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<title>
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Entry
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- *603368 - CYCLIN-DEPENDENT KINASE 6; CDK6
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- OMIM
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</ul>
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</nav>
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</div>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<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 />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</li>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</li>
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</ul>
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</div>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</form>
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<p />
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603368</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/603368">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
|
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</li>
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<li role="presentation">
|
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<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">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000105810;t=ENST00000424848" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=1021" 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>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603368" 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>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000105810;t=ENST00000424848" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001145306,NM_001259,XM_047419716" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001145306" 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>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603368" 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>
|
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</div>
|
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</div>
|
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</div>
|
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
|
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</span>
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</div>
|
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04533&isoform_id=04533_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>
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<div><a href="https://www.proteinatlas.org/search/CDK6" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/36623,266423,4502741,21885467,30354472,51094901,119597233,119597234,119597235,189069241,223718134,2217365168" 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>
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<div><a href="https://www.uniprot.org/uniprotkb/Q00534" 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>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=1021" 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>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000105810;t=ENST00000424848" 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>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDK6" 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>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=CDK6" 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>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+1021" 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>
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<dd><a href="http://v1.marrvel.org/search/gene/CDK6" 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>
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<dd><a href="https://monarchinitiative.org/NCBIGene:1021" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1021" 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>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000424848.3&hgg_start=92604921&hgg_end=92836573&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>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
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<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>
|
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1777" 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>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603368[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>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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|
<span class="panel-title">
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<span class="small">
|
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603368[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>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000105810" 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>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=CDK6" 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>
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<div><a href="https://www.gwascentral.org/search?q=CDK6" 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>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CDK6" 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>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CDK6&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>
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<div><a href="https://www.pharmgkb.org/gene/PA103" 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>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:1777" 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>
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<div><a href="https://flybase.org/reports/FBgn0016131.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>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1277162" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/CDK6#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>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1277162" 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>
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<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>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1021/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>
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<div><a href="https://www.orthodb.org/?ncbi=1021" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000406;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>
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<div><a href="https://zfin.org/ZDB-GENE-060503-786" 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>
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</div>
|
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</div>
|
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</div>
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<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>
|
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|
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1021" 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>
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<div><a href="https://reactome.org/content/query?q=CDK6&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>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<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.">
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</span>
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</span>
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</div>
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<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">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
603368
|
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</span>
|
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</span>
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</div>
|
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</div>
|
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
|
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|
|
CYCLIN-DEPENDENT KINASE 6; CDK6
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|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PLSTIRE
|
|
</span>
|
|
</h4>
|
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</div>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
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|
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
CDK6/MLL FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
