Format

Send to:

Choose Destination

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

Gene ID: 1029, updated on 1-Jun-2020

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

Genomic context

See CDKN2A in Genome Data Viewer
Location:
9p21.3
Exon count:
8
Annotation release Status Assembly Chr Location
109.20200522 current GRCh38.p13 (GCF_000001405.39) 9 NC_000009.12 (21967752..21995324, 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 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
Cutaneous malignant melanoma 2
MedGen: C1835044 OMIM: 155601 GeneReviews: Not available
Compare labs
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

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

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

Function Evidence Code Pubs
NF-kappaB binding IDA
Inferred from Direct Assay
more info
PubMed 
RNA binding HDA PubMed 
cyclin-dependent protein serine/threonine kinase inhibitor activity 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 G1/S transition of mitotic cell cycle TAS
Traceable Author Statement
more info
 
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 

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)

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, ENST00000304494.9
    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
    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 ...
    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, ENST00000579755.1
    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.

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
    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 ...
    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.
Support Center