4768 lines
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Entry
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- *600778 - CYCLIN-DEPENDENT KINASE INHIBITOR 1B; CDKN1B
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600778</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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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 role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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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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<a href="#animalModel">Animal Model</a>
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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/600778">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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=ENSG00000111276;t=ENST00000228872" 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=1027" 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=600778" 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 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=ENSG00000111276;t=ENST00000228872" 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_004064" 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_004064" 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=600778" 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=02867&isoform_id=02867_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/CDKN1B" 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/516559,1168871,2842411,4261944,4587316,4757962,6561874,6644441,7769665,9652560,12805035,18656929,38707292,48146915,54695976,54695978,119616681,147836705,151564566,189065529,194390932,197692283,197692547,311461940" 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/P46527" 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=1027" 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=ENSG00000111276;t=ENST00000228872" 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=CDKN1B" 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=CDKN1B" 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+1027" 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/CDKN1B" 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:1027" 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/1027" 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=chr12&hgg_gene=ENST00000228872.9&hgg_start=12717368&hgg_end=12722369&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">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" 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="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:1785" 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://search.clinicalgenome.org/kb/genes/HGNC:1785" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cdkn1b" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600778[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 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=600778[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/ENSG00000111276" 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=CDKN1B" 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=CDKN1B" 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=CDKN1B" 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=CDKN1B&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/PA105" 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:1785" 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/FBgn0010316.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:104565" 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/CDKN1B#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:104565" 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/1027/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=1027" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000516;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000516 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000517;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000517 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030521-13" 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">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" 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="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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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:1027" 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=CDKN1B&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>
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<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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 715907003<br />
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">ICD+</a>
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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>
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600778
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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 INHIBITOR 1B; CDKN1B
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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>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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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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p27(KIP1)<br />
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KIP1
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</span>
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</h4>
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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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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CDKN1B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CDKN1B</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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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: <a href="/geneMap/12/181?start=-3&limit=10&highlight=181">12p13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:12717368-12722369&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'})">12:12,717,368-12,722,369</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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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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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
|
|
<table class="table table-bordered table-condensed table-hover 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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<a href="/geneMap/12/181?start=-3&limit=10&highlight=181">
|
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12p13.1
|
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</a>
|
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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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Multiple endocrine neoplasia, type IV
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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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<a href="/entry/610755"> 610755 </a>
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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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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600778" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600778" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>CDKN1B, or p27(KIP1), is a cyclin-dependent kinase inhibitor that blocks the cell cycle in the G0/G1 phase upon differentiation signals or cellular insult. CDKN1B also regulates cell motility and apoptosis (summary by <a href="#7" class="mim-tip-reference" title="Cuesta, R., Martinez-Sanchez, A., Gebauer, F. <strong>miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells.</strong> Molec. Cell. Biol. 29: 2841-2851, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19273599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01971-08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19273599">Cuesta et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19273599" 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>Using a cDNA probe amplified from the MV1Lu mink cell line to screen a kidney cDNA library, <a href="#35" class="mim-tip-reference" title="Polyak, K., Lee, M.-H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., Massague, J. <strong>Cloning of p27(Kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.</strong> Cell 78: 59-66, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033212</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90572-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8033212">Polyak et al. (1994)</a> cloned human CDKN1B, which they called KIP1. The deduced 198-amino acid protein has a calculated molecular mass of 22.3 kD. It has a 60-amino acid N-terminal domain that shares 44% identity with the corresponding region of CIP1/WAF1 (CDKN1A; <a href="/entry/116899">116899</a>). It also has a C-terminal bipartite nuclear localization signal and a consensus CDC2 (CDK1; <a href="/entry/116940">116940</a>) phosphorylation site. KIP1 shares about 90% amino acid identity with mink and mouse Kip1, with highest identity in the N-terminal domain. Northern blot analysis detected variable expression of a 2.5-kb transcript in all human tissues examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8033212" 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="#41" class="mim-tip-reference" title="Stegmaier, K., Pendse, S., Barker, G. F., Bray-Ward, P., Ward, D. C., Montgomery, K. T., Krauter, K. S., Reynolds, C., Sklar, J., Donnelly, M., Bohlander, S. K., Rowley, J. D., Sallan, S. E., Gilliland, D. G., Golub, T. R. <strong>Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood.</strong> Blood 86: 38-44, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795247</a>]" pmid="7795247">Stegmaier et al. (1995)</a> studied loss of heterozygosity (LOH) in the region 12p13-p12 in acute lymphoblastic leukemia; this chromosomal region often shows deletion in such patients. In 15% of informative patients, there was evidence of LOH of the TEL locus (<a href="/entry/600618">600618</a>) which was not evident on cytogenetic analysis. Detailed examination of patients with LOH showed that the critically deleted region included a second candidate tumor suppressor gene, referred to by them as KIP1, which encodes the cyclin-dependent kinase inhibitor previously called p27 (<a href="#44" class="mim-tip-reference" title="Toyoshima, H., Hunter, T. <strong>p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21.</strong> Cell 78: 67-74, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033213</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90573-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8033213">Toyoshima and Hunter, 1994</a> and <a href="#35" class="mim-tip-reference" title="Polyak, K., Lee, M.-H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., Massague, J. <strong>Cloning of p27(Kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.</strong> Cell 78: 59-66, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033212</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90572-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8033212">Polyak et al., 1994</a>). Based on the STS content of TEL-positive YACs, <a href="#41" class="mim-tip-reference" title="Stegmaier, K., Pendse, S., Barker, G. F., Bray-Ward, P., Ward, D. C., Montgomery, K. T., Krauter, K. S., Reynolds, C., Sklar, J., Donnelly, M., Bohlander, S. K., Rowley, J. D., Sallan, S. E., Gilliland, D. G., Golub, T. R. <strong>Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood.</strong> Blood 86: 38-44, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795247</a>]" pmid="7795247">Stegmaier et al. (1995)</a> reported that KIP1 and TEL were in close proximity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8033213+7795247+8033212" 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="#35" class="mim-tip-reference" title="Polyak, K., Lee, M.-H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., Massague, J. <strong>Cloning of p27(Kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.</strong> Cell 78: 59-66, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033212</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90572-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8033212">Polyak et al. (1994)</a> showed that recombinant mouse Kip1 inhibited phosphorylation of histone H1 (see <a href="/entry/142709">142709</a>) by human cyclin A (see CCNA1; <a href="/entry/604036">604036</a>)-CDK2 (<a href="/entry/116953">116953</a>), cyclin E (CCNE1; <a href="/entry/123837">123837</a>)-CDK2, and cyclin B1 (CCNB1; <a href="/entry/123836">123836</a>)-CDK2 complexes. Addition of Kip1 also inhibited phosphorylation of RB (<a href="/entry/614041">614041</a>) by cyclin E-CDK2, cyclin A-CDK2, and cyclin D2 (CCND2; <a href="/entry/123833">123833</a>)-CDK4 (<a href="/entry/123829">123829</a>). The isolated N-terminal domain of Kip1 had similar inhibitory activity in these assays. Kip1 bound to preactivated cyclin E-CDK2 complexes and prevented phosphorylation and activation of CDK2 in A549 human lung carcinoma cells. Kip1 activity was lowest in S phase in MV1Lu cells, and Kip1 overexpression inhibited S phase entry. Kip1 mRNA content remained unchanged during the cell cycle, suggesting that Kip1 activity was controlled at a posttranscriptional level. <a href="#35" class="mim-tip-reference" title="Polyak, K., Lee, M.-H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P., Massague, J. <strong>Cloning of p27(Kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.</strong> Cell 78: 59-66, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033212</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90572-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8033212">Polyak et al. (1994)</a> concluded that KIP1 can inhibit both CDK activation and the kinase activity of assembled and activated cyclin-CDK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8033212" 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>CDK activation requires association with cyclins and phosphorylation by CAK (CCNH; <a href="/entry/601953">601953</a>) and leads to cell proliferation. Inhibition of cellular proliferation occurs upon association of CDK inhibitor (e.g., CDKN1B) with a cyclin-CDK complex. <a href="#38" class="mim-tip-reference" title="Sheaff, R. J., Groudine, M., Gordon, M., Roberts, J. M., Clurman, B. E. <strong>Cyclin E-CDK2 is a regulator of p27(Kip1).</strong> Genes Dev. 11: 1464-1478, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192873</a>] [<a href="https://doi.org/10.1101/gad.11.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192873">Sheaff et al. (1997)</a> showed that expression of CCNE1-CDK2 at physiologic levels of ATP resulted in phosphorylation of CDKN1B at thr187, leading to elimination of CDKN1B from the cell and progression of the cell cycle from G1 to S phase. At low ATP levels, the inhibitory functions of CDKN1B were enhanced, thereby arresting cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192873" 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>Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A (see <a href="/entry/604036">604036</a>)-associated CDK2 activity. <a href="#23" class="mim-tip-reference" title="Levkau, B., Koyama, H., Raines, E. W., Clurman, B. E., Herren, B., Orth, K., Roberts, J. M., Ross, R. <strong>Cleavage of p21(Cip1/Waf1) and p27(Kip1) mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade.</strong> Molec. Cell 1: 553-563, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660939</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80055-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660939">Levkau et al. (1998)</a> showed that in apoptotic cells the carboxyl-termini of the CDK inhibitors CDKN1A and CDKN1B are truncated by specific cleavage. The enzyme involved in this cleavage is CASP3 (<a href="/entry/600636">600636</a>) and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. These data suggested that CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660939" 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>High levels of p27(KIP1), present in quiescent (G0) cells, have been shown to decline upon mitogen induction (<a href="#39" class="mim-tip-reference" title="Sherr, C. J., Roberts, J. M. <strong>Inhibitors of mammalian G1 cyclin-dependent kinases.</strong> Genes Dev. 9: 1149-1163, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7758941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7758941</a>] [<a href="https://doi.org/10.1101/gad.9.10.1149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7758941">Sherr and Roberts, 1995</a>). <a href="#3" class="mim-tip-reference" title="Braun-Dullaeus, R. C., Mann, M. J., Ziegler, A., von der Leyen, H. E., Dzau, V. J. <strong>A novel role for the cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy.</strong> J. Clin. Invest. 104: 815-823, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10491417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10491417</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10491417[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI5339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10491417">Braun-Dullaeus et al. (1999)</a> explored the role of p27(KIP1) and other cell cycle proteins in mediating angiotensin II (see <a href="/entry/106150">106150</a>)-induced vascular smooth muscle cell hypertrophy or hyperplasia. Angiotensin II treatment (100 nM) of quiescent vascular smooth muscle cells led to upregulation of the cell cycle regulatory proteins cyclin D1 (<a href="/entry/168461">168461</a>), CDK2, proliferating cell nuclear antigen (<a href="/entry/176740">176740</a>), and CDK1. Levels of p27(KIP1), however, remained high, and the activation of the G1-phase CDK2 was inhibited as the cells underwent hypertrophy. Angiotensin II stimulated an increase in [(3)H]thymidine incorporation and the percentage of S-phase cells in p27(KIP1) antisense oligodeoxynucleotide (ODN)-transfected cells but not in control ODN transfected cells. The authors concluded that angiotensin II stimulation of quiescent cells in which p27(KIP1) levels are high results in hypertrophy but promotes hyperplasia when levels of p27(KIP1) are low, as in the presence of other growth factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10491417+7758941" 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="#29" class="mim-tip-reference" title="Medema, R. H., Kops, G. J. P. L., Bos, J. L., Burgering, B. M. T. <strong>AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27(kip1).</strong> Nature 404: 782-787, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783894</a>] [<a href="https://doi.org/10.1038/35008115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10783894">Medema et al. (2000)</a> demonstrated that p27(KIP1) is a major target of AFX-like forkhead proteins. They demonstrated that AFX integrates signals from PI3K/PKB (see AKT1; <a href="/entry/164730">164730</a>) signaling and RAS (see <a href="/entry/190020">190020</a>)/RAL (see <a href="/entry/179551">179551</a>) signaling to regulate transcription of p27(KIP1). They demonstrated that p27 -/- cells are significantly less inhibited by AFX activity than their p27 +/+ counterparts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10783894" 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="#10" class="mim-tip-reference" title="Dijkers, P. F., Birkenkamp, K. U., Lam, E. W.-F., Thomas, N. S. B., Lammers, J.-W. J., Koenderman, L., Coffer, P. J. <strong>FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity.</strong> J. Cell Biol. 156: 531-542, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11815629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11815629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11815629[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/10.1083/jcb.200108084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11815629">Dijkers et al. (2002)</a> showed that both cytokine withdrawal and Fkhrl1 (FOXO3A; <a href="/entry/602681">602681</a>) activation induced apoptosis in mammalian cell lines through a death receptor-independent pathway. This involved transcriptional upregulation of p27(KIP1) and proapoptotic Bim (BCL2L11; <a href="/entry/603827">603827</a>), loss of mitochondrial integrity, cytochrome c release, and caspase activation. PKB protected cells from cytokine withdrawal-induced apoptosis by inhibiting Fkhrl1, resulting in the maintenance of mitochondrial integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11815629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Peters, M. A., Ostrander, E. A. <strong>Prostate cancer: more than two to tango.</strong> Nature Genet. 