<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=CDK6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CDK6</a></em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/412?start=-3&limit=10&highlight=412">7q21.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:92604921-92836573&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'})">7:92,604,921-92,836,573</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
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|
<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
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
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<p>Cyclin-dependent kinase-6 (CDK6) plays a role in regulation of the G1 phase and the G1/S transition of the cell cycle (summary by <a href="#7" class="mim-tip-reference" title="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" 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>
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<p>The cyclin-dependent protein kinases (CDKs) regulate major cell cycle transitions in eukaryotic cells. By RT-PCR of HeLa cell mRNA with degenerate primers corresponding to conserved regions of CDC2 (<a href="/entry/116940">116940</a>), <a href="#11" class="mim-tip-reference" title="Meyerson, M., Enders, G. H., Wu, C.-L., Su, L.-K., Gorka, C., Nelson, C., Harlow, E., Tsai, L.-H. <strong>A family of human cdc2-related protein kinases.</strong> EMBO J. 11: 2909-2917, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639063</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1992.tb05360.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639063">Meyerson et al. (1992)</a> identified cDNAs encoding 7 novel human protein kinases. They designated 1 of these proteins PLSTIRE, following the accepted practice of naming cdc2-related kinases based on the amino acid sequence of the region corresponding to the conserved PSTAIRE motif of CDC2. The predicted 326-amino acid PLSTIRE protein shares 47% and 71% identity with CDC2 and PSK-J3 (CDK4; <a href="/entry/123829">123829</a>). The in vitro transcription/translation product has an apparent molecular weight of 40 kD by SDS-PAGE. Northern blot analysis revealed that the PLSTIRE gene was expressed as 13-, 8.5-, and 6-kb mRNAs in several human tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639063" 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="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al. (2013)</a> found expression of Cdk6 in the neuroepithelium of the cerebral cortex of the developing mouse brain. Cdk6 immunostaining was prominent at the apical ventricular surface and in the basal progenitor cells. Within the cell, Cdk6 localized to the cytosol of neurons and showed prominent staining around either side of the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" 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>
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<p><a href="#12" class="mim-tip-reference" title="Meyerson, M., Harlow, E. <strong>Identification of G1 kinase activity for cdk6, a novel cyclin D partner.</strong> Molec. Cell. Biol. 14: 2077-2086, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114739</a>] [<a href="https://doi.org/10.1128/mcb.14.3.2077-2086.1994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8114739">Meyerson and Harlow (1994)</a> demonstrated that PLSTIRE is associated with cyclins D1 (<a href="/entry/168461">168461</a>), D2 (<a href="/entry/123833">123833</a>), and D3 (<a href="/entry/123834">123834</a>) in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. PLSTIRE immunoprecipitated from human cells exhibited significant kinase activity, and was able to phosphorylate RB1 (<a href="/entry/614041">614041</a>). Based on these findings, they renamed the protein CDK6 (cyclin-dependent kinase 6). In primary T cells that were stimulated to enter the cell cycle, cellular CDK6 kinase activity first appeared in mid-G1, prior to the activation of any previously characterized CDK. <a href="#12" class="mim-tip-reference" title="Meyerson, M., Harlow, E. <strong>Identification of G1 kinase activity for cdk6, a novel cyclin D partner.</strong> Molec. Cell. Biol. 14: 2077-2086, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114739</a>] [<a href="https://doi.org/10.1128/mcb.14.3.2077-2086.1994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8114739">Meyerson and Harlow (1994)</a> suggested that CDK6, and the homologous CDK4, link growth factor stimulation with the onset of cell cycle progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8114739" 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="Guan, K.-L., Jenkins, C. W., Li, Y., Nichols, M. A., Wu, X., O'Keefe, C. L., Matera, A. G., Xiong, Y. <strong>Growth suppression by p18, a p16(INK4/MTS1)- and p14(INK4B/MTS2)-related CDK6 inhibitor, correlates with wild-type pRb function.</strong> Genes Dev. 8: 2939-2952, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001816</a>] [<a href="https://doi.org/10.1101/gad.8.24.2939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001816">Guan et al. (1994)</a> proposed that CDK4 and CDK6 are physiologic RB1 kinases that are inhibited by the p14 (<a href="/entry/600431">600431</a>), p16 (<a href="/entry/600160">600160</a>), and p18 (<a href="/entry/603369">603369</a>) CDK inhibitors. This inhibition prevents the phosphorylation of RB1 and keeps RB1 in its active growth-suppressing state. See CDKN2D (<a href="/entry/600927">600927</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8001816" 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="Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., Dean, D. C. <strong>Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.</strong> Cell 98: 859-869, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10499802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10499802</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81519-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10499802">Harbour et al. (1999)</a> presented evidence that phosphorylation of the C-terminal region of RB by CDK4/CDK6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see <a href="/entry/123837">123837</a>) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F (<a href="/entry/189971">189971</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10499802" 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="#16" class="mim-tip-reference" title="Veiga-Fernandes, H., Rocha, B. <strong>High expression of active CDK6 in the cytoplasm of CD8 memory cells favors rapid division.</strong> Nature Immun. 5: 31-37, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647273</a>] [<a href="https://doi.org/10.1038/ni1015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14647273">Veiga-Fernandes and Rocha (2003)</a> showed that, in contrast to naive CD8 (see <a href="/entry/186910">186910</a>) T cells in G0/G1 arrest, memory CD8 T cells in G0/G1 arrest have low expression of the cyclin-dependent kinase inhibitor p27(Kip1) (CDKN1B; <a href="/entry/600778">600778</a>) and high CDK6 activity. They found that preactivated CDK6 is associated with cyclin D3 (CCND3) in the cytoplasm, facilitating the switch to S phase and the rapid division of memory cells. <a href="#16" class="mim-tip-reference" title="Veiga-Fernandes, H., Rocha, B. <strong>High expression of active CDK6 in the cytoplasm of CD8 memory cells favors rapid division.</strong> Nature Immun. 5: 31-37, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647273</a>] [<a href="https://doi.org/10.1038/ni1015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14647273">Veiga-Fernandes and Rocha (2003)</a> concluded that naive T cells are in the classic state of G0/G1 arrest with low amounts of D cyclins and CDK6 and CDK2 (<a href="/entry/116953">116953</a>) activity but high levels of CDKN1B, whereas memory cells have high levels of CCND3 and CDK6 activity in a distinct G0/G1 state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14647273" 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 analysis, <a href="#8" class="mim-tip-reference" title="Lena, A. M., Mancini, M., Rivetti di Val Cervo, P. R., Saintigny, G., Mahe, C., Melino, G., Candi, E. <strong>MicroRNA-191 triggers keratinocytes senescence by SATB1 and CDK6 downregulation.</strong> Biochem. Biophys. Res. Commun. 