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    CDKN2A cyclin dependent kinase inhibitor 2A [ Homo sapiens (human) ]

    Gene ID: 1029, updated on 25-Jul-2016
    Official Symbol
    CDKN2Aprovided by HGNC
    Official Full Name
    cyclin dependent kinase inhibitor 2Aprovided by HGNC
    Primary source
    HGNC:HGNC:1787
    See related
    Ensembl:ENSG00000147889 HPRD:02542; MIM:600160; Vega:OTTHUMG00000019686
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    ARF; MLM; P14; P16; P19; CMM2; INK4; MTS1; TP16; CDK4I; CDKN2; INK4A; MTS-1; P14ARF; P19ARF; P16INK4; P16INK4A; P16-INK4A
    Summary
    This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
    Orthologs
    Location:
    9p21
    Exon count:
    8
    Annotation release Status Assembly Chr Location
    108 current GRCh38.p7 (GCF_000001405.33) 9 NC_000009.12 (21967752..21995043, complement)
    105 previous assembly GRCh37.p13 (GCF_000001405.25) 9 NC_000009.11 (21967751..21994490, complement)

    Chromosome 9 - NC_000009.12Genomic Context describing neighboring genes Neighboring gene tubulin beta 8 class VIII pseudogene 1 Neighboring gene methylthioadenosine phosphorylase Neighboring gene endogenous retrovirus group FRD member 3 Neighboring gene CDKN2A antisense RNA 1 (head to head) Neighboring gene CDKN2B antisense RNA 1 Neighboring gene cyclin dependent kinase inhibitor 2B Neighboring gene ubiquitin A-52 residue ribosomal protein fusion product 1 pseudogene 6

    GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

    Associated conditions

    Description Tests
    Cutaneous malignant melanoma 2
    MedGen: C1835044 OMIM: 155601 GeneReviews: Not available
    Compare labs
    Melanoma astrocytoma syndrome
    MedGen: C1835042 OMIM: 155755 GeneReviews: Not available
    Compare labs
    Melanoma-pancreatic cancer syndrome
    MedGen: C1838547 OMIM: 606719 GeneReviews: Not available
    Compare labs

    NHGRI GWAS Catalog

    Description
    A common variant on chromosome 9p21 affects the risk of myocardial infarction.
    NHGRI GWA Catalog
    A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
    NHGRI GWA Catalog
    Chromosome 7p11.2 (EGFR) variation influences glioma risk.
    NHGRI GWA Catalog
    Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.
    NHGRI GWA Catalog
    Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
    NHGRI GWA Catalog
    Genome-wide association meta-analysis identifies new endometriosis risk loci.
    NHGRI GWA Catalog
    Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.
    NHGRI GWA Catalog
    Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
    NHGRI GWA Catalog
    Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.
    NHGRI GWA Catalog
    Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.
    NHGRI GWA Catalog
    Genome-wide association study identifies five new breast cancer susceptibility loci.
    NHGRI GWA Catalog
    Genome-wide association study identifies five susceptibility loci for glioma.
    NHGRI GWA Catalog
    Genome-wide association study identifies three loci associated with melanoma risk.
    NHGRI GWA Catalog
    Genome-wide association study identifies three new melanoma susceptibility loci.
    NHGRI GWA Catalog
    Genome-wide association study identifies three novel loci for type 2 diabetes.
    NHGRI GWA Catalog
    Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
    NHGRI GWA Catalog
    Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction.
    NHGRI GWA Catalog
    Genome-wide association study of coronary artery disease in the Japanese.
    NHGRI GWA Catalog
    Genome-wide association study of intracranial aneurysm identifies three new risk loci.
    NHGRI GWA Catalog
    Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas.
    NHGRI GWA Catalog
    Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
    NHGRI GWA Catalog
    Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.
    NHGRI GWA Catalog
    Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies.
    NHGRI GWA Catalog
    Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.
    NHGRI GWA Catalog
    Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
    NHGRI GWA Catalog
    Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
    NHGRI GWA Catalog
    Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
    NHGRI GWA Catalog
    New gene functions in megakaryopoiesis and platelet formation.
    NHGRI GWA Catalog
    Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
    NHGRI GWA Catalog
    Susceptibility loci for intracranial aneurysm in European and Japanese populations.
    NHGRI GWA Catalog
    Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
    NHGRI GWA Catalog
    Two-marker association tests yield new disease associations for coronary artery disease and hypertension.
    NHGRI GWA Catalog
    Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype.
    NHGRI GWA Catalog

