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

    Gene ID: 1029, updated on 26-Jul-2021

    Summary

    Official Symbol
    CDKN2Aprovided by HGNC
    Official Full Name
    cyclin dependent kinase inhibitor 2Aprovided by HGNC
    Primary source
    HGNC:HGNC:1787
    See related
    Ensembl:ENSG00000147889 MIM:600160
    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]
    Expression
    Low expression observed in reference dataset See more
    Orthologs
    NEW
    Try the new Gene table
    Try the new Transcript table

    Genomic context

    See CDKN2A in Genome Data Viewer
    Location:
    9p21.3
    Exon count:
    8
    Annotation release Status Assembly Chr Location
    109.20210514 current GRCh38.p13 (GCF_000001405.39) 9 NC_000009.12 (21967752..21995324, complement)
    105.20201022 previous assembly GRCh37.p13 (GCF_000001405.25) 9 NC_000009.11 (21967751..21995323, complement)

    Chromosome 9 - NC_000009.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC107987026 Neighboring gene KH-type splicing regulatory protein pseudogene 1 Neighboring gene tubulin beta 8 class VIII pseudogene 1 Neighboring gene methylthioadenosine phosphorylase Neighboring gene CDKN2A divergent transcript Neighboring gene CDKN2B antisense RNA 1 Neighboring gene Sharpr-MPRA regulatory region 15403 Neighboring gene cyclin dependent kinase inhibitor 2B

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    Phenotypes

    Associated conditions

    Description Tests
    A common variant on chromosome 9p21 affects the risk of myocardial infarction.
    GeneReviews: Not available
    A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
    GeneReviews: Not available
    Chromosome 7p11.2 (EGFR) variation influences glioma risk.
    GeneReviews: Not available
    Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.
    GeneReviews: Not available
    Cutaneous malignant melanoma 2
    MedGen: C1835044 OMIM: 155601 GeneReviews: Not available
    Compare labs
    Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
    GeneReviews: Not available
    Genome-wide association meta-analysis identifies new endometriosis risk loci.
    GeneReviews: Not available
    Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.
    GeneReviews: Not available
    Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
    GeneReviews: Not available
    Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.
    GeneReviews: Not available
    Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.
    GeneReviews: Not available
    Genome-wide association study identifies five new breast cancer susceptibility loci.
    GeneReviews: Not available
    Genome-wide association study identifies five susceptibility loci for glioma.
    GeneReviews: Not available
    Genome-wide association study identifies three loci associated with melanoma risk.
    GeneReviews: Not available
    Genome-wide association study identifies three new melanoma susceptibility loci.
    GeneReviews: Not available
    Genome-wide association study identifies three novel loci for type 2 diabetes.
    GeneReviews: Not available
    Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
    GeneReviews: Not available
    Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction.
    GeneReviews: Not available
    Genome-wide association study of coronary artery disease in the Japanese.
    GeneReviews: Not available
    Genome-wide association study of intracranial aneurysm identifies three new risk loci.
    GeneReviews: Not available
    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.
    GeneReviews: Not available
    Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
    GeneReviews: Not available
    Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.
    GeneReviews: Not available
    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.
    GeneReviews: Not available
    Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.
    GeneReviews: Not available
    Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
    GeneReviews: Not available
    Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
    GeneReviews: Not available
    Melanoma and neural system tumor syndrome
    MedGen: C1835042 OMIM: 155755 GeneReviews: Not available
    Compare labs
    Melanoma-pancreatic cancer syndrome
    MedGen: C1838547 OMIM: 606719 GeneReviews: Not available
    Compare labs
    Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
    GeneReviews: Not available
    New gene functions in megakaryopoiesis and platelet formation.
    GeneReviews: Not available
    Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
    GeneReviews: Not available
    Susceptibility loci for intracranial aneurysm in European and Japanese populations.
    GeneReviews: Not available
    Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
    GeneReviews: Not available
    Two-marker association tests yield new disease associations for coronary artery disease and hypertension.
    GeneReviews: Not available
    Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype.
    GeneReviews: Not available

