009<br>Ada Hamosh - updated : 8/13/2008<br>Patricia A. Hartz - updated : 5/29/2008<br>Patricia A. Hartz - updated : 3/13/2008<br>Ada Hamosh - updated : 1/10/2008<br>Cassandra L. Kniffin - updated : 10/25/2007<br>Patricia A. Hartz - updated : 9/21/2007<br>Patricia A. Hartz - updated : 7/10/2007<br>Ada Hamosh - updated : 7/5/2007<br>Ada Hamosh - updated : 6/26/2007<br>Paul J. Converse - updated : 6/7/2007<br>Patricia A. Hartz - updated : 5/7/2007<br>Marla J. F. O'Neill - updated : 2/26/2007<br>Patricia A. Hartz - updated : 1/26/2007<br>Ada Hamosh - updated : 1/23/2007<br>Paul J. Converse - updated : 12/20/2006<br>Paul J. Converse - updated : 6/20/2006<br>Patricia A. Hartz - updated : 1/26/2006<br>Marla J. F. O'Neill - updated : 12/16/2005<br>Patricia A. Hartz - updated : 12/13/2005<br>Paul J. Converse - updated : 10/20/2005<br>Matthew B. Gross - reorganized : 10/3/2005<br>Joanna S. Amberger - updated : 10/3/2005<br>Patricia A. Hartz - updated : 9/20/2005<br>Ada Hamosh - updated : 9/7/2005<br>Patricia A. Hartz - updated : 6/30/2005<br>Ada Hamosh - updated : 6/3/2005<br>Ada Hamosh - updated : 2/2/2005<br>Ada Hamosh - updated : 6/8/2004<br>Patricia A. Hartz - updated : 5/12/2004<br>Ada Hamosh - updated : 1/22/2004<br>Ada Hamosh - updated : 12/3/2003<br>Cassandra L. Kniffin - updated : 5/16/2003<br>Ada Hamosh - updated : 5/6/2003<br>Deborah L. Stone - updated : 3/26/2003<br>Dawn Watkins-Chow - updated : 2/27/2003<br>Victor A. McKusick - updated : 2/20/2003<br>Stylianos E. Antonarakis - updated : 1/17/2003<br>Ada Hamosh - updated : 1/17/2003<br>Ada Hamosh - updated : 9/30/2002<br>Dawn Watkins-Chow - updated : 2/14/2002<br>Paul J. Converse - updated : 11/26/2001<br>Victor A. McKusick - updated : 7/6/2001<br>Ada Hamosh - updated : 4/26/2001<br>Ada Hamosh - updated : 11/30/2000<br>Ada Hamosh - updated : 8/2/2000<br>Ada Hamosh - updated : 7/27/2000<br>Patti M. Sherman - updated : 7/13/2000<br>Ada Hamosh - updated : 6/20/2000<br>Stylianos E. Antonarakis - updated : 3/27/2000<br>Ada Hamosh - updated : 10/20/1999<br>Victor A. McKusick - updated : 4/6/1999<br>Moyra Smith - updated : 3/28/1996
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 10/28/1991
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Edit History:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
mgross : 03/06/2025<br>alopez : 08/04/2022<br>carol : 03/02/2022<br>mgross : 03/01/2022<br>mgross : 02/09/2021<br>mgross : 01/25/2021<br>alopez : 09/16/2020<br>carol : 02/05/2020<br>alopez : 09/27/2019<br>alopez : 08/12/2019<br>alopez : 08/12/2019<br>carol : 08/07/2019<br>carol : 07/24/2019<br>carol : 07/08/2019<br>alopez : 03/07/2019<br>alopez : 12/21/2018<br>carol : 11/26/2018<br>alopez : 10/19/2018<br>alopez : 09/06/2018<br>carol : 02/13/2018<br>alopez : 02/12/2018<br>carol : 10/05/2017<br>alopez : 08/11/2017<br>carol : 04/27/2017<br>carol : 04/19/2017<br>mgross : 02/10/2017<br>alopez : 12/19/2016<br>carol : 09/06/2016<br>carol : 03/16/2016<br>carol : 1/30/2016<br>alopez : 6/3/2015<br>alopez : 3/11/2015<br>alopez : 11/10/2014<br>carol : 9/29/2014<br>carol : 9/25/2014<br>mcolton : 9/24/2014<br>mgross : 7/2/2014<br>mcolton : 7/2/2014<br>alopez : 1/31/2014<br>alopez : 1/15/2014<br>mgross : 10/7/2013<br>alopez : 1/16/2013<br>terry : 1/14/2013<br>terry : 12/20/2012<br>terry : 12/19/2012<br>carol : 9/17/2012<br>carol : 9/17/2012<br>mgross : 7/20/2012<br>terry : 7/16/2012<br>mgross : 6/8/2012<br>terry : 6/7/2012<br>alopez : 4/25/2012<br>alopez : 4/11/2012<br>alopez : 3/7/2012<br>carol : 2/15/2012<br>terry : 2/14/2012<br>carol : 2/1/2012<br>ckniffin : 1/25/2012<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>terry : 9/21/2011<br>alopez : 6/27/2011<br>terry : 6/22/2011<br>alopez : 5/24/2011<br>terry : 5/23/2011<br>alopez : 10/4/2010<br>terry : 9/29/2010<br>terry : 9/9/2010<br>alopez : 6/8/2010<br>terry : 6/8/2010<br>alopez : 6/1/2010<br>terry : 5/27/2010<br>terry : 5/27/2010<br>terry : 2/18/2010<br>mgross : 1/20/2010<br>alopez : 1/5/2010<br>terry : 12/29/2009<br>wwang : 10/20/2009<br>terry : 10/15/2009<br>wwang : 3/4/2009<br>ckniffin : 2/12/2009<br>alopez : 8/20/2008<br>terry : 8/13/2008<br>mgross : 6/3/2008<br>terry : 5/29/2008<br>mgross : 3/18/2008<br>terry : 3/13/2008<br>ckniffin : 2/5/2008<br>alopez : 1/28/2008<br>terry : 1/10/2008<br>wwang : 11/5/2007<br>ckniffin : 10/25/2007<br>mgross : 9/27/2007<br>terry : 9/21/2007<br>terry : 7/10/2007<br>alopez : 7/5/2007<br>alopez : 7/2/2007<br>terry : 6/26/2007<br>mgross : 6/7/2007<br>mgross : 6/7/2007<br>wwang : 5/7/2007<br>wwang : 2/26/2007<br>mgross : 1/26/2007<br>mgross : 1/26/2007<br>alopez : 1/25/2007<br>terry : 1/23/2007<br>mgross : 12/20/2006<br>carol : 8/16/2006<br>alopez : 8/3/2006<br>terry : 8/1/2006<br>mgross : 6/20/2006<br>mgross : 2/2/2006<br>terry : 1/26/2006<br>wwang : 12/16/2005<br>wwang : 12/13/2005<br>mgross : 10/20/2005<br>mgross : 10/20/2005<br>mgross : 10/4/2005<br>mgross : 10/3/2005<br>mgross : 10/3/2005<br>mgross : 10/3/2005<br>joanna : 10/3/2005<br>wwang : 9/21/2005<br>wwang : 9/20/2005<br>alopez : 9/14/2005<br>alopez : 9/14/2005<br>terry : 9/7/2005<br>wwang : 6/30/2005<br>wwang : 6/7/2005<br>wwang : 6/3/2005<br>alopez : 2/23/2005<br>terry : 2/2/2005<br>terry : 7/1/2004<br>alopez : 6/9/2004<br>terry : 6/8/2004<br>mgross : 5/13/2004<br>terry : 5/12/2004<br>alopez : 1/22/2004<br>terry : 1/22/2004<br>alopez : 12/8/2003<br>terry : 12/3/2003<br>alopez : 5/28/2003<br>cwells : 5/22/2003<br>ckniffin : 5/16/2003<br>alopez : 5/6/2003<br>alopez : 5/6/2003<br>terry : 5/6/2003<br>carol : 3/26/2003<br>carol : 3/26/2003<br>carol : 3/26/2003<br>tkritzer : 3/24/2003<br>tkritzer : 3/24/2003<br>alopez : 3/12/2003<br>carol : 3/4/2003<br>tkritzer : 2/27/2003<br>tkritzer : 2/27/2003<br>alopez : 2/21/2003<br>terry : 2/20/2003<br>mgross : 1/17/2003<br>alopez : 1/17/2003<br>terry : 1/17/2003<br>terry : 1/17/2003<br>alopez : 10/1/2002<br>tkritzer : 9/30/2002<br>carol : 3/1/2002<br>terry : 2/14/2002<br>mgross : 12/5/2001<br>terry : 11/26/2001<br>alopez : 7/16/2001<br>mcapotos : 7/6/2001<br>mcapotos : 5/7/2001<br>mcapotos : 5/3/2001<br>terry : 4/26/2001<br>mcapotos : 2/13/2001<br>carol : 12/1/2000<br>terry : 11/30/2000<br>terry : 10/6/2000<br>mgross : 9/15/2000<br>mcapotos : 8/7/2000<br>alopez : 8/2/2000<br>alopez : 7/27/2000<br>alopez : 7/27/2000<br>mcapotos : 7/21/2000<br>psherman : 7/13/2000<br>alopez : 6/21/2000<br>carol : 6/20/2000<br>mgross : 3/27/2000<br>alopez : 10/23/1999<br>terry : 10/20/1999<br>alopez : 4/7/1999<br>carol : 4/6/1999<br>mark : 1/19/1998<br>mark : 8/5/1996<br>mark : 4/25/1996<br>mark : 3/28/1996<br>mark : 3/28/1996<br>mark : 2/7/1996<br>mimadm : 6/7/1995<br>carol : 1/5/1995<br>davew : 6/9/1994<br>jason : 6/7/1994<br>carol : 7/1/1993<br>supermim : 3/16/1992
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div id="mimFooter">
|
|
|
|
|
|
<div class="container ">
|
|
<div class="row">
|
|
<br />
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="hidden-print mim-footer">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="visible-print-block mim-footer" style="position: relative;">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
<br />
|
|
Printed: March 13, 2025
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="modal fade" id="mimDonationPopupModal" tabindex="-1" role="dialog" aria-labelledby="mimDonationPopupModalTitle">
|
|
<div class="modal-dialog" role="document">
|
|
<div class="modal-content">
|
|
<div class="modal-header">
|
|
<button type="button" id="mimDonationPopupCancel" class="close" data-dismiss="modal" aria-label="Close"><span aria-hidden="true">×</span></button>
|
|
<h4 class="modal-title" id="mimDonationPopupModalTitle">
|
|
OMIM Donation:
|
|
</h4>
|
|
</div>
|
|
<div class="modal-body">
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Dear OMIM User,
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
To ensure long-term funding for the OMIM project, we have diversified
|
|
our revenue stream. We are determined to keep this website freely
|
|
accessible. Unfortunately, it is not free to produce. Expert curators
|
|
review the literature and organize it to facilitate your work. Over 90%
|
|
of the OMIM's operating expenses go to salary support for MD and PhD
|
|
science writers and biocurators. Please join your colleagues by making a
|
|
donation now and again in the future. Donations are an important
|
|
component of our efforts to ensure long-term funding to provide you the
|
|
information that you need at your fingertips.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Thank you in advance for your generous support, <br />
|
|
Ada Hamosh, MD, MPH <br />
|
|
Scientific Director, OMIM <br />
|
|
</p>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div class="modal-footer">
|
|
<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
</body>
|
|
|
|
</html>
|
|
|
|
|