27: 134-135, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175773</a>] [<a href="https://doi.org/10.1038/84739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175773">Peters and Ostrander (2001)</a> commented on the work of <a href="#9" class="mim-tip-reference" title="Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C., Pandolfi, P. P. <strong>Pten and p27(KIP1) cooperate in prostate cancer tumor suppression in the mouse.</strong> Nature Genet. 27: 222-224, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175795</a>] [<a href="https://doi.org/10.1038/84879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175795">Di Cristofano et al. (2001)</a>, demonstrating how cooperation between Cdkn1b and Pten (<a href="/entry/601728">601728</a>) contribute to suppression of prostate tumors. They gave a useful tabulation of the cytogenetic location of 16 mapped prostate cancer susceptibility loci and candidate genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11175795+11175773" 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>Phosphorylation leads to the ubiquitination and degradation of CDKN1B. <a href="#4" class="mim-tip-reference" title="Carrano, A. C., Eytan, E., Hershko, A., Pagano, M. <strong>SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.</strong> Nature Cell Biol. 1: 193-199, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10559916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10559916</a>] [<a href="https://doi.org/10.1038/12013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10559916">Carrano et al. (1999)</a> determined that SKP2 (<a href="/entry/601436">601436</a>) specifically recognizes phosphorylated CDKN1B predominantly in S phase rather than in G1 phase, and is the ubiquitin-protein ligase necessary for CDKN1B ubiquitination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10559916" 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="#40" class="mim-tip-reference" title="Shin, I., Yakes, F. M., Rojo, F., Shin, N.-Y., Bakin, A. V., Baselga, J., Arteaga, C. L. <strong>PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.</strong> Nature Med. 8: 1145-1152, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244301</a>] [<a href="https://doi.org/10.1038/nm759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244301">Shin et al. (2002)</a> demonstrated a novel mechanism of AKT-mediated regulation of p27(KIP1). Blockade of HER2/NEU (<a href="/entry/164870">164870</a>) in tumor cells inhibited AKT kinase activity and upregulated nuclear levels of p27(KIP1). Recombinant AKT and AKT precipitated from tumor cells phosphorylated wildtype p27 in vitro. P27 contains an AKT consensus RXRXXT(157)D within its nuclear localization motif. Active (myristoylated) AKT phosphorylated wildtype p27 in vivo but was unable to phosphorylate a T157A-p27 mutant. Wildtype p27 localized in the cytosol and nucleus, whereas the mutant p27 localized exclusively in the nucleus and was resistant to nuclear exclusion by AKT. Expression of phosphorylated AKT in primary human breast cancers statistically correlated with the expression of p27 in tumor cytosol. <a href="#40" class="mim-tip-reference" title="Shin, I., Yakes, F. M., Rojo, F., Shin, N.-Y., Bakin, A. V., Baselga, J., Arteaga, C. L. <strong>PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.</strong> Nature Med. 8: 1145-1152, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244301</a>] [<a href="https://doi.org/10.1038/nm759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244301">Shin et al. (2002)</a> concluded that AKT may contribute to tumor cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 from p27-induced inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244301" 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="#24" class="mim-tip-reference" title="Liang, J., Zubovitz, J., Petrocelli, T., Kotchetkov, R., Connor, M. K., Han, K., Lee, J.-H., Ciarallo, S., Catzavelos, C., Beniston, R., Franssen, E., Slingerland, J. M. <strong>PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.</strong> Nature Med. 8: 1153-1160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244302</a>] [<a href="https://doi.org/10.1038/nm761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244302">Liang et al. (2002)</a> demonstrated that AKT phosphorylates p27, impairs the nuclear import of p27, and opposes cytokine-mediated G1 arrest. In cells transfected with constitutively active AKT, wildtype p27 mislocalized to the cytoplasm, but mutant p27 was nuclear. In cells with activated AKT, wildtype p27 failed to cause G1 arrest, while the antiproliferative effect of the mutant p27 was not impaired. Cytoplasm p27 was seen in 41% (52 of 128) primary human breast cancers in conjunction with AKT activation and was correlated with a poor patient prognosis. <a href="#24" class="mim-tip-reference" title="Liang, J., Zubovitz, J., Petrocelli, T., Kotchetkov, R., Connor, M. K., Han, K., Lee, J.-H., Ciarallo, S., Catzavelos, C., Beniston, R., Franssen, E., Slingerland, J. M. <strong>PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.</strong> Nature Med. 8: 1153-1160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244302</a>] [<a href="https://doi.org/10.1038/nm761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244302">Liang et al. (2002)</a> concluded that their data showed a novel mechanism whereby AKT impairs p27 function that is associated with an aggressive phenotype in human breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244302" 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="#46" class="mim-tip-reference" title="Viglietto, G., Motti, M. L., Bruni, P., Melillo, R. M., D'Alessio, A., Califano, D., Vinci, F., Chiappetta, G., Tsichlis, P., Bellacosa, A., Fusco, A., Santoro, M. <strong>Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.</strong> Nature Med. 8: 1136-1144, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244303</a>] [<a href="https://doi.org/10.1038/nm762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244303">Viglietto et al. (2002)</a> independently demonstrated that AKT regulates cell proliferation in breast cancer cells by preventing p27(KIP1)-mediated growth arrest. They also showed that threonine at position 157 is an AKT phosphorylation site and causes retention of p27(KIP1) in the cytoplasm, precluding p27(KIP1)-induced G1 arrest. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244303" 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="Gopfert, U., Kullmann, M., Hengst, L. <strong>Cell cycle-dependent translation of p27 involves a responsive element in its 5-prime-UTR that overlaps with a uORF.</strong> Hum. Molec. Genet. 12: 1767-1779, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12837699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12837699</a>] [<a href="https://doi.org/10.1093/hmg/ddg177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12837699">Gopfert et al. (2003)</a> analyzed fragments of the p27 transcript for their contribution to cell cycle-regulated translation. An element in the p27 5-prime UTR rendered reporter translation cell cycle-sensitive with maximal translation in G1-arrested cells. The 114-bp element contained a G/C-rich hairpin domain that was predicted to form multiple stable stemloops and also overlapped with a small upstream open reading frame (ORF). Both structures contributed to cell cycle-regulated translation. The upstream ORF could be translated in vitro, and its sequence and position were evolutionarily conserved in mouse and chicken. The precise sequence or length of the upstream ORF-encoded peptide were not important for p27 translation, suggesting that ribosomal recruitment to its initiation codon, rather than the translation product itself, contributes to the regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12837699" 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 NIH-3T3 mouse fibroblasts and mouse embryonic fibroblasts, <a href="#19" class="mim-tip-reference" title="Kamura, T., Hara, T., Matsumoto, M., Ishida, N., Okumura, F., Hatakeyama, S., Yoshida, M., Nakayama, K., Nakayama, K. I. <strong>Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase.</strong> Nature Cell Biol. 6: 1229-1235, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531880</a>] [<a href="https://doi.org/10.1038/ncb1194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531880">Kamura et al. (2004)</a> found that Skp2 was the major ubiquitin ligase involved in ubiquitination of nuclear p27(KIP1) at the S and G2 phases, and that a complex made up of Kpc1 (RNF123; <a href="/entry/614472">614472</a>) and Kpc2 (UBAC1; <a href="/entry/608129">608129</a>) ubiquitinated cytoplasmic p27(KIP1) at G1 phase. Cytoplasmic degradation of p27(KIP1) required p27(KIP1) nuclear export by Crm1 (XPO1; <a href="/entry/602559">602559</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531880" 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 inverse relationship between proliferation and differentiation in osteoblasts has been well documented. <a href="#42" class="mim-tip-reference" title="Thomas, D. M., Johnson, S. A., Sims, N. A., Trivett, M. K., Slavin, J. L., Rubin, B. P., Waring, P., McArthur, G. A., Walkley, C. R., Holloway, A. J., Diyagama, D., Grim, J. E., Clurman, B. E., Bowtell, D. D. L., Lee, J.-S., Gutierrez, G. M., Piscopo, D. M., Carty, S. A., Hinds, P. W. <strong>Terminal osteoblast differentiation, mediated by runx2 and p27(KIP1) is disrupted in osteosarcoma.</strong> J. Cell Biol. 167: 925-934, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583032[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/10.1083/jcb.200409187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583032">Thomas et al. (2004)</a> found that Runx2 (<a href="/entry/600211">600211</a>), a master regulator of osteoblast differentiation in mammalian cells, was disrupted in 6 of 7 mammalian osteosarcoma cell lines. Immunohistochemical analysis of human osteosarcomas indicated that expression of p27(KIP1) was also lost as tumors lost osteogenic differentiation. <a href="#42" class="mim-tip-reference" title="Thomas, D. M., Johnson, S. A., Sims, N. A., Trivett, M. K., Slavin, J. L., Rubin, B. P., Waring, P., McArthur, G. A., Walkley, C. R., Holloway, A. J., Diyagama, D., Grim, J. E., Clurman, B. E., Bowtell, D. D. L., Lee, J.-S., Gutierrez, G. M., Piscopo, D. M., Carty, S. A., Hinds, P. W. <strong>Terminal osteoblast differentiation, mediated by runx2 and p27(KIP1) is disrupted in osteosarcoma.</strong> J. Cell Biol. 167: 925-934, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583032[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/10.1083/jcb.200409187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583032">Thomas et al. (2004)</a> found that ectopic expression of Runx2 induced growth arrest through p27(KIP1)-induced inhibition of S-phase cyclin complexes, followed by dephosphorylation of RB1 (<a href="/entry/614041">614041</a>) and G1 cell cycle arrest. They concluded that RUNX2 establishes a terminally differentiated state in osteoblasts through RB1- and p27(KIP1)-dependent mechanisms that are disrupted in osteosarcomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15583032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="White, P. M., Doetzlhofer, A., Lee, Y. S., Groves, A. K., Segil, N. <strong>Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells.</strong> Nature 441: 984-987, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791196</a>] [<a href="https://doi.org/10.1038/nature04849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791196">White et al. (2006)</a> showed that postmitotic supporting cells purified from the postnatal mouse cochlea retain the ability to divide and trans-differentiate into new hair cells in culture. Furthermore, they demonstrated that age-dependent changes in supporting cell proliferative capacity are due in part to changes in the ability to downregulate p27(Kip1). <a href="#47" class="mim-tip-reference" title="White, P. M., Doetzlhofer, A., Lee, Y. S., Groves, A. K., Segil, N. <strong>Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells.</strong> Nature 441: 984-987, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791196</a>] [<a href="https://doi.org/10.1038/nature04849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791196">White et al. (2006)</a> concluded that postnatal mammalian supporting cells are potential targets for therapeutic manipulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791196" 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="#17" class="mim-tip-reference" title="Grimmler, M., Wang, Y., Mund, T., Cilensek, Z., Keidel, E.-M., Waddell, M. B., Jakel, H., Kullmann, M., Kriwacki, R. W., Hengst, L. <strong>Cdk-inhibitory activity and stability of p27(Kip1) are directly regulated by oncogenic tyrosine kinases.</strong> Cell 128: 269-280, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254966</a>] [<a href="https://doi.org/10.1016/j.cell.2006.11.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17254966">Grimmler et al. (2007)</a> found that a conserved tyrosine (Y88) in the CDK-inhibitory domain of human p27 could be phosphorylated by the Src family kinase LYN (<a href="/entry/165120">165120</a>) and the oncogene product BCR-ABL (see <a href="/entry/189980">189980</a>). Phosphorylation of Y88 did not prevent binding of p27 to cyclin A/CDK2, but it caused phosphorylated Y88 and the inhibitory domain of p27 to be ejected from the CDK2 active site, restoring partial CDK activity. This allowed Y88-phosphorylated p27 to be efficiently phosphorylated on thr187 by CDK2, which in turn promoted its SCF-SKP2-dependent degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17254966" 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="Chu, I., Sun, J., Arnaout, A., Kahn, H., Hanna, W., Narod, S., Sun, P., Tan, C.-K., Hengst, L., Slingerland, J. <strong>p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.</strong> Cell 128: 281-294, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254967[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.cell.2006.11.049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17254967">Chu et al. (2007)</a> showed that the oncogenic kinase SRC (<a href="/entry/190090">190090</a>) phosphorylated human p27 at Y74 and Y88. SRC inhibitors increased cellular p27 stability, whereas SRC overexpression accelerated p27 proteolysis. SRC-phosphorylated p27 inhibited cyclin E/CDK2 poorly in vitro, and SRC transfection reduced p27/cyclin E/CDK2 complexes. SRC-activated human breast cancer cell lines exhibited reduced p27, and there was a correlation between SRC activation and reduced nuclear p27 in 482 primary human breast cancers. In tamoxifen-resistant breast cancer cell lines, SRC inhibition increased p27 levels and restored tamoxifen sensitivity. <a href="#6" class="mim-tip-reference" title="Chu, I., Sun, J., Arnaout, A., Kahn, H., Hanna, W., Narod, S., Sun, P., Tan, C.-K., Hengst, L., Slingerland, J. <strong>p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.</strong> Cell 128: 281-294, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254967[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.cell.2006.11.049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17254967">Chu et al. (2007)</a> concluded that SRC-mediated phosphorylation of p27 reduces its inhibitory action on cyclin E/CDK2, facilitating subsequent p27 proteolysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17254967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By yeast 2-hybrid analysis of an adult human heart cDNA library, <a href="#18" class="mim-tip-reference" title="Hauck, L., Harms, C., An, J., Rohne, J., Gertz, K., Dietz, R., Endres, M., von Harsdorf, R. <strong>Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart.</strong> Nature Med. 14: 315-324, 2008. Note: Erratum: Nature Med. 14: 585 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311148</a>] [<a href="https://doi.org/10.1038/nm1729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311148">Hauck et al. (2008)</a> showed that p27 interacted with the C-terminal region of casein kinase-2 (CK2)-alpha-prime (CSNK2A2; <a href="/entry/115442">115442</a>). Immunocytochemical analysis of primary rat ventricular cardiomyocytes revealed colocalization of p27 with CK2-alpha-prime. Angiotensin II, a potent inducer of cardiomyocyte hypertrophy, induced proteasomal degradation of p27 in primary rat cardiomyocytes through CK2-alpha-prime-dependent phosphorylation of p27 on ser83 and thr187, which are conserved in humans and rodents. Conversely, unphosphorylated p27 potently inhibited CK2-alpha-prime. <a href="#18" class="mim-tip-reference" title="Hauck, L., Harms, C., An, J., Rohne, J., Gertz, K., Dietz, R., Endres, M., von Harsdorf, R. <strong>Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart.</strong> Nature Med. 14: 315-324, 2008. Note: Erratum: Nature Med. 14: 585 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311148</a>] [<a href="https://doi.org/10.1038/nm1729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311148">Hauck et al. (2008)</a> concluded that downregulation of p27 by CK2-alpha-prime is necessary for development of agonist- and stress-induced cardiac hypertrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18311148" 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>MicroRNAs (miRNAs) are short noncoding RNAs that bind to complementary sequences in the 3-prime UTRs of target mRNAs and inhibit their expression. <a href="#21" class="mim-tip-reference" title="Kedde, M., Strasser, M. J., Boldajipour, B., Oude Vrielink, J. A. F., Slanchev, K., Sage, C. I., Nagel, R., Voorhoeve, P. M., van Duijse, J., Orom, U. A., Lund, A. H., Perrakis, A., Raz, E., Agami, R. <strong>RNA-binding protein Dnd1 inhibits microRNA access to target mRNA.</strong> Cell 131: 1273-1286, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18155131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18155131</a>] [<a href="https://doi.org/10.1016/j.cell.2007.11.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18155131">Kedde et al. (2007)</a> showed that the expression of DND1 (<a href="/entry/609385">609385</a>), an evolutionarily conserved RNA-binding protein, counteracted the inhibitory effect of several miRNAs in human cells and in primordial germ cells of zebrafish by preventing the association of miRNAs with their target mRNAs. <a href="#21" class="mim-tip-reference" title="Kedde, M., Strasser, M. J., Boldajipour, B., Oude Vrielink, J. A. F., Slanchev, K., Sage, C. I., Nagel, R., Voorhoeve, P. M., van Duijse, J., Orom, U. A., Lund, A. H., Perrakis, A., Raz, E., Agami, R. <strong>RNA-binding protein Dnd1 inhibits microRNA access to target mRNA.</strong> Cell 131: 1273-1286, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18155131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18155131</a>] [<a href="https://doi.org/10.1016/j.cell.2007.11.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18155131">Kedde et al. (2007)</a> detailed the effect of DND1 on the downregulation of p27 mRNA by miR221 (MIRN221; <a href="/entry/300568">300568</a>) in human cells. Introduction of DND1 abolished the interaction between miR221 and the 3-prime UTR of p27 mRNA and countered the downregulation of p27 expression by miR221. DND1 bound a uridine-rich region in the 3-prime UTR of p27 mRNA that is near the miR221-binding site and prevented miR221 binding. At least 1 of the 2 uridine-rich regions in the p27 3-prime UTR and the RNA-binding domain of DND1 were required to rescue p27 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18155131" 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="Cuesta, R., Martinez-Sanchez, A., Gebauer, F. <strong>miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells.</strong> Molec. Cell. Biol. 29: 2841-2851, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19273599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01971-08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19273599">Cuesta et al. (2009)</a> found that translation of p27 in HeLa cells and HL60 human promyelocytic leukemia cells was cap dependent. Translation via a proposed internal ribosome entry site appeared to be artifactual, resulting from the presence of cryptic promoters in the 5-prime UTR. <a href="#7" class="mim-tip-reference" title="Cuesta, R., Martinez-Sanchez, A., Gebauer, F. <strong>miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells.</strong> Molec. Cell. Biol. 29: 2841-2851, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19273599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01971-08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19273599">Cuesta et al. (2009)</a> showed that the dramatic increase in p27 following phorbol ester treatment was not due to increased mRNA levels, but rather to downregulation of MIR181A (see <a href="/entry/612742">612742</a>) and relief of MIR181A-dependent translational repression. The 3-prime UTR of p27 mRNA contains 2 possible MIR181A-binding sites, 1 of which overlaps the MIR221-binding site. Both MIR181A-binding sites could repress p27 translation either individually or synergistically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19273599" 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="#25" class="mim-tip-reference" title="Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J, Egia, A., Nakayama, K. I., Cordon-Cardo, C., Teruya-Feldstein, J., Pandolfi, P. P. <strong>Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.