423: 509-514, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22683624[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.bbrc.2012.05.153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683624">Lena et al. (2012)</a> found that microRNA-191 (MIR191; <a href="/entry/615150">615150</a>) was significantly upregulated in normal human neonatal epidermal keratinocytes (HEKn) following development of senescence in culture. Bioinformatic analysis and reporter gene assays revealed functional MIR191 target sequences in the 3-prime UTRs of transcripts for CDK6 and the AT-rich binding protein SATB1 (<a href="/entry/602075">602075</a>). Western blot analysis confirmed that ectopic expression of MIR191 in HEKn cells caused downregulation of SATB1 and CDK6, concomitant with decreased cell proliferation and expression of senescence markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683624" 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="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al. (2013)</a> found CDK6 in the cytoplasm and nuclei of nondividing HaCaT human keratinocytes. In dividing cells, cytoplasmic staining of CDK6 was reduced, and CDK6 localized with a centrosomal marker and accumulated at the centrosome during the mitotic cycle. Knockdown of CDK6 caused microtubule and centrosome aberrations and defects in the cell division cycle, manifest by supernumerary centrosomes, disorganized microtubules, abnormal mitotic spindles, and misshapen nuclei. CDK6-null cells also showed impaired cell motility and polarity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" 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 human cancer cells and patient-derived xenografts in mice, <a href="#17" class="mim-tip-reference" title="Wang, H., Nicolay, B. N., Chick, J. M., Gao, X., Geng, Y., Ren, H., Gao, H., Yang, G., Williams, J. A., Suski, J. M., Keibler, M. A., Sicinska, E., Gerdemann, U., Haining, W. N., Roberts, T. M., Polyak, K., Gygi, S. P., Dyson, N. J., Sicinski, P. <strong>The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.</strong> Nature 546: 426-430, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28607489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28607489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28607489[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/nature22797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28607489">Wang et al. (2017)</a> showed that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of 2 key enzymes in the glycolytic pathway, 6-phosphofructokinase (see PFKP, <a href="/entry/171840">171840</a>) and pyruvate kinase M2 (see <a href="/entry/179050">179050</a>). This redirects the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduced flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increased the levels of reactive oxygen species and caused apoptosis of tumor cells. The prosurvival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. <a href="#17" class="mim-tip-reference" title="Wang, H., Nicolay, B. N., Chick, J. M., Gao, X., Geng, Y., Ren, H., Gao, H., Yang, G., Williams, J. A., Suski, J. M., Keibler, M. A., Sicinska, E., Gerdemann, U., Haining, W. N., Roberts, T. M., Polyak, K., Gygi, S. P., Dyson, N. J., Sicinski, P. <strong>The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.</strong> Nature 546: 426-430, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28607489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28607489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28607489[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/nature22797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28607489">Wang et al. (2017)</a> proposed that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon inhibition of CDK4 and CDK6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28607489" 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="Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., Guo, J., Huang, Y.-H., Fan, C., Ren, S., Sun, Y., Freeman, G. J., Sicinski, P., Wei, W. <strong>Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.</strong> Nature 553: 91-95, 2018. Note: Erratum: Nature 571: E10, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160310[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/nature25015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29160310">Zhang et al. (2018)</a> showed that PDL1 (<a href="/entry/605402">605402</a>) protein abundance is regulated by cyclin D-CDK4 and the cullin 3 (<a href="/entry/603136">603136</a>)-SPOP (<a href="/entry/602650">602650</a>) E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 in vivo increases PDL1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1 (<a href="/entry/603619">603619</a>). Loss-of-function mutations in SPOP compromise ubiquitination-mediated PDL1 degradation, leading to increased PDL1 levels and reduced numbers of tumor-infiltrating lymphocytes in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD1 (<a href="/entry/600244">600244</a>) immunotherapy enhances tumor regression and markedly improves overall survival rates in mouse tumor models. <a href="#18" class="mim-tip-reference" title="Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., Guo, J., Huang, Y.-H., Fan, C., Ren, S., Sun, Y., Freeman, G. J., Sicinski, P., Wei, W. <strong>Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.</strong> Nature 553: 91-95, 2018. Note: Erratum: Nature 571: E10, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160310[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/nature25015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29160310">Zhang et al. (2018)</a> concluded that their study uncovered a novel molecular mechanism for regulating PDL1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD1-PDL1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29160310" 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>The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2 (CCNA2; <a href="/entry/123835">123835</a>)/CDK2 and RB1, leading to an irreversible commitment to proliferation. <a href="#3" class="mim-tip-reference" title="Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D. <strong>Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal.</strong> Nature 619: 363-370, 2023. Note: Erratum: Nature 630: E14, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37407814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37407814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37407814[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/s41586-023-06274-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37407814">Cornwell et al. (2023)</a> demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4/CDK6 promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37407814" 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>
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<p>By analysis of a somatic cell hybrid panel, <a href="#1" class="mim-tip-reference" title="Bullrich, F., MacLachlan, T. K., Sang, N., Druck, T., Veronese, M. L., Allen, S. L., Chiorazzi, N., Koff, A., Heubner, K., Croce, C. M., Giordano, A. <strong>Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27-Kip1, to regions involved in human cancer.</strong> Cancer Res. 55: 1199-1205, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7882308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7882308</a>]" pmid="7882308">Bullrich et al. (1995)</a> mapped the CDK6 gene to 7p13-cen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7882308" 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="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al. (2013)</a> identified the CDK6 gene within a chromosome 7q21.11-q21.3 critical interval. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" 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="#15" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 09/12/2024."None>Stumpf (2024)</a> mapped the CDK6 gene to chromosome 7q21.2 based on an alignment of the CDK6 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AC000065" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AC000065</a>) with the genomic sequence (GRCh38).</p>