    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp120 env HIV-1 gp120 upregulates the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) in human B cells PubMed
    Nef nef HIV-1 Nef is identified to have a physical interaction with cyclin-dependent kinase inhibitor 2A (CDKN2A) in human HEK293 and/or Jurkat cell lines by using affinity tagging and purification mass spectrometry analyses PubMed
    Tat tat HIV-1 Tat downregulates the expression of INK4/p16 in Tat-positive cells PubMed
    tat p14(ARF) inhibits transcription activation of the HIV-1 LTR by Tat protein; the ARF-mediated inhibition of the HIV-1 LTR occurs by promoting Tat degradation via an ubiquitin-independent pathway PubMed
    reverse transcriptase gag-pol RT activity of latently HIV-1-infected cells decreases in the presence of exogenous p16INK4A PubMed

    Go to the HIV-1, Human Interaction Database

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    Products Interactant Other Gene Complex Source Pubs Description

    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    NF-kappaB binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    cyclin-dependent protein serine/threonine kinase inhibitor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    poly(A) RNA binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    protein kinase binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    Process Evidence Code Pubs
    G1/S transition of mitotic cell cycle IDA
    Inferred from Direct Assay
    more info
    PubMed 
    Ras protein signal transduction IEP
    Inferred from Expression Pattern
    more info
    PubMed 
    cell cycle arrest IDA
    Inferred from Direct Assay
    more info
    PubMed 
    cell cycle arrest IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    cellular senescence IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    negative regulation of NF-kappaB transcription factor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of cell growth IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of cell proliferation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of cell proliferation IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    negative regulation of cell-matrix adhesion IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    negative regulation of cyclin-dependent protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of phosphorylation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    negative regulation of transcription, DNA-templated IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    positive regulation of cellular senescence IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    positive regulation of macrophage apoptotic process ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    positive regulation of smooth muscle cell apoptotic process ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    replicative senescence IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    senescence-associated heterochromatin focus assembly IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    Component Evidence Code Pubs
    cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    cytosol TAS
    Traceable Author Statement
    more info
     
    nucleus IDA
    Inferred from Direct Assay
    more info
    PubMed 
    senescence-associated heterochromatin focus IDA
    Inferred from Direct Assay
    more info
    PubMed 
    Preferred Names
    cyclin-dependent kinase inhibitor 2A
    Names
    CDK4 inhibitor p16-INK4
    alternative reading frame
    cell cycle negative regulator beta
    cyclin-dependent kinase 4 inhibitor A
    cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
    multiple tumor suppressor 1

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_007485.1 RefSeqGene

      Range
      5001..31740
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_11

    mRNA and Protein(s)

    1. NM_000077.4NP_000068.1  cyclin-dependent kinase inhibitor 2A isoform p16INK4a

      See identical proteins and their annotated locations for NP_000068.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) is also known as alpha. Transcripts 1 and 4, encoding p16INK4a and p14ARF, have distinct first exons which contain the translation start codon, and share a common second exon, which is translated in different reading frames. Thus, the p16INK4a protein encoded by this variant (1) lacks sequence similarity to the protein product of variant 4 (p14ARF).
      Source sequence(s)
      AL449423, BI258230, BQ012762, BX099567, L27211
      Consensus CDS
      CCDS6510.1
      UniProtKB/Swiss-Prot
      P42771
      UniProtKB/TrEMBL
      K7PML8
      Related
      ENSP00000307101, OTTHUMP00000021147, ENST00000304494, OTTHUMT00000051915
      Conserved Domains (2) summary
      cd00204
      Location:19130
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam12796
      Location:16108
      Ank_2; Ankyrin repeats (3 copies)
    2. NM_001195132.1NP_001182061.1  cyclin-dependent kinase inhibitor 2A isoform p16gamma

      See identical proteins and their annotated locations for NP_001182061.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) includes an additional exon that causes a frameshift in the 3' coding region, compared to variant 1 (encoding p16INK4a). The resulting isoform (p16gamma) has a distinct C-terminus and is longer than p16INK4a. This variant has been described in PMID:17486064. It is a candidate for nonsense-mediated mRNA decay (NMD), but it is not known if the endogenous protein is expressed in vivo.
      Source sequence(s)
      AL449423, BX099567, DQ318021
      Consensus CDS
      CCDS56565.1
      UniProtKB/Swiss-Prot
      P42771
      Related
      ENSP00000418915, OTTHUMP00000215051, ENST00000498124, OTTHUMT00000354927
      Conserved Domains (2) summary
      cd00204
      Location:19130
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam12796
      Location:16108
      Ank_2; Ankyrin repeats (3 copies)
    3. NM_058195.3NP_478102.2  cyclin-dependent kinase inhibitor 2A isoform p14ARF