</strong> Nature 464: 374-379, 2010. Note: Erratum: Nature 466: 398 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20237562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20237562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20237562[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/nature08815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20237562">Lin et al. (2010)</a> showed that although Skp2 inactivation on its own does not induce cellular senescence, aberrant protooncogenic signals as well as inactivation of tumor suppressor genes do trigger a potent, tumor-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic stress-driven senescence neither elicit activation of the p19(Arf) (see <a href="/entry/600160">600160</a>)-p53 (<a href="/entry/191170">191170</a>) pathway nor DNA damage, but instead depend on Atf4 (<a href="/entry/604064">604064</a>), p27, and p21 (<a href="/entry/116899">116899</a>). <a href="#25" class="mim-tip-reference" title="Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J, Egia, A., Nakayama, K. I., Cordon-Cardo, C., Teruya-Feldstein, J., Pandolfi, P. P. <strong>Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.</strong> Nature 464: 374-379, 2010. Note: Erratum: Nature 466: 398 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20237562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20237562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20237562[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/nature08815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20237562">Lin et al. (2010)</a> further demonstrated that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten (<a href="/entry/601728">601728</a>)-deficient cells and tumor regression in preclinical studies. <a href="#25" class="mim-tip-reference" title="Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J, Egia, A., Nakayama, K. I., Cordon-Cardo, C., Teruya-Feldstein, J., Pandolfi, P. P. <strong>Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.</strong> Nature 464: 374-379, 2010. Note: Erratum: Nature 466: 398 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20237562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20237562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20237562[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/nature08815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20237562">Lin et al. (2010)</a> concluded that their findings provided proof-of-principle evidence that pharmacologic inhibition of Skp2 may represent a general approach for cancer prevention and therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20237562" 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 HER2-HER3 (ERBB3; <a href="/entry/190151">190151</a>) dimer induces cell growth by activating a kinase cascade that includes phosphorylation of p27, resulting in p27 ubiquitination and proteasomal degradation. Trastuzumab blocks the HER2-HER3 interaction and is used to treat breast cancers with HER2 overexpression, although some of these cancers develop trastuzumab resistance. Using small interfering RNA (siRNA) to identify genes involved in trastuzumab resistance, <a href="#22" class="mim-tip-reference" title="Lee-Hoeflich, S. T., Pham, T. Q., Dowbenko, D., Munroe, X., Lee, J., Li, L., Zhou, W., Haverty, P. M., Pujara, K., Stinson, J., Chan, S. M., Eastham-Anderson, J., and 9 others. <strong>PPM1H is a p27 phosphatase implicated in trastuzumab resistance.</strong> Cancer Discov. 1: 326-337, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22586611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22586611</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-11-0062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22586611">Lee-Hoeflich et al. (2011)</a> identified several kinases and phosphatases that were upregulated in trastuzumab-resistant cancers, including PPM1H (<a href="/entry/616016">616016</a>). Knockdown of PPM1H by either siRNA or short hairpin RNA induced trastuzumab resistance and increased cell proliferation. <a href="#22" class="mim-tip-reference" title="Lee-Hoeflich, S. T., Pham, T. Q., Dowbenko, D., Munroe, X., Lee, J., Li, L., Zhou, W., Haverty, P. M., Pujara, K., Stinson, J., Chan, S. M., Eastham-Anderson, J., and 9 others. <strong>PPM1H is a p27 phosphatase implicated in trastuzumab resistance.</strong> Cancer Discov. 1: 326-337, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22586611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22586611</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-11-0062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22586611">Lee-Hoeflich et al. (2011)</a> found that PPM1H protected p27 from degradation by dephosphorylating thr187, thus removing a degradation signal and stabilizing p27-inhibited cell growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22586611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Das, C. M., Taylor, P., Gireud, M., Singh, A., Lee, D., Fuller, G., Ji, L., Fangusaro, J., Rajaram, V., Goldman, S., Eberhart, C., Gopalakrishnan, V. <strong>The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.</strong> Oncogene 32: 1691-1701, 2013. Note: Erratum: Oncogene 35: 6153-6154, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22665064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22665064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22665064[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/onc.2012.182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22665064">Das et al. (2013)</a> found that knockdown of REST (<a href="/entry/600571">600571</a>) resulted in a decline in medulloblastoma cell proliferation and accumulation of p27. In vitro analysis showed that REST and p27 expression were reciprocally correlated in human medulloblastoma samples. REST repressed expression of USP37 (<a href="/entry/620226">620226</a>), and USP37 expression promoted p27 deubiquitination. USP37 interacted with p27 to promote its deubiquitination and stabilization, thereby blocking cell proliferation. The authors concluded that REST regulates p27 stability and cell proliferation by controlling USP37. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22665064" 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="#1" class="mim-tip-reference" title="Baens, M., Aerssens, J., Van Zand, K., Van den Berghe, H., Marynen, P. <strong>Isolation and regional assignment of human chromosome 12p cDNAs.</strong> Genomics 29: 44-52, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530100</a>] [<a href="https://doi.org/10.1006/geno.1995.1213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530100">Baens et al. (1995)</a> characterized 117 cDNAs isolated by direct cDNA selection using pools of human chromosome 12p cosmids. Among these, 3 matched previously determined cDNA sequences, including the cyclin-dependent kinase inhibitor referred to as KIP1. STSs were developed for all cosmids. Regional assignment of the STSs by PCR analysis with somatic cell hybrids and fluorescence in situ hybridization (FISH) showed that the loci mapped to 12p13. <a href="#28" class="mim-tip-reference" title="Martin, E., Cacheux, V., Cave, H., Lapierre, J. M., Le Paslier, D., Grandchamp, B. <strong>Localization of the CDKN4/p27(Kip1) gene to human chromosome 12p12.3.</strong> Hum. Genet. 96: 668-670, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8522324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8522324</a>] [<a href="https://doi.org/10.1007/BF00210296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8522324">Martin et al. (1995)</a> mapped this gene, which they referred to as CDKN4, to 12p12.3 by fluorescence in situ hybridization. By PCR-based screening of genomic YAC clones of the CEPH library, they isolated 7 containing the KIP1 gene. In 4 of these YACs, they found a common STS, D12S358, and 1 of the 4 YACs also contained an additional STS, D12S320, which had been located 4 cM apart from D12S358 on the Genethon genetic map. Most of the YACs containing the KIP1 gene had been assigned to chromosome 12 from hybridization data of inter-Alu PCR products from somatic hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8530100+8522324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By FISH, <a href="#36" class="mim-tip-reference" title="Saito, T., Seki, N., Hattori, A., Hayashi, A., Abe, M., Araki, R., Fujimori, A., Fukumura, R., Kozuma, S., Matsuda, Y. <strong>Structure, expression profile, and chromosomal location of a mouse gene homologous to human DNA-PK(cs) interacting protein (KIP) gene.</strong> Mammalian Genome 10: 315-317, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10051332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10051332</a>] [<a href="https://doi.org/10.1007/s003359900994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10051332">Saito et al. (1999)</a> mapped the mouse Kip gene to chromosome 7D3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10051332" 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 a 48-year-old Caucasian female with primary hyperparathyroidism and a history of pituitary adenoma, consistent with multiple endocrine neoplasia type IV (MEN4; <a href="/entry/610755">610755</a>), <a href="#33" class="mim-tip-reference" title="Pellegata, N. S., Quintanilla-Martinez, L., Siggelkow, H., Samson, E., Bink, K., Hofler, H., Fend, F., Graw, J., Atkinson, M. J. <strong>Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia syndrome in rats and humans.</strong> Proc. Nat. Acad. Sci. 103: 15558-15563, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 19213 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17030811[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.0603877103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030811">Pellegata et al. (2006)</a> identified a heterozygous nonsense mutation in the CDKN1B gene (<a href="#0001">600778.0001</a>). The mutation was also identified in her older sister who had renal angiomyolipoma, her youngest sister, and that sister's teenaged daughter, who reported no symptoms but did not undergo thorough examination. No mutations in the MEN1 gene (<a href="/entry/613733">613733</a>) were found in the proband or her older sister. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Dutch woman with MEN4, <a href="#14" class="mim-tip-reference" title="Georgitsi, M., Raitila, A., Karhu, A., van der Luijt, R. B., Aalfs, C. M., Sane, T., Vierimaa, O., Makinen, M. J., Tuppurainen, K., Paschke, R., Gimm, O., Koch, C. A., and 11 others. <strong>Germline CDKN1B/p27(Kip1) mutation in multiple endocrine neoplasia.</strong> J. Clin. Endocr. Metab. 92: 3321-3325, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17519308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17519308</a>] [<a href="https://doi.org/10.1210/jc.2006-2843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17519308">Georgitsi et al. (2007)</a> identified a heterozygous truncating mutation in the CDKN1B gene (<a href="#0002">600778.0002</a>). Tumor tissue from the patient's cervical carcinoma showed loss of heterozygosity for the wildtype allele and negative immunostaining for the p27 protein. The patient was ascertained from a larger cohort of 37 patients, mostly Dutch, who were clinically suspected to have MEN but were negative for mutation in the MEN1 gene. The authors also studied 19 patients with familial acromegaly/pituitary adenomas and 50 Finnish patients with sporadic acromegaly who underwent direct sequencing of the CDKN1B gene; the Dutch woman was the only patient found to carry a CDKN1B mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17519308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a woman with MEN4, <a href="#31" class="mim-tip-reference" title="Molatore, S., Marinoni, I., Lee, M., Pulz, E., Ambrosio, M. R., degli Uberti, E. C., Zatelli, M. C., Pellegata, N. S. <strong>A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization.</strong> Hum. Mutat. 31: E1825-E1835, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20824794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20824794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20824794[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/10.1002/humu.21354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20824794">Molatore et al. (2010)</a> identified a heterozygous missense mutation in the CDKN1B gene (P69L; <a href="#0003">600778.0003</a>). The mutation caused reduced mutant protein levels due to more rapid degradation, had slightly higher cytoplasmic localization compared to wildtype, and lost the ability to bind CDK2. The P69L mutant protein was less effective at suppressing growth of neuroendocrine tumor cells in vitro compared to wildtype. The findings suggested a tumor suppressor role for p27 in neuroendocrine cells. The patient was 1 (3.7%) of 27 individuals with a MEN-like phenotype who was found to carry a CDKN1B mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20824794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 69-year-old Spanish woman with MEN4, <a href="#26" class="mim-tip-reference" title="Malanga, D., De Gisi, S., Riccardi, M., Scrima, M., De Marco, C., Robledo, M., Viglietto, G. <strong>Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype.</strong> Europ. J. Endocr. 166: 551-560, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22129891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22129891</a>] [<a href="https://doi.org/10.1530/EJE-11-0929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22129891">Malanga et al. (2012)</a> identified a heterozygous mutation in the CDKN1B gene (<a href="#0004">600778.0004</a>). In vitro functional expression studies using a luciferase reporter in HeLa cells showed that the mutation resulted in a significant reduction (30-60%) in transcription and possibly translation. Patient peripheral blood cells showed a significant 3-fold decrease in CDKN1B mRNA levels compared to controls, consistent with haploinsufficiency. The patient was 1 of 15 Spanish individuals with MEN-like features who underwent direct sequencing of the CDKN1B gene and was the only patient found to carry a mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22129891" 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>Small Intestine Neuroendocrine Tumors</em></strong></p><p>
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Using exome- and genome-sequence analysis of small intestine neuroendocrine tumors (SI-NETs), <a href="#12" class="mim-tip-reference" title="Francis, J. M., Kiezun, A., Ramos, A. H., Serra, S., Pedamallu, C. S., Qian, Z. R., Banck, M. S., Kanwar, R., Kulkarni, A. A., Karpathakis, A., Manzo, V., Contractor, T., and 35 others. <strong>Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.</strong> Nature Genet. 45: 1483-1486, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24185511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24185511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24185511[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/ng.2821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24185511">Francis et al. (2013)</a> identified recurrent somatic mutations and deletions in CDKN1B, which encodes p27. <a href="#12" class="mim-tip-reference" title="Francis, J. M., Kiezun, A., Ramos, A. H., Serra, S., Pedamallu, C. S., Qian, Z. R., Banck, M. S., Kanwar, R., Kulkarni, A. A., Karpathakis, A., Manzo, V., Contractor, T., and 35 others. <strong>Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.</strong> Nature Genet. 45: 1483-1486, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24185511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24185511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24185511[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/ng.2821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24185511">Francis et al. (2013)</a> observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24185511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Disease Associations</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Chang, B., Zheng, S. L., Isaacs, S. D., Wiley, K. E., Turner, A., Li, G., Walsh, P. C., Meyers, D. A., Isaacs, W. B., Xu, J. <strong>A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer.</strong> Cancer Res. 64: 1997-1999, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15026335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15026335</a>] [<a href="https://doi.org/10.1158/0008-5472.can-03-2340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15026335">Chang et al. (2004)</a> analyzed the CDKN1B gene in 188 families with hereditary prostate cancer (see <a href="/entry/176807">176807</a>) and found a significant association between the SNP -79C/T (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34330;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs34330</a>) and prostate cancer. The -79C allele was overtransmitted from parents to affected offspring, an association that was observed primarily in offspring whose age at diagnosis was less than 65 years. <a href="#5" class="mim-tip-reference" title="Chang, B., Zheng, S. L., Isaacs, S. D., Wiley, K. E., Turner, A., Li, G., Walsh, P. C., Meyers, D. A., Isaacs, W. B., Xu, J. <strong>A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer.</strong> Cancer Res. 64: 1997-1999, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15026335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15026335</a>] [<a href="https://doi.org/10.1158/0008-5472.can-03-2340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15026335">Chang et al. (2004)</a> suggested that germline variants of this gene play a role in prostate cancer susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15026335" 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="Grey, W., Izatt, L., Sahraoui, W., Ng, Y.-M., Ogilvie, C., Hulse, A., Tse, E., Holic, R., Yu, V. <strong>Deficiency of the cyclin-dependent kinase inhibitor, CDKN1B, results in overgrowth and neurodevelopmental delay.</strong> Hum. Mutat. 34: 864-868, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23505216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23505216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23505216[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/10.1002/humu.22314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23505216">Grey et al. (2013)</a> found biallelic loss of CDKN1B gene expression in a boy with overgrowth and severe neurodevelopmental delay with autism. He also had left-sided strabismus, maldescended testes, and challenging behavior. Array CGH identified a heterozygous, approximately 108-kb deletion on chromosome 12p13 encompassing the 5-prime end of CDKN1B, APOLD1 (<a href="/entry/612456">612456</a>), and the 5-prime untranslated region of DDX47 (<a href="/entry/615428">615428</a>). The patient's unaffected mother also carried this deletion. Both individuals had decreased CDKN1B mRNA expression, but only the boy had decreased protein levels. Sanger sequencing showed that the proband also had a de novo heterozygous -73G-A transition in the promoter of the CDKN1B gene that was demonstrated to result in significantly decreased protein expression. <a href="#16" class="mim-tip-reference" title="Grey, W., Izatt, L., Sahraoui, W., Ng, Y.-M., Ogilvie, C., Hulse, A., Tse, E., Holic, R., Yu, V. <strong>Deficiency of the cyclin-dependent kinase inhibitor, CDKN1B, results in overgrowth and neurodevelopmental delay.</strong> Hum. Mutat. 34: 864-868, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23505216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23505216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23505216[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/10.1002/humu.22314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23505216">Grey et al. (2013)</a> postulated that the neurologic phenotype in the proband fit a recessive model of inheritance and was due to decreased expression of the CDKN1B below a threshold necessary to ensure normal neurodevelopment. The findings were also consistent with a mouse knockout model that has gigantism and hyperplasia of multiple organs (<a href="#11" class="mim-tip-reference" title="Fero, M. L., Rivkin, M., Tasch, M., Porter, P., Carow, C. E., Firpo, E., Polyak, K., Tsai, L.-H., Broudy, V., Perlmutter, R. M., Kaushansky, K., Roberts, J. M. <strong>A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.</strong> Cell 85: 733-744, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8646781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8646781</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81239-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8646781">Fero et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8646781+23505216" 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="#11" class="mim-tip-reference" title="Fero, M. L., Rivkin, M., Tasch, M., Porter, P., Carow, C. E., Firpo, E., Polyak, K., Tsai, L.-H., Broudy, V., Perlmutter, R. M., Kaushansky, K., Roberts, J. M. <strong>A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.