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<p>In an infant diagnosed at the age of 3 weeks with acute lymphoblastic leukemia (ALL; <a href="/entry/613065">613065</a>) after presenting with hepatosplenomegaly and marked leukocytosis, <a href="#13" class="mim-tip-reference" title="Raffini, L. J., Slater, D. J., Rappaport, E. F., Lo Nigro, L., Cheung, N.-K. V., Biegel, J. A., Nowell, P. C., Lange, B. J., Felix, C. A. <strong>Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6.</strong> Proc. Nat. Acad. Sci. 99: 4568-4573, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930009[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.062066799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930009">Raffini et al. (2002)</a> found a 3-way rearrangement of the MLL (<a href="/entry/159555">159555</a>), AF4 (<a href="/entry/159557">159557</a>), and CDK6 genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. CDK6 is overexpressed or disrupted by translocation in many cancers, e.g., T cell lymphoblastic lymphoma (<a href="#2" class="mim-tip-reference" title="Chilosi, M., Doglioni, C., Yan, Z., Lestani, M., Menestrina, F., Sorio, C., Benedetti, A., Vinante, F., Pizzolo, G., Inghirami, G. <strong>Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.</strong> Am. J. Path. 152: 209-217, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422538</a>]" pmid="9422538">Chilosi et al., 1998</a>), T cell ALL, natural killer/T cell nasal lymphoma (<a href="#9" class="mim-tip-reference" title="Lien, H.-C., Lin, C.-W., Huang, P.-H., Chang, M.-L., Hsu, S.-M. <strong>Expression of cyclin-dependent kinase 6 (cdk6) and frequent loss of CD44 in nasal-nasopharyngeal NK/T-cell lymphomas: comparison with CD56-negative peripheral T-cell lymphomas.</strong> Lab. Invest. 80: 893-900, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10879740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10879740</a>] [<a href="https://doi.org/10.1038/labinvest.3780093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10879740">Lien et al., 2000</a>), and glioblastoma multiforme (<a href="#4" class="mim-tip-reference" title="Costello, J. F., Plass, C., Arap, W., Chapman, V. M., Held, W. A., Berger, M. S., Su Huang, H. J., Cavenee, W. K. <strong>Cyclin-dependent kinase 6 (cdk6) amplification in human gliomas identified using two-dimensional separation of genomic DNA.</strong> Cancer Res. 57: 1250-1254, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9102208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9102208</a>]" pmid="9102208">Costello et al., 1997</a>). B cell splenic lymphomas with villous lymphocytes are characterized by t(2;7)(p12;q21) translocation juxtaposing CDK6 to the IGKC gene (<a href="/entry/147200">147200</a>). The patient of <a href="#13" class="mim-tip-reference" title="Raffini, L. J., Slater, D. J., Rappaport, E. F., Lo Nigro, L., Cheung, N.-K. V., Biegel, J. A., Nowell, P. C., Lange, B. J., Felix, C. A. <strong>Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6.</strong> Proc. Nat. Acad. Sci. 99: 4568-4573, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930009[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.062066799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930009">Raffini et al. (2002)</a> had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9102208+10879740+11930009+9422538" 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>
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In affected members of a Pakistani family with autosomal recessive primary microcephaly-12 (MCPH12; <a href="/entry/616080">616080</a>), <a href="#7" class="mim-tip-reference" title="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al. (2013)</a> identified a homozygous missense mutation in the CDK6 gene (A197T; <a href="#0001">603368.0001</a>). The mutation, which was found by homozygosity mapping, candidate gene analysis, and whole-exome sequencing, segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" 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>Associations Pending Confirmation</em></strong></p><p>
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Because of sequence and functional similarities between CDK4 (<a href="/entry/123829">123829</a>), mutations in which cause familial melanoma (<a href="/entry/609048">609048</a>), and CDK6, <a href="#14" class="mim-tip-reference" title="Shennan, M. G., Badin, A.-C., Walsh, S., Summers, A., From, L., McKenzie, M., Goldstein, A. M., Tucker, M. A., Hogg, D., Lassam, N. <strong>Lack of germline CDK6 mutations in familial melanoma.</strong> Oncogene 19: 1849-1852, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10777219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10777219</a>] [<a href="https://doi.org/10.1038/sj.onc.1203507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10777219">Shennan et al. (2000)</a> hypothesized that germline mutations in CDK6 might predispose to melanoma. They detected no CDK6 mutations, however, within the p16-binding domain in index cases from 60 melanoma-prone kindreds lacking germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. They concluded that germline mutations in CDK6 do not make a significant contribution to melanoma predisposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10777219" 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>For a discussion of a possible association between variation in the CDK6 gene and stature, see STQTL11 (<a href="/entry/612223">612223</a>).</p>
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<p><a href="#10" class="mim-tip-reference" title="Malumbres, M., Sotillo, R., Santamaria, D., Galan, J., Cerezo, A., Ortega, S., Dubus, P., Barbacid, M. <strong>Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6.</strong> Cell 118: 493-504, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15315761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15315761</a>] [<a href="https://doi.org/10.1016/j.cell.2004.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15315761">Malumbres et al. (2004)</a> found that Cdk6-null mice were viable and developed normally, although hematopoiesis was slightly impaired. Embryos defective for Cdk4 and Cdk6 died during the late stages of embryonic development due to severe anemia. However, these embryos displayed normal organogenesis, and most cell types proliferated normally. In vitro, embryonic fibroblasts lacking Cdk4 and Cdk6 proliferated and became immortal upon serial passage. Quiescent Cdk4/Cdk6-null cells responded to serum stimulation and entered S phase with normal kinetics, although with lower efficiency. These results indicated that D-type cyclin-dependent kinases are not essential for cell cycle entry and suggested the existence of alternative mechanisms to initiate cell proliferation upon mitogenic stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15315761" 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>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603368[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>
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<strong>.0001 MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE (1 family)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231255 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231255;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=rs606231255" 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=rs606231255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144853" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144853" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144853</a>
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<p>In affected members of a large consanguineous Pakistani family with autosomal recessive primary microcephaly-12 (MCPH12; <a href="/entry/616080">616080</a>), <a href="#7" class="mim-tip-reference" title="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al. (2013)</a> identified a homozygous c.589G-A transition in exon 5 of the CDK6 gene, resulting in an ala197-to-thr (A197T) substitution at a highly conserved residue in vertebrates. The mutation, which was found by homozygosity mapping, candidate gene sequencing and whole-exome sequencing, segregated with the disorder in the family and was not present in the Exome Sequencing Project database, in 394 Pakistani controls, or in 380 German controls. During interphase, patient cells showed normal CDK6 localization, but during mitosis, mutant CDK6 did not localize at the centrosome, the mitotic spindles were disorganized with abnormal microtubule formation, and the nuclei were misshapen. Supernumerary centrosomes were also observed during mitosis. Patient cells showed a reduced growth rate and increased apoptosis compared to controls, as well as impaired motility and polarity. <a href="#7" class="mim-tip-reference" title="Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. <strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong> Hum. Molec. Genet. 22: 5199-5214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>] [<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918663">Hussain et al. (2013)</a> postulated a loss-of-function effect of the mutation because the abnormalities observed in patient cells were similar to those observed in in vitro CDK6 knockdown studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" 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>
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<a id="Bullrich1995" class="mim-anchor"></a>
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Bullrich, F., MacLachlan, T. K., Sang, N., Druck, T., Veronese, M. L., Allen, S. L., Chiorazzi, N., Koff, A., Heubner, K., Croce, C. M., Giordano, A.