      See identical proteins and their annotated locations for NP_478102.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4), also known as beta, encodes isoform p14ARF. Transcripts 1 and 4, encoding p16INK4a and p14ARF have distinct first exons which contain the translation start codon, and share a common second exon, which is translated in different reading frames. Thus, the p16INK4a protein encoded by this variant (1) lacks sequence similarity to the protein product of variant 4 (p14ARF). Note that this variant may use an alternative upstream start codon, which would produce an isoform that is 41 aa longer at the N-terminus, or an alternative downstream start codon, which would produce an isoform (smARF, described in PMID:16713577) that is 47 aa shorter at the N-terminus; it is unclear if the isoforms derived from the alternative start codons are present in vivo. The p14ARF isoform is known to be nucleoplasmic but may also be recruited to mitochondria, as described in PMID:20107316.
      Source sequence(s)
      BQ012762, BX099567, S78535, U38945
      Consensus CDS
      CCDS6511.2
      UniProtKB/Swiss-Prot
      Q8N726
      Related
      ENSP00000462950, OTTHUMP00000215053, ENST00000579755, OTTHUMT00000051918
      Conserved Domains (1) summary
      pfam07392
      Location:454
      P19Arf_N; Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus
    4. NM_058197.4NP_478104.2  cyclin-dependent kinase inhibitor 2A isoform p12

      See identical proteins and their annotated locations for NP_478104.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) contains an alternate open reading frame (ARF), when compared to variants 1 or 4. The ARF results from an alternative splicing between a distinct first exon, which contains the translation start codon, and the common second exon. Thus, the protein encoded by this variant (p12) lacks sequence similarity to the protein product of variant 4. This variant is specifically expressed in pancreas, and has been described in PMID:10445844. It is a candidate for nonsense-mediated mRNA decay (NMD), but it is not known if the endogenous protein is expressed in vivo.
      Source sequence(s)
      AF115544, AL449423, BQ012762, BX099567
      UniProtKB/Swiss-Prot
      P42771
      UniProtKB/TrEMBL
      G3XAG3
      Related
      ENSP00000369496, OTTHUMP00000215052, ENST00000380151, OTTHUMT00000051917
      Conserved Domains (2) summary
      pfam13637
      Location:1650
      Ank_4; Ankyrin repeats (many copies)
      cl02529
      Location:1949
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...

    RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 108 details...

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p7 Primary Assembly

    Genomic

    1. NC_000009.12 Reference GRCh38.p7 Primary Assembly

      Range
      21967752..21995043 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011517679.1XP_011515981.1  

      See identical proteins and their annotated locations for XP_011515981.1

      UniProtKB/Swiss-Prot
      P42771
      Related
      ENSP00000467857, OTTHUMP00000263033, ENST00000498628, OTTHUMT00000051920
      Conserved Domains (2) summary
      cd00204
      Location:279
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam13857
      Location:1267
      Ank_5; Ankyrin repeats (many copies)
    2. XM_005251343.1XP_005251400.1  

      See identical proteins and their annotated locations for XP_005251400.1

      UniProtKB/Swiss-Prot
      P42771
      Related
      ENSP00000467390, OTTHUMP00000263104, ENST00000578845, OTTHUMT00000446068
      Conserved Domains (2) summary
      cd00204
      Location:279
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam13857
      Location:1267
      Ank_5; Ankyrin repeats (many copies)
    3. XM_011517676.2XP_011515978.1  

      Conserved Domains (2) summary
      cd00204
      Location:19130
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam12796
      Location:16108
      Ank_2; Ankyrin repeats (3 copies)
    4. XM_011517675.2XP_011515977.1  

      Conserved Domains (2) summary
      cd00204
      Location:19130
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam12796
      Location:16108
      Ank_2; Ankyrin repeats (3 copies)

    RNA

    1. XR_929159.2 RNA Sequence

    Alternate CHM1_1.1

    Genomic

    1. NC_018920.2 Alternate CHM1_1.1

      Range
      21967646..21994319 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_058196.1: Suppressed sequence

      Description
      NM_058196.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.