</strong> Cell 85: 733-744, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8646781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8646781</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81239-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8646781">Fero et al. (1996)</a> found that targeted disruption of the murine p27(Kip1) gene caused a gene dose-dependent increase in animal size without other gross morphologic abnormalities. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thymic hyperplasia was associated with increased T-lymphocyte proliferation, and T cells showed enhanced IL2 (<a href="/entry/147680">147680</a>) responsiveness in vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. In the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells. That p27 and Rb function in the same regulatory pathway was suggested by the finding that p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia. The absence of p27 also caused an ovulatory defect and female sterility. Maturation of second ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8646781" 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="#49" class="mim-tip-reference" title="Zindy, F., Cunningham, J. J., Sherr, C. J., Jogal, S., Smeyne, R. J., Roussel, M. F. <strong>Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases.</strong> Proc. Nat. Acad. Sci. 96: 13462-13467, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10557343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10557343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10557343[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.96.23.13462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10557343">Zindy et al. (1999)</a> generated mice with targeted deletions of both the Ink4d (<a href="/entry/600927">600927</a>) and Kip1 genes. They found that terminally differentiated, postmitotic neurons in these mice reentered the cell cycle, divided, and underwent apoptosis. <a href="#49" class="mim-tip-reference" title="Zindy, F., Cunningham, J. J., Sherr, C. J., Jogal, S., Smeyne, R. J., Roussel, M. F. <strong>Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases.</strong> Proc. Nat. Acad. Sci. 96: 13462-13467, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10557343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10557343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10557343[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.96.23.13462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10557343">Zindy et al. (1999)</a> noted that when either Ink4d or Kip1 alone are deleted, the postmitotic state is maintained, suggesting a redundant role for these genes in mature neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10557343" 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="#30" class="mim-tip-reference" title="Mitsuhashi, T., Aoki, Y., Eksioglu, Y. Z., Takahashi, T., Bhide, P. G., Reeves, S. A., Caviness, V. S., Jr. <strong>Overexpression of p27(Kip1) lengthens the G1 phase in a mouse model that targets inducible gene expression to central nervous system progenitor cells.</strong> Proc. Nat. Acad. Sci. 98: 6435-6440, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371649</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11371649[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.111051398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371649">Mitsuhashi et al. (2001)</a> described a mouse model in which p27(Kip1) transgene expression was spatially restricted to the central nervous system neuroepithelium and temporally controlled with doxycycline. Transgene-specific transcripts were detectable within 6 hours of doxycycline administration, and maximum nonlethal expression was approached within 12 hours. After 18 to 26 hours of transgene expression, the G1 phase of the cell cycle was estimated to increase from 9 to 13 hours in the neocortical neuroepithelium, the maximum G1 phase length attainable in this proliferative population in normal mice. Thus, the data established a direct link between p27(Kip1) and control of G1 phase length in the mammalian central nervous system and unveiled intrinsic mechanisms that constrain the G1 phase length to a putative physiologic maximum despite ongoing p27(Kip1) transgene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371649" 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>Phosphorylation of p27(Kip1) on threonine-187 by CDK2 is thought to initiate the major pathway for p27 proteolysis. To test the importance of this pathway critically in vivo, <a href="#27" class="mim-tip-reference" title="Malek, N. P., Sundberg, H., McGrew, S., Nakayama, K., Kyriakides, T. R., Roberts, J. M. <strong>A mouse knock-in model exposes sequential proteolytic pathways that regulate p27(Kip1) in G1 and S phase.</strong> Nature 413: 323-327, 2001. Note: Erratum: Nature 413: 652 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11565035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11565035</a>] [<a href="https://doi.org/10.1038/35095083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11565035">Malek et al. (2001)</a> replaced the murine p27 gene with one that encoded alanine instead of threonine at position 187. <a href="#27" class="mim-tip-reference" title="Malek, N. P., Sundberg, H., McGrew, S., Nakayama, K., Kyriakides, T. R., Roberts, J. M. <strong>A mouse knock-in model exposes sequential proteolytic pathways that regulate p27(Kip1) in G1 and S phase.</strong> Nature 413: 323-327, 2001. Note: Erratum: Nature 413: 652 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11565035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11565035</a>] [<a href="https://doi.org/10.1038/35095083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11565035">Malek et al. (2001)</a> demonstrated that cells expressing p27 with the T187A change were unable to downregulate p27 during the S and G2 phases of the cell cycle, but that this had a surprisingly modest effect on cell proliferation both in vitro and in vivo. <a href="#27" class="mim-tip-reference" title="Malek, N. P., Sundberg, H., McGrew, S., Nakayama, K., Kyriakides, T. R., Roberts, J. M. <strong>A mouse knock-in model exposes sequential proteolytic pathways that regulate p27(Kip1) in G1 and S phase.</strong> Nature 413: 323-327, 2001. Note: Erratum: Nature 413: 652 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11565035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11565035</a>] [<a href="https://doi.org/10.1038/35095083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11565035">Malek et al. (2001)</a> demonstrated a second proteolytic pathway for controlling p27, one that is activated by mitogens and degrades p27 exclusively during G1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11565035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Uchida, T., Nakamura, T., Hashimoto, N., Matsuda, T., Kotani, K., Sakaue, H., Kido, Y., Hayashi, Y., Nakayama, K. I., White, M. F., Kasuga, M. <strong>Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice.</strong> Nature Med. 11: 175-182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15685168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15685168</a>] [<a href="https://doi.org/10.1038/nm1187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15685168">Uchida et al. (2005)</a> generated mice expressing human CDKN1B under the control of the promoter of the rat insulin gene and observed that increased expression of p27 in pancreatic beta cells induced severe diabetes as a result of inhibition of beta-cell proliferation. In mice lacking either insulin receptor substrate-2 (Irs2 -/-; see <a href="/entry/600797">600797</a>) or the long form of the leptin receptor (Lepr -/-; see <a href="/entry/601007">601007</a>), they found progressive accumulation of p27 in the nucleus of beta cells. Deletion of Cdkn1b ameliorated hyperglycemia in these mouse models of type II diabetes (<a href="/entry/125853">125853</a>) by increasing islet mass and maintaining compensatory hyperinsulinemia, which the authors attributed predominantly to stimulation of pancreatic beta-cell proliferation. <a href="#45" class="mim-tip-reference" title="Uchida, T., Nakamura, T., Hashimoto, N., Matsuda, T., Kotani, K., Sakaue, H., Kido, Y., Hayashi, Y., Nakayama, K. I., White, M. F., Kasuga, M. <strong>Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice.</strong> Nature Med. 11: 175-182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15685168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15685168</a>] [<a href="https://doi.org/10.1038/nm1187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15685168">Uchida et al. (2005)</a> concluded that p27 contributes to beta-cell failure in the development of type II diabetes in Irs2 -/- and Lepr -/- (db/db) mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15685168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Wolfraim, L. A., Letterio, J. J. <strong>Cutting edge: p27(Kip1) deficiency reduces the requirement for CD28-mediated costimulation in naive CD8+ but not CD4+ T lymphocytes.</strong> J. Immun. 174: 2481-2484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728451</a>] [<a href="https://doi.org/10.4049/jimmunol.174.5.2481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728451">Wolfraim and Letterio (2005)</a> found increased numbers of both Cd4 (<a href="/entry/186940">186940</a>)-positive and Cd8 (see <a href="/entry/186910">186910</a>)-positive T cells in p27(Kip1)-deficient mice. However, there was a greater increase in the numbers of Cd8-positive T cells, resulting in a lower Cd4:Cd8 ratio, due in part to enhanced proliferation of naive Cd8-positive T cells, but not naive Cd4-positive T cells, under conditions of limiting Cd28 (<a href="/entry/186760">186760</a>)-mediated costimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728451" 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>Nmyc (<a href="/entry/164840">164840</a>) promotes rapid cell division of granule neuron progenitors (GNPs) in mice, and its conditional loss during embryonic cerebellar development results in severe GNP deficiency, perturbs foliation, and leads to reduced cerebellar mass. Since loss of Nmyc triggers precocious expression of Kip1 and Ink4c (CDKN2C; <a href="/entry/603369">603369</a>) in the cerebellar primordium, <a href="#50" class="mim-tip-reference" title="Zindy, F., Knoepfler, P. S., Xie, S., Sherr, C. J., Eisenman, R. N., Roussel, M. F. <strong>N-Myc and the cyclin-dependent kinase inhibitors p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development.</strong> Proc. Nat. Acad. Sci. 103: 11579-11583, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864777[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.0604727103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864777">Zindy et al. (2006)</a> disrupted Kip1 and Ink4c in Nmyc-null cerebella and found that this partially rescued GNP cell proliferation and cerebellar foliation. They concluded that expression of NMYC and concomitant downregulation of INK4C and KIP1 contribute to the proper development of the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16864777" 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="#37" class="mim-tip-reference" title="Sharov, A. A., Sharova, T. Y., Mardaryev, A. N., di Vignano, A. T., Atoyan, R., Weiner, L., Yang, S., Brissette, J. L., Dotto, G. P., Botchkarev, V. A. <strong>Bone morphogenetic protein signaling regulates the size of hair follicles and modulates the expression of cell cycle-associated genes.</strong> Proc. Nat. Acad. Sci. 103: 18166-18171, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17114283[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.0608899103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17114283">Sharov et al. (2006)</a> showed that inhibition of BMP (see BMP1, <a href="/entry/112264">112264</a>) signaling in mouse keratinocytes altered the development of hair follicles. Microarray and real-time PCR analysis of laser-captured hair matrix cells showed a strong decrease in the expression of p27(Kip1) and increased expression of selected cyclins in the transgenic mice. p27(Kip1) knockout mice showed a similar increase in anagen hair follicles associated with increased cell proliferation in hair bulbs. Alternatively, activation of BMP signaling in human keratinocytes induced growth arrest and stimulated p27(Kip1) expression. <a href="#37" class="mim-tip-reference" title="Sharov, A. A., Sharova, T. Y., Mardaryev, A. N., di Vignano, A. T., Atoyan, R., Weiner, L., Yang, S., Brissette, J. L., Dotto, G. P., Botchkarev, V. A. <strong>Bone morphogenetic protein signaling regulates the size of hair follicles and modulates the expression of cell cycle-associated genes.</strong> Proc. Nat. Acad. Sci. 103: 18166-18171, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17114283[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.0608899103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17114283">Sharov et al. (2006)</a> concluded that p27(Kip1) mediates the effects of BMP signaling on hair follicle size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17114283" 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="#13" class="mim-tip-reference" title="Fritz, A., Walch, A., Piotrowska, K., Rosemann, M., Schaffer, E., Weber, K., Timper, A., Wildner, G., Graw, J., Hofler, H., Atkinson, M. J. <strong>Recessive transmission of a multiple endocrine neoplasia syndrome in the rat.</strong> Cancer Res. 62: 3048-3051, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12036912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12036912</a>]" pmid="12036912">Fritz et al. (2002)</a> described a multiple endocrine neoplasia-like autosomal recessive disorder in the rat. Animals exhibiting the mutant phenotype developed multiple neuroendocrine malignancies within the first year of life, including bilateral adrenal pheochromocytoma, multiple extraadrenal pheochromocytoma, bilateral medullary thyroid cell neoplasia, bilateral parathyroid hyperplasia, and pituitary adenoma. The appearance of neoplastic disease was preceded by the development of bilateral juvenile cataracts. Although the spectrum of affected tissues was reminiscent of human forms of MEN, no germline mutations were detected in the RET (<a href="/entry/164761">164761</a>) or MEN1 (<a href="/entry/613733">613733</a>) genes. Segregation studies in F1 and F2 crosses yielded frequencies of affected animals consistent with an autosomal recessive mode of inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12036912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In rats with an MEN-like syndrome (Menx), with phenotypic overlap of MEN1 (<a href="/entry/131100">131100</a>) and MEN2A (<a href="/entry/171400">171400</a>), <a href="#33" class="mim-tip-reference" title="Pellegata, N. S., Quintanilla-Martinez, L., Siggelkow, H., Samson, E., Bink, K., Hofler, H., Fend, F., Graw, J., Atkinson, M. J. <strong>Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia syndrome in rats and humans.</strong> Proc. Nat. Acad. Sci. 103: 15558-15563, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 19213 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17030811[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.0603877103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030811">Pellegata et al. (2006)</a> performed linkage analysis and identified a locus in a 4-Mb segment on rat chromosome 4, which includes the Cdkn1b gene. Sequencing revealed a homozygous frameshift mutation in the Cdkn1b gene resulting in a dramatic reduction of p27(Kip1) protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Besson, A., Hwang, H. C., Cicero, S., Donovan, S. L., Gurian-West, M., Johnson, D., Clurman, B. E., Dyer, M. A., Roberts, J. M. <strong>Discovery of an oncogenic activity in p27(Kip1) that causes stem cell expansion and a multiple tumor phenotype.</strong> Genes Dev. 21: 1731-1746, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17626791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17626791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17626791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1556607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17626791">Besson et al. (2007)</a> generated knockin mice expressing a mutant p27 protein, called p27(CK-), that was unable to interact with cyclins and cyclin-dependent kinases. In contrast to complete deletion of the Cdkn1b gene, which causes spontaneous tumors only in pituitary, p27(CK-) dominantly caused hyperplastic lesions and tumors in multiple organs. The high incidence of spontaneous tumors in lung and retina was associated with amplification of stem/progenitor cell populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17626791" 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="#20" class="mim-tip-reference" title="Karlas, A., Machuy, N., Shin, Y., Pleissner, K.-P., Artarini, A., Heuer, D., Becker, D., Khalil, H., Ogilvie, L. A., Hess, S., Maurer, A. P., Muller, E., Wolff, T., Rudel, T., Meyer, T. F. <strong>Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication.</strong> Nature 463: 818-822, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081832</a>] [<a href="https://doi.org/10.1038/nature08760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20081832">Karlas et al. (2010)</a> reported the discovery of 287 human host cell genes, including CDKN1B, influencing influenza A virus replication in a genomewide RNA interference screen. Using an independent assay, <a href="#20" class="mim-tip-reference" title="Karlas, A., Machuy, N., Shin, Y., Pleissner, K.-P., Artarini, A., Heuer, D., Becker, D., Khalil, H., Ogilvie, L. A., Hess, S., Maurer, A. P., Muller, E., Wolff, T., Rudel, T., Meyer, T. F. <strong>Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication.</strong> Nature 463: 818-822, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081832</a>] [<a href="https://doi.org/10.1038/nature08760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20081832">Karlas et al. (2010)</a> confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. CDKN1B inhibited both viral strains. Furthermore, H1N1 virus-infected p27-null mice accumulated significantly lower viral titers in the lung, providing in vivo evidence for the importance of this gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20081832" 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>In a 48-year-old Caucasian female with primary hyperparathyroidism and a history of pituitary adenoma (MEN4; <a href="/entry/610755">610755</a>), <a href="#33" class="mim-tip-reference" title="Pellegata, N. S., Quintanilla-Martinez, L., Siggelkow, H., Samson, E., Bink, K., Hofler, H., Fend, F., Graw, J., Atkinson, M. J. <strong>Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia syndrome in rats and humans.</strong> Proc. Nat. Acad. Sci. 103: 15558-15563, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 19213 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17030811[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.0603877103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030811">Pellegata et al. (2006)</a> identified a heterozygous 692G-A transition in the CDKN1B gene, resulting in a trp76-to-ter (W76X) substitution. The mutation was also identified in her older sister who had renal angiomyolipoma, her youngest sister, and that sister's teenaged daughter, who reported no symptoms but did not undergo thorough examination. The mutation was not found in 380 unrelated healthy controls. Molecular and immunohistochemical analysis of the renal angiomyolipoma showed that it retained the CDKN1B wildtype allele and demonstrated RNA expression but showed no p27 protein staining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030811" 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="#31" class="mim-tip-reference" title="Molatore, S., Marinoni, I., Lee, M., Pulz, E., Ambrosio, M. R., degli Uberti, E. C., Zatelli, M. C., Pellegata, N. S. <strong>A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization.</strong> Hum. Mutat. 31: E1825-E1835, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20824794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20824794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20824794[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/10.1002/humu.21354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20824794">Molatore et al. (2010)</a> demonstrated that the mutant W76X protein localized only to the cytoplasm and not to the nucleus. The mutant protein was unable to suppress the growth of neuroendocrine tumor cells in vitro, and lost its pro-apoptotic ability. The truncated protein was expressed in normal kidney tissue from the patient reported by <a href="#33" class="mim-tip-reference" title="Pellegata, N. S., Quintanilla-Martinez, L., Siggelkow, H., Samson, E., Bink, K., Hofler, H., Fend, F., Graw, J., Atkinson, M. J. <strong>Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia syndrome in rats and humans.</strong> Proc. Nat. Acad. Sci. 103: 15558-15563, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 19213 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17030811[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.0603877103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030811">Pellegata et al. (2006)</a>, suggesting that it is stable. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17030811+20824794" 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786201007 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786201007;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=rs786201007" 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=rs786201007" 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=RCV000162205" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162205" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162205</a>