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<strong>Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27-Kip1, to regions involved in human cancer.</strong>
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Cancer Res. 55: 1199-1205, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7882308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7882308</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7882308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Chilosi1998" class="mim-anchor"></a>
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Chilosi, M., Doglioni, C., Yan, Z., Lestani, M., Menestrina, F., Sorio, C., Benedetti, A., Vinante, F., Pizzolo, G., Inghirami, G.
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<strong>Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.</strong>
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Am. J. Path. 152: 209-217, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422538</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9422538" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Cornwell2023" class="mim-anchor"></a>
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Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D.
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<strong>Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal.</strong>
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Nature 619: 363-370, 2023. Note: Erratum: Nature 630: E14, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37407814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37407814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37407814[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=37407814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-023-06274-3" target="_blank">Full Text</a>]
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<a id="Costello1997" class="mim-anchor"></a>
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Costello, J. F., Plass, C., Arap, W., Chapman, V. M., Held, W. A., Berger, M. S., Su Huang, H. J., Cavenee, W. K.
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<strong>Cyclin-dependent kinase 6 (cdk6) amplification in human gliomas identified using two-dimensional separation of genomic DNA.</strong>
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Cancer Res. 57: 1250-1254, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9102208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9102208</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9102208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Guan, K.-L., Jenkins, C. W., Li, Y., Nichols, M. A., Wu, X., O'Keefe, C. L., Matera, A. G., Xiong, Y.
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<strong>Growth suppression by p18, a p16(INK4/MTS1)- and p14(INK4B/MTS2)-related CDK6 inhibitor, correlates with wild-type pRb function.</strong>
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Genes Dev. 8: 2939-2952, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8001816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1101/gad.8.24.2939" target="_blank">Full Text</a>]
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Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., Dean, D. C.
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<strong>Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.</strong>
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Cell 98: 859-869, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10499802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10499802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10499802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81519-6" target="_blank">Full Text</a>]
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Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others.
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<strong>CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.</strong>
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Hum. Molec. Genet. 22: 5199-5214, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt374" target="_blank">Full Text</a>]
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<a id="Lena2012" class="mim-anchor"></a>
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Lena, A. M., Mancini, M., Rivetti di Val Cervo, P. R., Saintigny, G., Mahe, C., Melino, G., Candi, E.
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<strong>MicroRNA-191 triggers keratinocytes senescence by SATB1 and CDK6 downregulation.</strong>
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Biochem. Biophys. Res. Commun. 423: 509-514, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22683624[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=22683624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2012.05.153" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Lien2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lien, H.-C., Lin, C.-W., Huang, P.-H., Chang, M.-L., Hsu, S.-M.
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<strong>Expression of cyclin-dependent kinase 6 (cdk6) and frequent loss of CD44 in nasal-nasopharyngeal NK/T-cell lymphomas: comparison with CD56-negative peripheral T-cell lymphomas.</strong>
|
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Lab. Invest. 80: 893-900, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10879740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10879740</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10879740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/labinvest.3780093" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Malumbres2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Malumbres, M., Sotillo, R., Santamaria, D., Galan, J., Cerezo, A., Ortega, S., Dubus, P., Barbacid, M.
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<strong>Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6.</strong>
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Cell 118: 493-504, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15315761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15315761</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15315761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2004.08.002" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Meyerson1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Meyerson, M., Enders, G. H., Wu, C.-L., Su, L.-K., Gorka, C., Nelson, C., Harlow, E., Tsai, L.-H.
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<strong>A family of human cdc2-related protein kinases.</strong>
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EMBO J. 11: 2909-2917, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/j.1460-2075.1992.tb05360.x" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Meyerson1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Meyerson, M., Harlow, E.
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<strong>Identification of G1 kinase activity for cdk6, a novel cyclin D partner.</strong>
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Molec. Cell. Biol. 14: 2077-2086, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8114739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/mcb.14.3.2077-2086.1994" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Raffini2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Raffini, L. J., Slater, D. J., Rappaport, E. F., Lo Nigro, L., Cheung, N.-K. V., Biegel, J. A., Nowell, P. C., Lange, B. J., Felix, C. A.