    HIV-1 interactions

    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

    Pathways from PubChem

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Homology

    Gene Ontology Provided by GOA

    Process Evidence Code Pubs
    involved_in G1/S transition of mitotic cell cycle IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in Ras protein signal transduction IEP
    Inferred from Expression Pattern
    more info
    PubMed 
    involved_in cellular senescence IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in negative regulation of NF-kappaB transcription factor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of cell growth IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of cell population proliferation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of cell population proliferation IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in negative regulation of cell-matrix adhesion IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    acts_upstream_of_or_within negative regulation of cyclin-dependent protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of cyclin-dependent protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of phosphorylation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of transcription, DNA-templated IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in positive regulation of cellular senescence IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in positive regulation of macrophage apoptotic process ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    involved_in positive regulation of smooth muscle cell apoptotic process ISS
    Inferred from Sequence or Structural Similarity
    more info
    PubMed 
    involved_in regulation of cell cycle IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in regulation of cell cycle IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in replicative senescence IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in senescence-associated heterochromatin focus assembly IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    Component Evidence Code Pubs
    located_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in cytosol TAS
    Traceable Author Statement
    more info
     
    located_in nucleus IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in senescence-associated heterochromatin focus IDA
    Inferred from Direct Assay
    more info
    PubMed 

    General protein information

    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

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    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_000077.5NP_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)
      BI258230, BQ012762, BX099567, L27211
      Consensus CDS
      CCDS6510.1
      UniProtKB/Swiss-Prot
      P42771
      UniProtKB/TrEMBL
      K7PML8
      Related
      ENSP00000307101.5, ENST00000304494.10
      Conserved Domains (3) 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)
      sd00045
      Location:1642
      ANK; ANK repeat [structural motif]
    2. NM_001195132.2NP_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
      ENSP00000418915.1, ENST00000498124.1
      Conserved Domains (3) 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)
      sd00045
      Location:1642
      ANK; ANK repeat [structural motif]
    3. NM_001363763.2NP_001350692.1  cyclin-dependent kinase inhibitor 2A isoform 6

      Status: REVIEWED

      Source sequence(s)
      AL449423
      Consensus CDS
      CCDS87644.1
      Related
      ENSP00000467857.1, ENST00000498628.6
      Conserved Domains (2) summary
      COG0666
      Location:2100
      ANKYR; Ankyrin repeat [Signal transduction mechanisms]
      sd00045
      Location:2557
      ANK; ANK repeat [structural motif]
    4. NM_058195.4NP_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 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 p14ARF protein encoded by this variant (4) lacks sequence similarity to the protein product of variant 1 (p16INK4a). 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 protein 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
      ENSP00000462950.1, ENST00000579755.2
      Conserved Domains (1) summary
      pfam07392
      Location:454
      P19Arf_N; Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus
    5. NM_058197.5NP_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
      ENSP00000369496.3, ENST00000380151.3
      Conserved Domains (2) summary
      sd00045
      Location:1642
      ANK; ANK repeat [structural motif]
      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 Updated Annotation Release 109.20210514

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

    Reference GRCh38.p13 Primary Assembly

    Genomic

    1. NC_000009.12 Reference GRCh38.p13 Primary Assembly

      Range
      21967752..21995324 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_005251343.1XP_005251400.1  cyclin-dependent kinase inhibitor 2A isoform X3

      See identical proteins and their annotated locations for XP_005251400.1

      UniProtKB/Swiss-Prot
      P42771
      Related
      ENSP00000467390.1, ENST00000578845.2
      Conserved Domains (2) summary
      COG0666
      Location:2100
      ANKYR; Ankyrin repeat [Signal transduction mechanisms]
      sd00045
      Location:2557
      ANK; ANK repeat [structural motif]
    2. XM_011517676.2XP_011515978.1  cyclin-dependent kinase inhibitor 2A isoform X2

      Conserved Domains (3) 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)
      sd00045
      Location:1642
      ANK; ANK repeat [structural motif]
    3. XM_011517675.2XP_011515977.1  cyclin-dependent kinase inhibitor 2A isoform X1

      Conserved Domains (3) 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)
      sd00045
      Location:1642
      ANK; ANK repeat [structural motif]

    RNA

    1. XR_929159.2 RNA Sequence

    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.
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