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<p>In a Dutch woman with multiple endocrine neoplasia type IV (MEN4; <a href="/entry/610755">610755</a>), <a href="#14" class="mim-tip-reference" title="Georgitsi, M., Raitila, A., Karhu, A., van der Luijt, R. B., Aalfs, C. M., Sane, T., Vierimaa, O., Makinen, M. J., Tuppurainen, K., Paschke, R., Gimm, O., Koch, C. A., and 11 others. <strong>Germline CDKN1B/p27(Kip1) mutation in multiple endocrine neoplasia.</strong> J. Clin. Endocr. Metab. 92: 3321-3325, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17519308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17519308</a>] [<a href="https://doi.org/10.1210/jc.2006-2843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17519308">Georgitsi et al. (2007)</a> identified a heterozygous 19-bp duplication in exon 1 of the CDKN1B gene (c.59_77dup19), resulting in a frameshift and premature termination. The patient developed small-cell neuroendocrine cervical carcinoma, an ACTH-secreting pituitary adenoma, and hyperparathyroidism in her forties. She was also diagnosed with multiple sclerosis. Tumor tissue from the cervical carcinoma showed loss of heterozygosity for the wildtype allele and negative immunostaining for the p27 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17519308" 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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<strong>.0003 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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"><span class="text-primary">●</span> rs777354267 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777354267;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs777354267?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs777354267" 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=rs777354267" 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=RCV000162207 OR RCV002415708" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162207, RCV002415708" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162207...</a>
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<p>In a 79-year-old Caucasian woman with multiple endocrine neoplasia type IV (MEN4; <a href="/entry/610755">610755</a>), <a href="#31" class="mim-tip-reference" title="Molatore, S., Marinoni, I., Lee, M., Pulz, E., Ambrosio, M. R., degli Uberti, E. C., Zatelli, M. C., Pellegata, N. S. <strong>A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization.</strong> Hum. Mutat. 31: E1825-E1835, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20824794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20824794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20824794[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/10.1002/humu.21354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20824794">Molatore et al. (2010)</a> identified a heterozygous c.678C-T transition in the CDKN1B gene, resulting in a pro69-to-leu (P69L) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP database or in 370 control individuals. In vitro cellular expression studies showed that the mutation caused reduced mutant protein levels due to more rapid degradation, as well as slightly higher cytoplasmic localization compared to wildtype. Molecular modeling indicated that the mutation affected a CDK2 (<a href="/entry/116953">116953</a>)-binding site, and immunoblot analysis confirmed that the mutant protein could not bind CDK2. The P69L mutant protein was less effective at suppressing growth of neuroendocrine tumor cells in vitro compared to wildtype. The patient had bronchial carcinoid, a nonfunctioning pituitary microadenoma, parathyroid adenoma, and papillary thyroid carcinoma. Both bronchial carcinoid and parathyroid adenoma tissue showed decreased or even absent p27 protein expression, but loss of heterozygosity for the wildtype CDKN1B allele was observed only in the carcinoid sample. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20824794" 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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<strong>.0004 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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"><span class="text-primary">●</span> rs774454456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs774454456;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs774454456?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs774454456" 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=rs774454456" 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=RCV000162206 OR RCV000210358 OR RCV000354456 OR RCV000994850 OR RCV002247626 OR RCV003947663" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162206, RCV000210358, RCV000354456, RCV000994850, RCV002247626, RCV003947663" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162206...</a>
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<p>In a 69-year-old Spanish woman with multiple endocrine neoplasia type IV (MEN4; <a href="/entry/610755">610755</a>), <a href="#26" class="mim-tip-reference" title="Malanga, D., De Gisi, S., Riccardi, M., Scrima, M., De Marco, C., Robledo, M., Viglietto, G. <strong>Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype.</strong> Europ. J. Endocr. 166: 551-560, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22129891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22129891</a>] [<a href="https://doi.org/10.1530/EJE-11-0929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22129891">Malanga et al. (2012)</a> identified a heterozygous 4-bp deletion in the 5-prime untranslated region of the CDKN1B gene (c.-32_-29delGAGA). In vitro functional expression studies using a luciferase reporter in HeLa cells showed that the mutation resulted in a significant reduction (30-60%) in transcription and possibly translation. Patient peripheral blood cells showed a significant 3-fold decrease in CDKN1B mRNA levels compared to controls, consistent with haploinsufficiency. The patient had gastric carcinoid tumor and hyperparathyroidism; there was no family history of endocrine neoplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22129891" 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786201010 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786201010;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=rs786201010" 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=rs786201010" 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=RCV000162208" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162208" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162208</a>
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<p>In a 62-year-old woman with multiple endocrine neoplasia type IV (MEN4; <a href="/entry/610755">610755</a>), <a href="#32" class="mim-tip-reference" title="Occhi, G., Regazzo, D., Trivellin, G., Boaretto, F., Ciato, D., Bobisse, S., Ferasin, S., Cetani, F., Pardi, E., Korbonits, M., Pellegata, N. S., Sidarovich, V., Quattrone, A., Opocher, G., Mantero, F., Scaroni, C. <strong>A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype.</strong> PLoS Genet. 9: e1003350, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23555276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23555276</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23555276[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/10.1371/journal.pgen.1003350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23555276">Occhi et al. (2013)</a> identified a heterozygous 4-bp deletion (c.-456_-453delCCTT) in a highly conserved region in the 5-prime untranslated region of the CDKN1B gene. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 600 control chromosomes. The deletion shifted the upstream open reading frame (ORF) termination codon, thus lengthening the upstream ORF-encoded peptide from 29 to 158 amino acids and shortening the intracistronic space from 429 to 38 bp, with a possible negative influence on translation reinitiation from the main ATG. This change was predicted to prevent proper functioning of the 40S ribosomal subunit during translation. Patient cells showed normal levels of mutant mRNA, but decreased expression of the p27 protein, with weak cytoplasmic staining. Pancreatic tumor cells from the patient showed weak cytoplasmic p27 staining; there was no loss of heterozygosity for the wildtype allele. In vitro functional cellular expression assays showed that the 4-bp deletion impaired translation of a reporter gene by affecting translation reinitiation. The findings elucidated a novel mechanism by which p27 levels can be modulated by changes in the upstream ORF. The patient had acromegaly and a well-differentiated nonfunctioning pancreatic endocrine neoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23555276" 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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<strong>.0006 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</strong>
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CDKN1B, 2-BP DEL, 371CT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786201011 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786201011;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=rs786201011" 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=rs786201011" 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=RCV000162209 OR RCV003298195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162209, RCV003298195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162209...</a>
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<p>In a 53-year-old Italian woman with multiple endocrine neoplasia type IV (MEN4; <a href="/entry/610755">610755</a>), <a href="#43" class="mim-tip-reference" title="Tonelli, F., Giudici, F., Giusti, F., Marini, F., Cianferotti, L., Nesi, G., Brandi, M. L. <strong>A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome.</strong> Europ. J. Endocr. 171: K7-K17, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24819502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24819502</a>] [<a href="https://doi.org/10.1530/EJE-14-0080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24819502">Tonelli et al. (2014)</a> identified a heterozygous 2-bp deletion (c.371_372delCT) in exon 1 of the CDKN1B gene, resulting in a frameshift and premature termination at codon 145. The patient had hyperparathyroidism due to parathyroid adenomas and gastrointestinal neuroendocrine tumors; she also had a history of hypothyroidism due to Hashimoto thyroiditis. Analysis of the patient's hyperplastic parathyroid tissue showed reduced nuclear p27 staining, but there was no loss of heterozygosity of the wildtype CDKN1B allele. The patient's asymptomatic 35-year-old son also carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24819502" 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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<strong>REFERENCES</strong>
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Baens, M., Aerssens, J., Van Zand, K., Van den Berghe, H., Marynen, P.
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Genomics 29: 44-52, 1995.
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[<a href="https://doi.org/10.1006/geno.1995.1213" target="_blank">Full Text</a>]
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Besson, A., Hwang, H. C., Cicero, S., Donovan, S. L., Gurian-West, M., Johnson, D., Clurman, B. E., Dyer, M. A., Roberts, J. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17626791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17626791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17626791[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=17626791" 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.1556607" target="_blank">Full Text</a>]
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Braun-Dullaeus, R. C., Mann, M. J., Ziegler, A., von der Leyen, H. E., Dzau, V. J.
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<strong>A novel role for the cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10491417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10491417</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10491417[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=10491417" 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/10.1172/JCI5339" target="_blank">Full Text</a>]
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Carrano, A. C., Eytan, E., Hershko, A., Pagano, M.
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<strong>SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.</strong>
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Nature Cell Biol. 1: 193-199, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10559916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10559916</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10559916" 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/10.1038/12013" target="_blank">Full Text</a>]
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Chang, B., Zheng, S. L., Isaacs, S. D., Wiley, K. E., Turner, A., Li, G., Walsh, P. C., Meyers, D. A., Isaacs, W. B., Xu, J.
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<strong>A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer.</strong>
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Cancer Res. 64: 1997-1999, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15026335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15026335</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15026335" 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/10.1158/0008-5472.can-03-2340" target="_blank">Full Text</a>]
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Chu, I., Sun, J., Arnaout, A., Kahn, H., Hanna, W., Narod, S., Sun, P., Tan, C.-K., Hengst, L., Slingerland, J.
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<strong>p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.</strong>
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Cell 128: 281-294, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17254967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17254967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17254967[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=17254967" 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.2006.11.049" target="_blank">Full Text</a>]
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<a id="Cuesta2009" class="mim-anchor"></a>
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Cuesta, R., Martinez-Sanchez, A., Gebauer, F.
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<strong>miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19273599[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=19273599" 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.01971-08" target="_blank">Full Text</a>]
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Das, C. M., Taylor, P., Gireud, M., Singh, A., Lee, D., Fuller, G., Ji, L., Fangusaro, J., Rajaram, V., Goldman, S., Eberhart, C., Gopalakrishnan, V.
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<strong>The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.</strong>
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Oncogene 32: 1691-1701, 2013. Note: Erratum: Oncogene 35: 6153-6154, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22665064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22665064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22665064[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=22665064" 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/onc.2012.182" target="_blank">Full Text</a>]
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Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C., Pandolfi, P. P.
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<strong>Pten and p27(KIP1) cooperate in prostate cancer tumor suppression in the mouse.</strong>
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Nature Genet. 27: 222-224, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175795" 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/10.1038/84879" target="_blank">Full Text</a>]
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Dijkers, P. F., Birkenkamp, K. U., Lam, E. W.-F., Thomas, N. S. B., Lammers, J.-W. J., Koenderman, L., Coffer, P. J.
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<strong>FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity.</strong>
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J. Cell Biol. 156: 531-542, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11815629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11815629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11815629[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=11815629" 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/10.1083/jcb.200108084" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg177" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2006.11.047" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583032[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=15583032" 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/10.1083/jcb.200409187" target="_blank">Full Text</a>]
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<a id="43" class="mim-anchor"></a>
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<a id="Tonelli2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tonelli, F., Giudici, F., Giusti, F., Marini, F., Cianferotti, L., Nesi, G., Brandi, M. L.
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<strong>A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome.</strong>
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Europ. J. Endocr. 171: K7-K17, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24819502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24819502</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24819502" 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/10.1530/EJE-14-0080" target="_blank">Full Text</a>]
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</p>
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<a id="44" class="mim-anchor"></a>
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<a id="Toyoshima1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Toyoshima, H., Hunter, T.
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<strong>p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21.</strong>
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Cell 78: 67-74, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8033213" 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/10.1016/0092-8674(94)90573-8" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="45" class="mim-anchor"></a>
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<a id="Uchida2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Uchida, T., Nakamura, T., Hashimoto, N., Matsuda, T., Kotani, K., Sakaue, H., Kido, Y., Hayashi, Y., Nakayama, K. I., White, M. F., Kasuga, M.
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<strong>Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice.</strong>
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Nature Med. 11: 175-182, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15685168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15685168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15685168" 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/nm1187" target="_blank">Full Text</a>]
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<a id="46" class="mim-anchor"></a>
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<a id="Viglietto2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Viglietto, G., Motti, M. L., Bruni, P., Melillo, R. M., D'Alessio, A., Califano, D., Vinci, F., Chiappetta, G., Tsichlis, P., Bellacosa, A., Fusco, A., Santoro, M.
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<strong>Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.</strong>
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Nature Med. 8: 1136-1144, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244303</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244303" 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/nm762" target="_blank">Full Text</a>]
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<a id="47" class="mim-anchor"></a>
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<a id="White2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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White, P. M., Doetzlhofer, A., Lee, Y. S., Groves, A. K., Segil, N.