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<strong>Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6.</strong>
|
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Proc. Nat. Acad. Sci. 99: 4568-4573, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930009[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=11930009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.062066799" target="_blank">Full Text</a>]
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Shennan2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shennan, M. G., Badin, A.-C., Walsh, S., Summers, A., From, L., McKenzie, M., Goldstein, A. M., Tucker, M. A., Hogg, D., Lassam, N.
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<strong>Lack of germline CDK6 mutations in familial melanoma.</strong>
|
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Oncogene 19: 1849-1852, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10777219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10777219</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10777219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1203507" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Stumpf2024" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 09/12/2024.
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Veiga-Fernandes2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Veiga-Fernandes, H., Rocha, B.
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<strong>High expression of active CDK6 in the cytoplasm of CD8 memory cells favors rapid division.</strong>
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Nature Immun. 5: 31-37, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647273</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14647273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ni1015" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Wang2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, H., Nicolay, B. N., Chick, J. M., Gao, X., Geng, Y., Ren, H., Gao, H., Yang, G., Williams, J. A., Suski, J. M., Keibler, M. A., Sicinska, E., Gerdemann, U., Haining, W. N., Roberts, T. M., Polyak, K., Gygi, S. P., Dyson, N. J., Sicinski, P.
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<strong>The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.</strong>
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Nature 546: 426-430, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28607489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28607489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28607489[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=28607489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature22797" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Zhang2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., Guo, J., Huang, Y.-H., Fan, C., Ren, S., Sun, Y., Freeman, G. J., Sicinski, P., Wei, W.
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<strong>Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.</strong>
|
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Nature 553: 91-95, 2018. Note: Erratum: Nature 571: E10, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160310[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=29160310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature25015" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 09/12/2024
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<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">
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<span class="mim-text-font">
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Bao Lige - updated : 02/08/2024<br>Ada Hamosh - updated : 04/12/2018<br>Ada Hamosh - updated : 12/05/2017<br>Cassandra L. Kniffin - updated : 11/5/2014<br>Patricia A. Hartz - updated : 3/22/2013<br>Ada Hamosh - updated : 7/29/2008<br>Stylianos E. Antonarakis - updated : 9/2/2004<br>Paul J. Converse - updated : 5/13/2004<br>Victor A. McKusick - updated : 10/11/2002<br>Victor A. McKusick - updated : 7/13/2000<br>Stylianos E. Antonarakis - updated : 9/29/1999
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 12/18/1998
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 09/12/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<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">
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<span class="mim-text-font">
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carol : 07/19/2024<br>mgross : 02/08/2024<br>carol : 10/03/2019<br>alopez : 09/26/2018<br>alopez : 04/12/2018<br>alopez : 12/05/2017<br>carol : 11/05/2014<br>ckniffin : 11/5/2014<br>mgross : 3/28/2013<br>terry : 3/22/2013<br>alopez : 6/17/2011<br>wwang : 10/13/2009<br>wwang : 2/3/2009<br>alopez : 8/5/2008<br>alopez : 8/5/2008<br>alopez : 8/4/2008<br>terry : 7/29/2008<br>terry : 4/5/2005<br>alopez : 2/7/2005<br>mgross : 9/2/2004<br>mgross : 5/13/2004<br>tkritzer : 11/19/2002<br>tkritzer : 10/17/2002<br>tkritzer : 10/14/2002<br>tkritzer : 10/11/2002<br>terry : 12/7/2001<br>terry : 3/20/2001<br>alopez : 7/21/2000<br>terry : 7/13/2000<br>mgross : 9/29/1999<br>mgross : 9/29/1999<br>alopez : 12/18/1998
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<span class="mim-font">
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<strong>*</strong> 603368
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<div>
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<h3>
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<span class="mim-font">
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CYCLIN-DEPENDENT KINASE 6; CDK6
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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PLSTIRE
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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CDK6/MLL FUSION GENE, INCLUDED
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</span>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CDK6</em></strong>
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</span>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:92,604,921-92,836,573 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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7q21.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Microcephaly 12, primary, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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616080
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cyclin-dependent kinase-6 (CDK6) plays a role in regulation of the G1 phase and the G1/S transition of the cell cycle (summary by Hussain et al., 2013). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The cyclin-dependent protein kinases (CDKs) regulate major cell cycle transitions in eukaryotic cells. By RT-PCR of HeLa cell mRNA with degenerate primers corresponding to conserved regions of CDC2 (116940), Meyerson et al. (1992) identified cDNAs encoding 7 novel human protein kinases. They designated 1 of these proteins PLSTIRE, following the accepted practice of naming cdc2-related kinases based on the amino acid sequence of the region corresponding to the conserved PSTAIRE motif of CDC2. The predicted 326-amino acid PLSTIRE protein shares 47% and 71% identity with CDC2 and PSK-J3 (CDK4; 123829). The in vitro transcription/translation product has an apparent molecular weight of 40 kD by SDS-PAGE. Northern blot analysis revealed that the PLSTIRE gene was expressed as 13-, 8.5-, and 6-kb mRNAs in several human tissues. </p><p>Hussain et al. (2013) found expression of Cdk6 in the neuroepithelium of the cerebral cortex of the developing mouse brain. Cdk6 immunostaining was prominent at the apical ventricular surface and in the basal progenitor cells. Within the cell, Cdk6 localized to the cytosol of neurons and showed prominent staining around either side of the nucleus. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Meyerson and Harlow (1994) demonstrated that PLSTIRE is associated with cyclins D1 (168461), D2 (123833), and D3 (123834) in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. PLSTIRE immunoprecipitated from human cells exhibited significant kinase activity, and was able to phosphorylate RB1 (614041). Based on these findings, they renamed the protein CDK6 (cyclin-dependent kinase 6). In primary T cells that were stimulated to enter the cell cycle, cellular CDK6 kinase activity first appeared in mid-G1, prior to the activation of any previously characterized CDK. Meyerson and Harlow (1994) suggested that CDK6, and the homologous CDK4, link growth factor stimulation with the onset of cell cycle progression. </p><p>Guan et al. (1994) proposed that CDK4 and CDK6 are physiologic RB1 kinases that are inhibited by the p14 (600431), p16 (600160), and p18 (603369) CDK inhibitors. This inhibition prevents the phosphorylation of RB1 and keeps RB1 in its active growth-suppressing state. See CDKN2D (600927). </p><p>Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB by CDK4/CDK6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see 123837) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F (189971). </p><p>Veiga-Fernandes and Rocha (2003) showed that, in contrast to naive CD8 (see 186910) T cells in G0/G1 arrest, memory CD8 T cells in G0/G1 arrest have low expression of the cyclin-dependent kinase inhibitor p27(Kip1) (CDKN1B; 600778) and high CDK6 activity. They found that preactivated CDK6 is associated with cyclin D3 (CCND3) in the cytoplasm, facilitating the switch to S phase and the rapid division of memory cells. Veiga-Fernandes and Rocha (2003) concluded that naive T cells are in the classic state of G0/G1 arrest with low amounts of D cyclins and CDK6 and CDK2 (116953) activity but high levels of CDKN1B, whereas memory cells have high levels of CCND3 and CDK6 activity in a distinct G0/G1 state. </p><p>Using microarray analysis, Lena et al. (2012) found that microRNA-191 (MIR191; 615150) was significantly upregulated in normal human neonatal epidermal keratinocytes (HEKn) following development of senescence in culture. Bioinformatic analysis and reporter gene assays revealed functional MIR191 target sequences in the 3-prime UTRs of transcripts for CDK6 and the AT-rich binding protein SATB1 (602075). Western blot analysis confirmed that ectopic expression of MIR191 in HEKn cells caused downregulation of SATB1 and CDK6, concomitant with decreased cell proliferation and expression of senescence markers. </p><p>Hussain et al. (2013) found CDK6 in the cytoplasm and nuclei of nondividing HaCaT human keratinocytes. In dividing cells, cytoplasmic staining of CDK6 was reduced, and CDK6 localized with a centrosomal marker and accumulated at the centrosome during the mitotic cycle. Knockdown of CDK6 caused microtubule and centrosome aberrations and defects in the cell division cycle, manifest by supernumerary centrosomes, disorganized microtubules, abnormal mitotic spindles, and misshapen nuclei. CDK6-null cells also showed impaired cell motility and polarity. </p><p>Using human cancer cells and patient-derived xenografts in mice, Wang et al. (2017) showed that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of 2 key enzymes in the glycolytic pathway, 6-phosphofructokinase (see PFKP, 171840) and pyruvate kinase M2 (see 179050). This redirects the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduced flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increased the levels of reactive oxygen species and caused apoptosis of tumor cells. The prosurvival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. Wang et al. (2017) proposed that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon inhibition of CDK4 and CDK6. </p><p>Zhang et al. (2018) showed that PDL1 (605402) protein abundance is regulated by cyclin D-CDK4 and the cullin 3 (603136)-SPOP (602650) E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 in vivo increases PDL1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1 (603619). Loss-of-function mutations in SPOP compromise ubiquitination-mediated PDL1 degradation, leading to increased PDL1 levels and reduced numbers of tumor-infiltrating lymphocytes in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD1 (600244) immunotherapy enhances tumor regression and markedly improves overall survival rates in mouse tumor models. Zhang et al. (2018) concluded that their study uncovered a novel molecular mechanism for regulating PDL1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD1-PDL1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers. </p><p>The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2 (CCNA2; 123835)/CDK2 and RB1, leading to an irreversible commitment to proliferation. Cornwell et al. (2023) demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4/CDK6 promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost. </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 a somatic cell hybrid panel, Bullrich et al. (1995) mapped the CDK6 gene to 7p13-cen. </p><p>Hussain et al. (2013) identified the CDK6 gene within a chromosome 7q21.11-q21.3 critical interval. </p><p>Stumpf (2024) mapped the CDK6 gene to chromosome 7q21.2 based on an alignment of the CDK6 sequence (GenBank AC000065) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
<span class="mim-text-font">
|
|
<p>In an infant diagnosed at the age of 3 weeks with acute lymphoblastic leukemia (ALL; 613065) after presenting with hepatosplenomegaly and marked leukocytosis, Raffini et al. (2002) found a 3-way rearrangement of the MLL (159555), AF4 (159557), and CDK6 genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. CDK6 is overexpressed or disrupted by translocation in many cancers, e.g., T cell lymphoblastic lymphoma (Chilosi et al., 1998), T cell ALL, natural killer/T cell nasal lymphoma (Lien et al., 2000), and glioblastoma multiforme (Costello et al., 1997). B cell splenic lymphomas with villous lymphocytes are characterized by t(2;7)(p12;q21) translocation juxtaposing CDK6 to the IGKC gene (147200). The patient of Raffini et al. (2002) had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript. </p>