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<strong>Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells.</strong>
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Nature 441: 984-987, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791196" 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/nature04849" target="_blank">Full Text</a>]
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<a id="Wolfraim2005" class="mim-anchor"></a>
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Wolfraim, L. A., Letterio, J. J.
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<strong>Cutting edge: p27(Kip1) deficiency reduces the requirement for CD28-mediated costimulation in naive CD8+ but not CD4+ T lymphocytes.</strong>
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J. Immun. 174: 2481-2484, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728451" 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/10.4049/jimmunol.174.5.2481" target="_blank">Full Text</a>]
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<a id="Zindy1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zindy, F., Cunningham, J. J., Sherr, C. J., Jogal, S., Smeyne, R. J., Roussel, M. F.
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<strong>Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases.</strong>
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Proc. Nat. Acad. Sci. 96: 13462-13467, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10557343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10557343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10557343[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=10557343" 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.96.23.13462" target="_blank">Full Text</a>]
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<a id="50" class="mim-anchor"></a>
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<a id="Zindy2006" class="mim-anchor"></a>
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<p class="mim-text-font">
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Zindy, F., Knoepfler, P. S., Xie, S., Sherr, C. J., Eisenman, R. N., Roussel, M. F.
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<strong>N-Myc and the cyclin-dependent kinase inhibitors p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development.</strong>
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Proc. Nat. Acad. Sci. 103: 11579-11583, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864777[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=16864777" 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.0604727103" target="_blank">Full Text</a>]
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</ol>
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<br />
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<span class="mim-text-font">
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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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Bao Lige - updated : 01/31/2023
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</span>
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</div>
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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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Cassandra L. Kniffin - updated : 3/10/2015<br>Patricia A. Hartz - updated : 9/22/2014<br>Ada Hamosh - updated : 1/14/2014<br>Cassandra L. Kniffin - updated : 7/24/2013<br>Patricia A. Hartz - updated : 12/9/2011<br>Patricia A. Hartz - updated : 10/24/2011<br>Matthew B. Gross - updated : 5/5/2010<br>Ada Hamosh - updated : 4/15/2010<br>Ada Hamosh - updated : 3/5/2010<br>Patricia A. Hartz - updated : 6/6/2008<br>Patricia A. Hartz - updated : 5/28/2008<br>Patricia A. Hartz - updated : 8/23/2007<br>Marla J. F. O'Neill - updated : 2/12/2007<br>Patricia A. Hartz - updated : 2/2/2007<br>Paul J. Converse - updated : 10/19/2006<br>Patricia A. Hartz - updated : 10/3/2006<br>Ada Hamosh - updated : 8/1/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Patricia A. Hartz - updated : 7/25/2005<br>Marla J. F. O'Neill - updated : 7/8/2005<br>Marla J. F. O'Neill - updated : 6/21/2005<br>George E. Tiller - updated : 5/4/2005<br>Ada Hamosh - updated : 5/29/2003<br>Ada Hamosh - updated : 11/19/2002<br>Ada Hamosh - updated : 9/21/2001<br>Victor A. McKusick - updated : 6/27/2001<br>Paul J. Converse - updated : 4/18/2001<br>Paul J. Converse - updated : 2/8/2001<br>Victor A. McKusick - updated : 1/26/2001<br>Ada Hamosh - updated : 4/12/2000<br>Carol A. Bocchini - updated : 6/15/1999<br>Stylianos E. Antonarakis - updated : 1/21/1999
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<a id="creationDate" class="mim-anchor"></a>
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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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Victor A. McKusick : 10/4/1995
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alopez : 01/12/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 09/11/2023<br>carol : 06/08/2023<br>mgross : 01/31/2023<br>carol : 05/09/2017<br>carol : 03/10/2015<br>mcolton : 3/10/2015<br>ckniffin : 3/10/2015<br>mgross : 9/22/2014<br>alopez : 1/14/2014<br>alopez : 1/14/2014<br>alopez : 1/6/2014<br>mgross : 9/24/2013<br>carol : 7/26/2013<br>ckniffin : 7/24/2013<br>terry : 3/28/2013<br>alopez : 3/21/2013<br>mgross : 2/6/2012<br>mgross : 2/6/2012<br>terry : 12/9/2011<br>terry : 10/24/2011<br>carol : 6/17/2011<br>carol : 2/9/2011<br>carol : 7/23/2010<br>wwang : 5/14/2010<br>mgross : 5/5/2010<br>alopez : 4/19/2010<br>alopez : 4/19/2010<br>terry : 4/15/2010<br>alopez : 3/8/2010<br>alopez : 3/8/2010<br>terry : 3/5/2010<br>wwang : 10/14/2008<br>wwang : 6/12/2008<br>terry : 6/6/2008<br>mgross : 6/3/2008<br>mgross : 6/3/2008<br>terry : 5/28/2008<br>mgross : 8/31/2007<br>terry : 8/23/2007<br>carol : 5/3/2007<br>wwang : 2/12/2007<br>alopez : 2/2/2007<br>mgross : 10/23/2006<br>terry : 10/19/2006<br>mgross : 10/10/2006<br>terry : 10/3/2006<br>alopez : 8/3/2006<br>terry : 8/1/2006<br>wwang : 12/7/2005<br>mgross : 7/25/2005<br>mgross : 7/25/2005<br>wwang : 7/20/2005<br>wwang : 7/15/2005<br>terry : 7/8/2005<br>wwang : 6/24/2005<br>terry : 6/21/2005<br>tkritzer : 5/4/2005<br>terry : 7/30/2003<br>mgross : 5/30/2003<br>terry : 5/29/2003<br>cwells : 11/19/2002<br>terry : 11/18/2002<br>alopez : 9/24/2001<br>terry : 9/21/2001<br>cwells : 7/12/2001<br>cwells : 7/6/2001<br>terry : 6/27/2001<br>mgross : 4/18/2001<br>cwells : 2/13/2001<br>cwells : 2/8/2001<br>alopez : 1/29/2001<br>terry : 1/26/2001<br>alopez : 4/12/2000<br>terry : 4/12/2000<br>carol : 11/23/1999<br>carol : 6/15/1999<br>carol : 1/21/1999<br>mark : 5/7/1997<br>mark : 5/7/1997<br>mark : 3/28/1997<br>mark : 10/3/1996<br>terry : 9/17/1996<br>mark : 1/10/1996<br>mark : 1/4/1996<br>mark : 12/5/1995<br>terry : 10/30/1995<br>mark : 10/4/1995
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<strong>*</strong> 600778
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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 INHIBITOR 1B; CDKN1B
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<em>Alternative titles; symbols</em>
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<h4>
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p27(KIP1)<br />
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KIP1
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<strong><em>HGNC Approved Gene Symbol: CDKN1B</em></strong>
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<strong>SNOMEDCT:</strong> 715907003;
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Cytogenetic location: 12p13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:12,717,368-12,722,369 </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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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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12p13.1
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</td>
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<td>
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<span class="mim-font">
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Multiple endocrine neoplasia, type IV
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</td>
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<span class="mim-font">
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610755
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<p>CDKN1B, or p27(KIP1), is a cyclin-dependent kinase inhibitor that blocks the cell cycle in the G0/G1 phase upon differentiation signals or cellular insult. CDKN1B also regulates cell motility and apoptosis (summary by Cuesta et al., 2009). </p>
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<h4>
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<strong>Cloning and Expression</strong>
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</h4>
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<p>Using a cDNA probe amplified from the MV1Lu mink cell line to screen a kidney cDNA library, Polyak et al. (1994) cloned human CDKN1B, which they called KIP1. The deduced 198-amino acid protein has a calculated molecular mass of 22.3 kD. It has a 60-amino acid N-terminal domain that shares 44% identity with the corresponding region of CIP1/WAF1 (CDKN1A; 116899). It also has a C-terminal bipartite nuclear localization signal and a consensus CDC2 (CDK1; 116940) phosphorylation site. KIP1 shares about 90% amino acid identity with mink and mouse Kip1, with highest identity in the N-terminal domain. Northern blot analysis detected variable expression of a 2.5-kb transcript in all human tissues examined. </p><p>Stegmaier et al. (1995) studied loss of heterozygosity (LOH) in the region 12p13-p12 in acute lymphoblastic leukemia; this chromosomal region often shows deletion in such patients. In 15% of informative patients, there was evidence of LOH of the TEL locus (600618) which was not evident on cytogenetic analysis. Detailed examination of patients with LOH showed that the critically deleted region included a second candidate tumor suppressor gene, referred to by them as KIP1, which encodes the cyclin-dependent kinase inhibitor previously called p27 (Toyoshima and Hunter, 1994 and Polyak et al., 1994). Based on the STS content of TEL-positive YACs, Stegmaier et al. (1995) reported that KIP1 and TEL were in close proximity. </p>
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<strong>Gene Function</strong>
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<p>Polyak et al. (1994) showed that recombinant mouse Kip1 inhibited phosphorylation of histone H1 (see 142709) by human cyclin A (see CCNA1; 604036)-CDK2 (116953), cyclin E (CCNE1; 123837)-CDK2, and cyclin B1 (CCNB1; 123836)-CDK2 complexes. Addition of Kip1 also inhibited phosphorylation of RB (614041) by cyclin E-CDK2, cyclin A-CDK2, and cyclin D2 (CCND2; 123833)-CDK4 (123829). The isolated N-terminal domain of Kip1 had similar inhibitory activity in these assays. Kip1 bound to preactivated cyclin E-CDK2 complexes and prevented phosphorylation and activation of CDK2 in A549 human lung carcinoma cells. Kip1 activity was lowest in S phase in MV1Lu cells, and Kip1 overexpression inhibited S phase entry. Kip1 mRNA content remained unchanged during the cell cycle, suggesting that Kip1 activity was controlled at a posttranscriptional level. Polyak et al. (1994) concluded that KIP1 can inhibit both CDK activation and the kinase activity of assembled and activated cyclin-CDK. </p><p>CDK activation requires association with cyclins and phosphorylation by CAK (CCNH; 601953) and leads to cell proliferation. Inhibition of cellular proliferation occurs upon association of CDK inhibitor (e.g., CDKN1B) with a cyclin-CDK complex. Sheaff et al. (1997) showed that expression of CCNE1-CDK2 at physiologic levels of ATP resulted in phosphorylation of CDKN1B at thr187, leading to elimination of CDKN1B from the cell and progression of the cell cycle from G1 to S phase. At low ATP levels, the inhibitory functions of CDKN1B were enhanced, thereby arresting cell proliferation. </p><p>Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A (see 604036)-associated CDK2 activity. Levkau et al. (1998) showed that in apoptotic cells the carboxyl-termini of the CDK inhibitors CDKN1A and CDKN1B are truncated by specific cleavage. The enzyme involved in this cleavage is CASP3 (600636) and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. These data suggested that CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation. </p><p>High levels of p27(KIP1), present in quiescent (G0) cells, have been shown to decline upon mitogen induction (Sherr and Roberts, 1995). Braun-Dullaeus et al. (1999) explored the role of p27(KIP1) and other cell cycle proteins in mediating angiotensin II (see 106150)-induced vascular smooth muscle cell hypertrophy or hyperplasia. Angiotensin II treatment (100 nM) of quiescent vascular smooth muscle cells led to upregulation of the cell cycle regulatory proteins cyclin D1 (168461), CDK2, proliferating cell nuclear antigen (176740), and CDK1. Levels of p27(KIP1), however, remained high, and the activation of the G1-phase CDK2 was inhibited as the cells underwent hypertrophy. Angiotensin II stimulated an increase in [(3)H]thymidine incorporation and the percentage of S-phase cells in p27(KIP1) antisense oligodeoxynucleotide (ODN)-transfected cells but not in control ODN transfected cells. The authors concluded that angiotensin II stimulation of quiescent cells in which p27(KIP1) levels are high results in hypertrophy but promotes hyperplasia when levels of p27(KIP1) are low, as in the presence of other growth factors. </p><p>Medema et al. (2000) demonstrated that p27(KIP1) is a major target of AFX-like forkhead proteins. They demonstrated that AFX integrates signals from PI3K/PKB (see AKT1; 164730) signaling and RAS (see 190020)/RAL (see 179551) signaling to regulate transcription of p27(KIP1). They demonstrated that p27 -/- cells are significantly less inhibited by AFX activity than their p27 +/+ counterparts. </p><p>Dijkers et al. (2002) showed that both cytokine withdrawal and Fkhrl1 (FOXO3A; 602681) activation induced apoptosis in mammalian cell lines through a death receptor-independent pathway. This involved transcriptional upregulation of p27(KIP1) and proapoptotic Bim (BCL2L11; 603827), loss of mitochondrial integrity, cytochrome c release, and caspase activation. PKB protected cells from cytokine withdrawal-induced apoptosis by inhibiting Fkhrl1, resulting in the maintenance of mitochondrial integrity. </p><p>Peters and Ostrander (2001) commented on the work of Di Cristofano et al. (2001), demonstrating how cooperation between Cdkn1b and Pten (601728) contribute to suppression of prostate tumors. They gave a useful tabulation of the cytogenetic location of 16 mapped prostate cancer susceptibility loci and candidate genes. </p><p>Phosphorylation leads to the ubiquitination and degradation of CDKN1B. Carrano et al. (1999) determined that SKP2 (601436) specifically recognizes phosphorylated CDKN1B predominantly in S phase rather than in G1 phase, and is the ubiquitin-protein ligase necessary for CDKN1B ubiquitination. </p><p>Shin et al. (2002) demonstrated a novel mechanism of AKT-mediated regulation of p27(KIP1). Blockade of HER2/NEU (164870) in tumor cells inhibited AKT kinase activity and upregulated nuclear levels of p27(KIP1). Recombinant AKT and AKT precipitated from tumor cells phosphorylated wildtype p27 in vitro. P27 contains an AKT consensus RXRXXT(157)D within its nuclear localization motif. Active (myristoylated) AKT phosphorylated wildtype p27 in vivo but was unable to phosphorylate a T157A-p27 mutant. Wildtype p27 localized in the cytosol and nucleus, whereas the mutant p27 localized exclusively in the nucleus and was resistant to nuclear exclusion by AKT. Expression of phosphorylated AKT in primary human breast cancers statistically correlated with the expression of p27 in tumor cytosol. Shin et al. (2002) concluded that AKT may contribute to tumor cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 from p27-induced inhibition. </p><p>Liang et al. (2002) demonstrated that AKT phosphorylates p27, impairs the nuclear import of p27, and opposes cytokine-mediated G1 arrest. In cells transfected with constitutively active AKT, wildtype p27 mislocalized to the cytoplasm, but mutant p27 was nuclear. In cells with activated AKT, wildtype p27 failed to cause G1 arrest, while the antiproliferative effect of the mutant p27 was not impaired. Cytoplasm p27 was seen in 41% (52 of 128) primary human breast cancers in conjunction with AKT activation and was correlated with a poor patient prognosis. Liang et al. (2002) concluded that their data showed a novel mechanism whereby AKT impairs p27 function that is associated with an aggressive phenotype in human breast cancer. </p><p>Viglietto et al. (2002) independently demonstrated that AKT regulates cell proliferation in breast cancer cells by preventing p27(KIP1)-mediated growth arrest. They also showed that threonine at position 157 is an AKT phosphorylation site and causes retention of p27(KIP1) in the cytoplasm, precluding p27(KIP1)-induced G1 arrest. </p><p>Gopfert et al. (2003) analyzed fragments of the p27 transcript for their contribution to cell cycle-regulated translation. An element in the p27 5-prime UTR rendered reporter translation cell cycle-sensitive with maximal translation in G1-arrested cells. The 114-bp element contained a G/C-rich hairpin domain that was predicted to form multiple stable stemloops and also overlapped with a small upstream open reading frame (ORF). Both structures contributed to cell cycle-regulated translation. The upstream ORF could be translated in vitro, and its sequence and position were evolutionarily conserved in mouse and chicken. The precise sequence or length of the upstream ORF-encoded peptide were not important for p27 translation, suggesting that ribosomal recruitment to its initiation codon, rather than the translation product itself, contributes to the regulation. </p><p>Using NIH-3T3 mouse fibroblasts and mouse embryonic fibroblasts, Kamura et al. (2004) found that Skp2 was the major ubiquitin ligase involved in ubiquitination of