|
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</span>
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<div>
|
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<br />
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</div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Primary Microcephaly 12, Autosomal Recessive</em></strong></p><p>
|
|
In affected members of a Pakistani family with autosomal recessive primary microcephaly-12 (MCPH12; 616080), Hussain et al. (2013) identified a homozygous missense mutation in the CDK6 gene (A197T; 603368.0001). The mutation, which was found by homozygosity mapping, candidate gene analysis, and whole-exome sequencing, segregated with the disorder in the family. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
Because of sequence and functional similarities between CDK4 (123829), mutations in which cause familial melanoma (609048), and CDK6, Shennan et al. (2000) hypothesized that germline mutations in CDK6 might predispose to melanoma. They detected no CDK6 mutations, however, within the p16-binding domain in index cases from 60 melanoma-prone kindreds lacking germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. They concluded that germline mutations in CDK6 do not make a significant contribution to melanoma predisposition. </p><p>For a discussion of a possible association between variation in the CDK6 gene and stature, see STQTL11 (612223).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Malumbres et al. (2004) found that Cdk6-null mice were viable and developed normally, although hematopoiesis was slightly impaired. Embryos defective for Cdk4 and Cdk6 died during the late stages of embryonic development due to severe anemia. However, these embryos displayed normal organogenesis, and most cell types proliferated normally. In vitro, embryonic fibroblasts lacking Cdk4 and Cdk6 proliferated and became immortal upon serial passage. Quiescent Cdk4/Cdk6-null cells responded to serum stimulation and entered S phase with normal kinetics, although with lower efficiency. These results indicated that D-type cyclin-dependent kinases are not essential for cell cycle entry and suggested the existence of alternative mechanisms to initiate cell proliferation upon mitogenic stimulation. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>1 Selected Example):</strong>
|
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</span>
|
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</h4>
|
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<div>
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<p />
|
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE (1 family)</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CDK6, ALA197THR
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<br />
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SNP: rs606231255,
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ClinVar: RCV000144853
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a large consanguineous Pakistani family with autosomal recessive primary microcephaly-12 (MCPH12; 616080), Hussain et al. (2013) identified a homozygous c.589G-A transition in exon 5 of the CDK6 gene, resulting in an ala197-to-thr (A197T) substitution at a highly conserved residue in vertebrates. The mutation, which was found by homozygosity mapping, candidate gene sequencing and whole-exome sequencing, segregated with the disorder in the family and was not present in the Exome Sequencing Project database, in 394 Pakistani controls, or in 380 German controls. During interphase, patient cells showed normal CDK6 localization, but during mitosis, mutant CDK6 did not localize at the centrosome, the mitotic spindles were disorganized with abnormal microtubule formation, and the nuclei were misshapen. Supernumerary centrosomes were also observed during mitosis. Patient cells showed a reduced growth rate and increased apoptosis compared to controls, as well as impaired motility and polarity. Hussain et al. (2013) postulated a loss-of-function effect of the mutation because the abnormalities observed in patient cells were similar to those observed in in vitro CDK6 knockdown studies. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
|
<ol>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Bullrich, F., MacLachlan, T. K., Sang, N., Druck, T., Veronese, M. L., Allen, S. L., Chiorazzi, N., Koff, A., Heubner, K., Croce, C. M., Giordano, A.
|
|
<strong>Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27-Kip1, to regions involved in human cancer.</strong>
|
|
Cancer Res. 55: 1199-1205, 1995.
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[PubMed: 7882308]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Chilosi, M., Doglioni, C., Yan, Z., Lestani, M., Menestrina, F., Sorio, C., Benedetti, A., Vinante, F., Pizzolo, G., Inghirami, G.
|
|
<strong>Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.</strong>
|
|
Am. J. Path. 152: 209-217, 1998.
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[PubMed: 9422538]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D.
|
|
<strong>Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal.</strong>
|
|
Nature 619: 363-370, 2023. Note: Erratum: Nature 630: E14, 2024.
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[PubMed: 37407814]
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[Full Text: https://doi.org/10.1038/s41586-023-06274-3]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Costello, J. F., Plass, C., Arap, W., Chapman, V. M., Held, W. A., Berger, M. S., Su Huang, H. J., Cavenee, W. K.
|
|
<strong>Cyclin-dependent kinase 6 (cdk6) amplification in human gliomas identified using two-dimensional separation of genomic DNA.</strong>
|
|
Cancer Res. 57: 1250-1254, 1997.
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[PubMed: 9102208]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Guan, K.-L., Jenkins, C. W., Li, Y., Nichols, M. A., Wu, X., O'Keefe, C. L., Matera, A. G., Xiong, Y.
|
|
<strong>Growth suppression by p18, a p16(INK4/MTS1)- and p14(INK4B/MTS2)-related CDK6 inhibitor, correlates with wild-type pRb function.</strong>
|
|
Genes Dev. 8: 2939-2952, 1994.
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|
[PubMed: 8001816]
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[Full Text: https://doi.org/10.1101/gad.8.24.2939]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., Dean, D. C.
|
|
<strong>Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.</strong>
|
|
Cell 98: 859-869, 1999.
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|
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|
[PubMed: 10499802]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81519-6]
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