nuclear p27(KIP1) at the S and G2 phases, and that a complex made up of Kpc1 (RNF123; 614472) and Kpc2 (UBAC1; 608129) ubiquitinated cytoplasmic p27(KIP1) at G1 phase. Cytoplasmic degradation of p27(KIP1) required p27(KIP1) nuclear export by Crm1 (XPO1; 602559). </p><p>The inverse relationship between proliferation and differentiation in osteoblasts has been well documented. Thomas et al. (2004) found that Runx2 (600211), a master regulator of osteoblast differentiation in mammalian cells, was disrupted in 6 of 7 mammalian osteosarcoma cell lines. Immunohistochemical analysis of human osteosarcomas indicated that expression of p27(KIP1) was also lost as tumors lost osteogenic differentiation. Thomas et al. (2004) found that ectopic expression of Runx2 induced growth arrest through p27(KIP1)-induced inhibition of S-phase cyclin complexes, followed by dephosphorylation of RB1 (614041) and G1 cell cycle arrest. They concluded that RUNX2 establishes a terminally differentiated state in osteoblasts through RB1- and p27(KIP1)-dependent mechanisms that are disrupted in osteosarcomas. </p><p>White et al. (2006) showed that postmitotic supporting cells purified from the postnatal mouse cochlea retain the ability to divide and trans-differentiate into new hair cells in culture. Furthermore, they demonstrated that age-dependent changes in supporting cell proliferative capacity are due in part to changes in the ability to downregulate p27(Kip1). White et al. (2006) concluded that postnatal mammalian supporting cells are potential targets for therapeutic manipulation. </p><p>Grimmler et al. (2007) found that a conserved tyrosine (Y88) in the CDK-inhibitory domain of human p27 could be phosphorylated by the Src family kinase LYN (165120) and the oncogene product BCR-ABL (see 189980). Phosphorylation of Y88 did not prevent binding of p27 to cyclin A/CDK2, but it caused phosphorylated Y88 and the inhibitory domain of p27 to be ejected from the CDK2 active site, restoring partial CDK activity. This allowed Y88-phosphorylated p27 to be efficiently phosphorylated on thr187 by CDK2, which in turn promoted its SCF-SKP2-dependent degradation. </p><p>Chu et al. (2007) showed that the oncogenic kinase SRC (190090) phosphorylated human p27 at Y74 and Y88. SRC inhibitors increased cellular p27 stability, whereas SRC overexpression accelerated p27 proteolysis. SRC-phosphorylated p27 inhibited cyclin E/CDK2 poorly in vitro, and SRC transfection reduced p27/cyclin E/CDK2 complexes. SRC-activated human breast cancer cell lines exhibited reduced p27, and there was a correlation between SRC activation and reduced nuclear p27 in 482 primary human breast cancers. In tamoxifen-resistant breast cancer cell lines, SRC inhibition increased p27 levels and restored tamoxifen sensitivity. Chu et al. (2007) concluded that SRC-mediated phosphorylation of p27 reduces its inhibitory action on cyclin E/CDK2, facilitating subsequent p27 proteolysis. </p><p>By yeast 2-hybrid analysis of an adult human heart cDNA library, Hauck et al. (2008) showed that p27 interacted with the C-terminal region of casein kinase-2 (CK2)-alpha-prime (CSNK2A2; 115442). Immunocytochemical analysis of primary rat ventricular cardiomyocytes revealed colocalization of p27 with CK2-alpha-prime. Angiotensin II, a potent inducer of cardiomyocyte hypertrophy, induced proteasomal degradation of p27 in primary rat cardiomyocytes through CK2-alpha-prime-dependent phosphorylation of p27 on ser83 and thr187, which are conserved in humans and rodents. Conversely, unphosphorylated p27 potently inhibited CK2-alpha-prime. Hauck et al. (2008) concluded that downregulation of p27 by CK2-alpha-prime is necessary for development of agonist- and stress-induced cardiac hypertrophy. </p><p>MicroRNAs (miRNAs) are short noncoding RNAs that bind to complementary sequences in the 3-prime UTRs of target mRNAs and inhibit their expression. Kedde et al. (2007) showed that the expression of DND1 (609385), an evolutionarily conserved RNA-binding protein, counteracted the inhibitory effect of several miRNAs in human cells and in primordial germ cells of zebrafish by preventing the association of miRNAs with their target mRNAs. Kedde et al. (2007) detailed the effect of DND1 on the downregulation of p27 mRNA by miR221 (MIRN221; 300568) in human cells. Introduction of DND1 abolished the interaction between miR221 and the 3-prime UTR of p27 mRNA and countered the downregulation of p27 expression by miR221. DND1 bound a uridine-rich region in the 3-prime UTR of p27 mRNA that is near the miR221-binding site and prevented miR221 binding. At least 1 of the 2 uridine-rich regions in the p27 3-prime UTR and the RNA-binding domain of DND1 were required to rescue p27 expression. </p><p>Cuesta et al. (2009) found that translation of p27 in HeLa cells and HL60 human promyelocytic leukemia cells was cap dependent. Translation via a proposed internal ribosome entry site appeared to be artifactual, resulting from the presence of cryptic promoters in the 5-prime UTR. Cuesta et al. (2009) showed that the dramatic increase in p27 following phorbol ester treatment was not due to increased mRNA levels, but rather to downregulation of MIR181A (see 612742) and relief of MIR181A-dependent translational repression. The 3-prime UTR of p27 mRNA contains 2 possible MIR181A-binding sites, 1 of which overlaps the MIR221-binding site. Both MIR181A-binding sites could repress p27 translation either individually or synergistically. </p><p>Lin et al. (2010) showed that although Skp2 inactivation on its own does not induce cellular senescence, aberrant protooncogenic signals as well as inactivation of tumor suppressor genes do trigger a potent, tumor-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic stress-driven senescence neither elicit activation of the p19(Arf) (see 600160)-p53 (191170) pathway nor DNA damage, but instead depend on Atf4 (604064), p27, and p21 (116899). Lin et al. (2010) further demonstrated that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten (601728)-deficient cells and tumor regression in preclinical studies. Lin et al. (2010) concluded that their findings provided proof-of-principle evidence that pharmacologic inhibition of Skp2 may represent a general approach for cancer prevention and therapy. </p><p>The HER2-HER3 (ERBB3; 190151) dimer induces cell growth by activating a kinase cascade that includes phosphorylation of p27, resulting in p27 ubiquitination and proteasomal degradation. Trastuzumab blocks the HER2-HER3 interaction and is used to treat breast cancers with HER2 overexpression, although some of these cancers develop trastuzumab resistance. Using small interfering RNA (siRNA) to identify genes involved in trastuzumab resistance, Lee-Hoeflich et al. (2011) identified several kinases and phosphatases that were upregulated in trastuzumab-resistant cancers, including PPM1H (616016). Knockdown of PPM1H by either siRNA or short hairpin RNA induced trastuzumab resistance and increased cell proliferation. Lee-Hoeflich et al. (2011) found that PPM1H protected p27 from degradation by dephosphorylating thr187, thus removing a degradation signal and stabilizing p27-inhibited cell growth. </p><p>Das et al. (2013) found that knockdown of REST (600571) resulted in a decline in medulloblastoma cell proliferation and accumulation of p27. In vitro analysis showed that REST and p27 expression were reciprocally correlated in human medulloblastoma samples. REST repressed expression of USP37 (620226), and USP37 expression promoted p27 deubiquitination. USP37 interacted with p27 to promote its deubiquitination and stabilization, thereby blocking cell proliferation. The authors concluded that REST regulates p27 stability and cell proliferation by controlling USP37. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>Baens et al. (1995) characterized 117 cDNAs isolated by direct cDNA selection using pools of human chromosome 12p cosmids. Among these, 3 matched previously determined cDNA sequences, including the cyclin-dependent kinase inhibitor referred to as KIP1. STSs were developed for all cosmids. Regional assignment of the STSs by PCR analysis with somatic cell hybrids and fluorescence in situ hybridization (FISH) showed that the loci mapped to 12p13. Martin et al. (1995) mapped this gene, which they referred to as CDKN4, to 12p12.3 by fluorescence in situ hybridization. By PCR-based screening of genomic YAC clones of the CEPH library, they isolated 7 containing the KIP1 gene. In 4 of these YACs, they found a common STS, D12S358, and 1 of the 4 YACs also contained an additional STS, D12S320, which had been located 4 cM apart from D12S358 on the Genethon genetic map. Most of the YACs containing the KIP1 gene had been assigned to chromosome 12 from hybridization data of inter-Alu PCR products from somatic hybrids. </p><p>By FISH, Saito et al. (1999) mapped the mouse Kip gene to chromosome 7D3. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Multiple Endocrine Neoplasia, Type IV</em></strong></p><p>
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In a 48-year-old Caucasian female with primary hyperparathyroidism and a history of pituitary adenoma, consistent with multiple endocrine neoplasia type IV (MEN4; 610755), Pellegata et al. (2006) identified a heterozygous nonsense mutation in the CDKN1B gene (600778.0001). The mutation was also identified in her older sister who had renal angiomyolipoma, her youngest sister, and that sister's teenaged daughter, who reported no symptoms but did not undergo thorough examination. No mutations in the MEN1 gene (613733) were found in the proband or her older sister. </p><p>In a Dutch woman with MEN4, Georgitsi et al. (2007) identified a heterozygous truncating mutation in the CDKN1B gene (600778.0002). Tumor tissue from the patient's cervical carcinoma showed loss of heterozygosity for the wildtype allele and negative immunostaining for the p27 protein. The patient was ascertained from a larger cohort of 37 patients, mostly Dutch, who were clinically suspected to have MEN but were negative for mutation in the MEN1 gene. The authors also studied 19 patients with familial acromegaly/pituitary adenomas and 50 Finnish patients with sporadic acromegaly who underwent direct sequencing of the CDKN1B gene; the Dutch woman was the only patient found to carry a CDKN1B mutation. </p><p>In a woman with MEN4, Molatore et al. (2010) identified a heterozygous missense mutation in the CDKN1B gene (P69L; 600778.0003). The mutation caused reduced mutant protein levels due to more rapid degradation, had slightly higher cytoplasmic localization compared to wildtype, and lost the ability to bind CDK2. The P69L mutant protein was less effective at suppressing growth of neuroendocrine tumor cells in vitro compared to wildtype. The findings suggested a tumor suppressor role for p27 in neuroendocrine cells. The patient was 1 (3.7%) of 27 individuals with a MEN-like phenotype who was found to carry a CDKN1B mutation. </p><p>In a 69-year-old Spanish woman with MEN4, Malanga et al. (2012) identified a heterozygous mutation in the CDKN1B gene (600778.0004). In vitro functional expression studies using a luciferase reporter in HeLa cells showed that the mutation resulted in a significant reduction (30-60%) in transcription and possibly translation. Patient peripheral blood cells showed a significant 3-fold decrease in CDKN1B mRNA levels compared to controls, consistent with haploinsufficiency. The patient was 1 of 15 Spanish individuals with MEN-like features who underwent direct sequencing of the CDKN1B gene and was the only patient found to carry a mutation. </p><p><strong><em>Small Intestine Neuroendocrine Tumors</em></strong></p><p>
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Using exome- and genome-sequence analysis of small intestine neuroendocrine tumors (SI-NETs), Francis et al. (2013) identified recurrent somatic mutations and deletions in CDKN1B, which encodes p27. Francis et al. (2013) observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs. </p><p><strong><em>Other Disease Associations</em></strong></p><p>
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Chang et al. (2004) analyzed the CDKN1B gene in 188 families with hereditary prostate cancer (see 176807) and found a significant association between the SNP -79C/T (rs34330) and prostate cancer. The -79C allele was overtransmitted from parents to affected offspring, an association that was observed primarily in offspring whose age at diagnosis was less than 65 years. Chang et al. (2004) suggested that germline variants of this gene play a role in prostate cancer susceptibility. </p><p>Grey et al. (2013) found biallelic loss of CDKN1B gene expression in a boy with overgrowth and severe neurodevelopmental delay with autism. He also had left-sided strabismus, maldescended testes, and challenging behavior. Array CGH identified a heterozygous, approximately 108-kb deletion on chromosome 12p13 encompassing the 5-prime end of CDKN1B, APOLD1 (612456), and the 5-prime untranslated region of DDX47 (615428). The patient's unaffected mother also carried this deletion. Both individuals had decreased CDKN1B mRNA expression, but only the boy had decreased protein levels. Sanger sequencing showed that the proband also had a de novo heterozygous -73G-A transition in the promoter of the CDKN1B gene that was demonstrated to result in significantly decreased protein expression. Grey et al. (2013) postulated that the neurologic phenotype in the proband fit a recessive model of inheritance and was due to decreased expression of the CDKN1B below a threshold necessary to ensure normal neurodevelopment. The findings were also consistent with a mouse knockout model that has gigantism and hyperplasia of multiple organs (Fero et al., 1996). </p>
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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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<p>Fero et al. (1996) found that targeted disruption of the murine p27(Kip1) gene caused a gene dose-dependent increase in animal size without other gross morphologic abnormalities. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thymic hyperplasia was associated with increased T-lymphocyte proliferation, and T cells showed enhanced IL2 (147680) responsiveness in vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. In the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells. That p27 and Rb function in the same regulatory pathway was suggested by the finding that p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia. The absence of p27 also caused an ovulatory defect and female sterility. Maturation of second ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired. </p><p>Zindy et al. (1999) generated mice with targeted deletions of both the Ink4d (600927) and Kip1 genes. They found that terminally differentiated, postmitotic neurons in these mice reentered the cell cycle, divided, and underwent apoptosis. Zindy et al. (1999) noted that when either Ink4d or Kip1 alone are deleted, the postmitotic state is maintained, suggesting a redundant role for these genes in mature neurons. </p><p>Mitsuhashi et al. (2001) described a mouse model in which p27(Kip1) transgene expression was spatially restricted to the central nervous system neuroepithelium and temporally controlled with doxycycline. Transgene-specific transcripts were detectable within 6 hours of doxycycline administration, and maximum nonlethal expression was approached within 12 hours. After 18 to 26 hours of transgene expression, the G1 phase of the cell cycle was estimated to increase from 9 to 13 hours in the neocortical neuroepithelium, the maximum G1 phase length attainable in this proliferative population in normal mice. Thus, the data established a direct link between p27(Kip1) and control of G1 phase length in the mammalian central nervous system and unveiled intrinsic mechanisms that constrain the G1 phase length to a putative physiologic maximum despite ongoing p27(Kip1) transgene expression. </p><p>Phosphorylation of p27(Kip1) on threonine-187 by CDK2 is thought to initiate the major pathway for p27 proteolysis. To test the importance of this pathway critically in vivo, Malek et al. (2001) replaced the murine p27 gene with one that encoded alanine instead of threonine at position 187. Malek et al. (2001) demonstrated that cells expressing p27 with the T187A change were unable to downregulate p27 during the S and G2 phases of the cell cycle, but that this had a surprisingly modest effect on cell proliferation both in vitro and in vivo. Malek et al. (2001) demonstrated a second proteolytic pathway for controlling p27, one that is activated by mitogens and degrades p27 exclusively during G1. </p><p>Uchida et al. (2005) generated mice expressing human CDKN1B under the control of the promoter of the rat insulin gene and observed that increased expression of p27 in pancreatic beta cells induced severe diabetes as a result of inhibition of beta-cell proliferation. In mice lacking either insulin receptor substrate-2 (Irs2 -/-; see 600797) or the long form of the leptin receptor (Lepr -/-; see 601007), they found progressive accumulation of p27 in the nucleus of beta cells. Deletion of Cdkn1b ameliorated hyperglycemia in these mouse models of type II diabetes (125853) by increasing islet mass and maintaining compensatory hyperinsulinemia, which the authors attributed predominantly to stimulation of pancreatic beta-cell proliferation. Uchida et al. (2005) concluded that p27 contributes to beta-cell failure in the development of type II diabetes in Irs2 -/- and Lepr -/- (db/db) mice. </p><p>Wolfraim and Letterio (2005) found increased numbers of both Cd4 (186940)-positive and Cd8 (see 186910)-positive T cells in p27(Kip1)-deficient mice. However, there was a greater increase in the numbers of Cd8-positive T cells, resulting in a lower Cd4:Cd8 ratio, due in part to enhanced proliferation of naive Cd8-positive T cells, but not naive Cd4-positive T cells, under conditions of limiting Cd28 (186760)-mediated costimulation. </p><p>Nmyc (164840) promotes rapid cell division of granule neuron progenitors (GNPs) in mice, and its conditional loss during embryonic cerebellar development results in severe GNP deficiency, perturbs foliation, and leads to reduced cerebellar mass. Since loss of Nmyc triggers precocious expression of Kip1 and Ink4c (CDKN2C; 603369) in the cerebellar primordium, Zindy et al. (2006) disrupted Kip1 and Ink4c in Nmyc-null cerebella and found that this partially rescued GNP cell proliferation and cerebellar foliation. They concluded that expression of NMYC and concomitant downregulation of INK4C and KIP1 contribute to the proper development of the cerebellum. </p><p>Sharov et al. (2006) showed that inhibition of BMP (see BMP1, 112264) signaling in mouse keratinocytes altered the development of hair follicles. Microarray and real-time PCR analysis of laser-captured hair matrix cells showed a strong decrease in the expression of p27(Kip1) and increased expression of selected cyclins in the transgenic mice. p27(Kip1) knockout mice showed a similar increase in anagen hair follicles associated with increased cell proliferation in hair bulbs. Alternatively, activation of BMP signaling in human keratinocytes induced growth arrest and stimulated p27(Kip1) expression. Sharov et al. (2006) concluded that p27(Kip1) mediates the effects of BMP signaling on hair follicle size. </p><p>Fritz et al. (2002) described a multiple endocrine neoplasia-like autosomal recessive disorder in the rat. Animals exhibiting the mutant phenotype developed multiple neuroendocrine malignancies within the first year of life, including bilateral adrenal pheochromocytoma, multiple extraadrenal pheochromocytoma, bilateral medullary thyroid cell neoplasia, bilateral parathyroid hyperplasia, and pituitary adenoma. The appearance of neoplastic disease was preceded by the development of bilateral juvenile cataracts. Although the spectrum of affected tissues was reminiscent of human forms of MEN, no germline mutations were detected in the RET (164761) or MEN1 (613733) genes. Segregation studies in F1 and F2 crosses yielded frequencies of affected animals consistent with an autosomal recessive mode of inheritance. </p><p>In rats with an MEN-like syndrome (Menx), with phenotypic overlap of MEN1 (131100) and MEN2A (171400), Pellegata et al. (2006) performed linkage analysis and identified a locus in a 4-Mb segment on rat chromosome 4, which includes the Cdkn1b gene. Sequencing revealed a homozygous frameshift mutation in the Cdkn1b gene resulting in a dramatic reduction of p27(Kip1) protein. </p><p>Besson et al. (2007) generated knockin mice expressing a mutant p27 protein, called p27(CK-), that was unable to interact with cyclins and cyclin-dependent kinases. In contrast to complete deletion of the Cdkn1b gene, which causes spontaneous tumors only in pituitary, p27(CK-) dominantly caused hyperplastic lesions and tumors in multiple organs. The high incidence of spontaneous tumors in lung and retina was associated with amplification of stem/progenitor cell populations. </p><p>Karlas et al. (2010) reported the discovery of 287 human host cell genes, including CDKN1B, influencing influenza A virus replication in a genomewide RNA interference screen. Using an independent assay, Karlas et al. (2010) confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. CDKN1B inhibited both viral strains. Furthermore, H1N1 virus-infected p27-null mice accumulated significantly lower viral titers in the lung, providing in vivo evidence for the importance of this gene. </p>
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</span>
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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>6 Selected Examples):</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>
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<span class="mim-font">
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<strong>.0001 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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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CDKN1B, TRP76TER
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<br />
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SNP: rs121917832,
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ClinVar: RCV000009371
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 48-year-old Caucasian female with primary hyperparathyroidism and a history of pituitary adenoma (MEN4; 610755), Pellegata et al. (2006) identified a heterozygous 692G-A transition in the CDKN1B gene, resulting in a trp76-to-ter (W76X) substitution. The mutation was also identified in her older sister who had renal angiomyolipoma, her youngest sister, and that sister's teenaged daughter, who reported no symptoms but did not undergo thorough examination. The mutation was not found in 380 unrelated healthy controls. Molecular and immunohistochemical analysis of the renal angiomyolipoma showed that it retained the CDKN1B wildtype allele and demonstrated RNA expression but showed no p27 protein staining. </p><p>Molatore et al. (2010) demonstrated that the mutant W76X protein localized only to the cytoplasm and not to the nucleus. The mutant protein was unable to suppress the growth of neuroendocrine tumor cells in vitro, and lost its pro-apoptotic ability. The truncated protein was expressed in normal kidney tissue from the patient reported by Pellegata et al. (2006), suggesting that it is stable. </p>
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</span>
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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>.0002 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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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CDKN1B, 19-BP DUP, NT59
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<br />
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SNP: rs786201007,
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ClinVar: RCV000162205
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Dutch woman with multiple endocrine neoplasia type IV (MEN4; 610755), Georgitsi et al. (2007) identified a heterozygous 19-bp duplication in exon 1 of the CDKN1B gene (c.59_77dup19), resulting in a frameshift and premature termination. The patient developed small-cell neuroendocrine cervical carcinoma, an ACTH-secreting pituitary adenoma, and hyperparathyroidism in her forties. She was also diagnosed with multiple sclerosis. Tumor tissue from the cervical carcinoma showed loss of heterozygosity for the wildtype allele and negative immunostaining for the p27 protein. </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">
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<strong>.0003 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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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CDKN1B, PRO69LEU
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<br />
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SNP: rs777354267,
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gnomAD: rs777354267,
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ClinVar: RCV000162207, RCV002415708
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 79-year-old Caucasian woman with multiple endocrine neoplasia type IV (MEN4; 610755), Molatore et al. (2010) identified a heterozygous c.678C-T transition in the CDKN1B gene, resulting in a pro69-to-leu (P69L) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP database or in 370 control individuals. In vitro cellular expression studies showed that the mutation caused reduced mutant protein levels due to more rapid degradation, as well as slightly higher cytoplasmic localization compared to wildtype. Molecular modeling indicated that the mutation affected a CDK2 (116953)-binding site, and immunoblot analysis confirmed that the mutant protein could not bind CDK2. The P69L mutant protein was less effective at suppressing growth of neuroendocrine tumor cells in vitro compared to wildtype. The patient had bronchial carcinoid, a nonfunctioning pituitary microadenoma, parathyroid adenoma, and papillary thyroid carcinoma. Both bronchial carcinoid and parathyroid adenoma tissue showed decreased or even absent p27 protein expression, but loss of heterozygosity for the wildtype CDKN1B allele was observed only in the carcinoid sample. </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">
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<strong>.0004 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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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CDKN1B, 4-BP DEL, -32GAGA
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<br />
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SNP: rs774454456,
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gnomAD: rs774454456,
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ClinVar: RCV000162206, RCV000210358, RCV000354456, RCV000994850, RCV002247626, RCV003947663
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 69-year-old Spanish woman with multiple endocrine neoplasia type IV (MEN4; 610755), Malanga et al. (2012) identified a heterozygous 4-bp deletion in the 5-prime untranslated region of the CDKN1B gene (c.-32_-29delGAGA). In vitro functional expression studies using a luciferase reporter in HeLa cells showed that the mutation resulted in a significant reduction (30-60%) in transcription and possibly translation. Patient peripheral blood cells showed a significant 3-fold decrease in CDKN1B mRNA levels compared to controls, consistent with haploinsufficiency. The patient had gastric carcinoid tumor and hyperparathyroidism; there was no family history of endocrine neoplasia. </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">
|
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<strong>.0005 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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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CDKN1B, 4-BP DEL, -456CCTT
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<br />
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SNP: rs786201010,
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ClinVar: RCV000162208
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 62-year-old woman with multiple endocrine neoplasia type IV (MEN4; 610755), Occhi et al. (2013) identified a heterozygous 4-bp deletion (c.-456_-453delCCTT) in a highly conserved region in the 5-prime untranslated region of the CDKN1B gene. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 600 control chromosomes. The deletion shifted the upstream open reading frame (ORF) termination codon, thus lengthening the upstream ORF-encoded peptide from 29 to 158 amino acids and shortening the intracistronic space from 429 to 38 bp, with a possible negative influence on translation reinitiation from the main ATG. This change was predicted to prevent proper functioning of the 40S ribosomal subunit during translation. Patient cells showed normal levels of mutant mRNA, but decreased expression of the p27 protein, with weak cytoplasmic staining. Pancreatic tumor cells from the patient showed weak cytoplasmic p27 staining; there was no loss of heterozygosity for the wildtype allele. In vitro functional cellular expression assays showed that the 4-bp deletion impaired translation of a reporter gene by affecting translation reinitiation. The findings elucidated a novel mechanism by which p27 levels can be modulated by changes in the upstream ORF. The patient had acromegaly and a well-differentiated nonfunctioning pancreatic endocrine neoplasm. </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>.0006 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV</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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CDKN1B, 2-BP DEL, 371CT
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<br />
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SNP: rs786201011,
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ClinVar: RCV000162209, RCV003298195
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 53-year-old Italian woman with multiple endocrine neoplasia type IV (MEN4; 610755), Tonelli et al. (2014) identified a heterozygous 2-bp deletion (c.371_372delCT) in exon 1 of the CDKN1B gene, resulting in a frameshift and premature termination at codon 145. The patient had hyperparathyroidism due to parathyroid adenomas and gastrointestinal neuroendocrine tumors; she also had a history of hypothyroidism due to Hashimoto thyroiditis. Analysis of the patient's hyperplastic parathyroid tissue showed reduced nuclear p27 staining, but there was no loss of heterozygosity of the wildtype CDKN1B allele. The patient's asymptomatic 35-year-old son also carried the mutation. </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">
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|
<strong>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Baens, M., Aerssens, J., Van Zand, K., Van den Berghe, H., Marynen, P.
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<strong>Isolation and regional assignment of human chromosome 12p cDNAs.</strong>
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Genomics 29: 44-52, 1995.
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[PubMed: 8530100]
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[Full Text: https://doi.org/10.1006/geno.1995.1213]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Besson, A., Hwang, H. C., Cicero, S., Donovan, S. L., Gurian-West, M., Johnson, D., Clurman, B. E., Dyer, M. A., Roberts, J. M.
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<strong>Discovery of an oncogenic activity in p27(Kip1) that causes stem cell expansion and a multiple tumor phenotype.</strong>
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Genes Dev. 21: 1731-1746, 2007.
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[PubMed: 17626791]
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[Full Text: https://doi.org/10.1101/gad.1556607]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Braun-Dullaeus, R. C., Mann, M. J., Ziegler, A., von der Leyen, H. E., Dzau, V. J.
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<strong>A novel role for the cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy.</strong>
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J. Clin. Invest. 104: 815-823, 1999.
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[PubMed: 10491417]
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[Full Text: https://doi.org/10.1172/JCI5339]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Carrano, A. C., Eytan, E., Hershko, A., Pagano, M.
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<strong>SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.</strong>
|
|
Nature Cell Biol. 1: 193-199, 1999.
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[PubMed: 10559916]
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[Full Text: https://doi.org/10.1038/12013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chang, B., Zheng, S. L., Isaacs, S. D., Wiley, K. E., Turner, A., Li, G., Walsh, P. C., Meyers, D. A., Isaacs, W. B., Xu, J.
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|
<strong>A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer.</strong>
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Cancer Res. 64: 1997-1999, 2004.
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[PubMed: 15026335]
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[Full Text: https://doi.org/10.1158/0008-5472.can-03-2340]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chu, I., Sun, J., Arnaout, A., Kahn, H., Hanna, W., Narod, S., Sun, P., Tan, C.-K., Hengst, L., Slingerland, J.
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<strong>p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.</strong>
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Cell 128: 281-294, 2007.
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[PubMed: 17254967]
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[Full Text: https://doi.org/10.1016/j.cell.2006.11.049]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cuesta, R., Martinez-Sanchez, A., Gebauer, F.
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<strong>miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells.</strong>
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Molec. Cell. Biol. 29: 2841-2851, 2009.
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[PubMed: 19273599]
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[Full Text: https://doi.org/10.1128/MCB.01971-08]
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</p>
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</li>
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Zindy, F., Knoepfler, P. S., Xie, S., Sherr, C. J., Eisenman, R. N., Roussel, M. F.
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Bao Lige - updated : 01/31/2023<br>Cassandra L. Kniffin - updated : 3/10/2015<br>Patricia A. Hartz - updated : 9/22/2014<br>Ada Hamosh - updated : 1/14/2014<br>Cassandra L. Kniffin - updated : 7/24/2013<br>Patricia A. Hartz - updated : 12/9/2011<br>Patricia A. Hartz - updated : 10/24/2011<br>Matthew B. Gross - updated : 5/5/2010<br>Ada Hamosh - updated : 4/15/2010<br>Ada Hamosh - updated : 3/5/2010<br>Patricia A. Hartz - updated : 6/6/2008<br>Patricia A. Hartz - updated : 5/28/2008<br>Patricia A. Hartz - updated : 8/23/2007<br>Marla J. F. O'Neill - updated : 2/12/2007<br>Patricia A. Hartz - updated : 2/2/2007<br>Paul J. Converse - updated : 10/19/2006<br>Patricia A. Hartz - updated : 10/3/2006<br>Ada Hamosh - updated : 8/1/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Patricia A. Hartz - updated : 7/25/2005<br>Marla J. F. O'Neill - updated : 7/8/2005<br>Marla J. F. O'Neill - updated : 6/21/2005<br>George E. Tiller - updated : 5/4/2005<br>Ada Hamosh - updated : 5/29/2003<br>Ada Hamosh - updated : 11/19/2002<br>Ada Hamosh - updated : 9/21/2001<br>Victor A. McKusick - updated : 6/27/2001<br>Paul J. Converse - updated : 4/18/2001<br>Paul J. Converse - updated : 2/8/2001<br>Victor A. McKusick - updated : 1/26/2001<br>Ada Hamosh - updated : 4/12/2000<br>Carol A. Bocchini - updated : 6/15/1999<br>Stylianos E. Antonarakis - updated : 1/21/1999
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