CDKN2A (cyclin dependent kinase 2a / p16)

2007-08-01   Raphael Saffroy , Antoinette Lemoine , Brigitte Debuire 

Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France

Identity

HGNC
LOCATION
9p21.3
IMAGE
Atlas Image
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
IMAGE
Atlas Image
LEGEND
CDKN2A (cyclin dependent kinase 2a / p16) Hybridization with Vysis CDKN2A/CEP 9 FISH Probe (Abbott Molecular, US) showing the CDKN2A gene on 9p21.3 (red signals) - Courtesy Adriana Zamecnikova.
LOCUSID
ALIAS
ARF,CDK4I,CDKN2,CMM2,INK4,INK4A,MLM,MTS-1,MTS1,P14,P14ARF,P16,P16-INK4A,P16INK4,P16INK4A,P19,P19ARF,TP16
FUSION GENES

DNA/RNA

Description

The gene encompasses 6.6 kb of DNA; 3 exons.

Transcription

471 nucleotides mRNA. The CDKN2 gene generates several transcript variants from different promoters. Each transcript differs in its first exon (E1), and utilizes alternate polyadenylation sites. E1-alpha, which is spliced into the common exons E2 and E3, gives rise to the p16-INK4 transcript. A putative DNA replication origin has been identified in close proximity of INK4/Arf locus that appears to transcriptionally repress p16 in a manner dependent on CDC6.

Proteins

Description

156 amino acids; 16.5 kDa protein.

Expression

Moderately expressed in many organs as thymus, liver, pancreas, prostate, lung, or kidney.

Function

P16-INK4a interacts strongly with cyclin-dependent kinase 4 and cyclin-dependent kinase 6 and inhibits their ability to interact with cyclins D. P16-INK4a induces cell cycle arrest at G1 and G2/M checkpoints, blocking them from phosphorylating RB1 and preventing exit from G1 phase of the cell cycle. P16-INK4a could act as a negative regulator of normal cells proliferation.

Homology

Belongs to the cdkn2 cyclin-dependent kinase inhibitor family.

Implicated in

Entity name
Cutaneous malignant melanoma 2 (CMM2)
Disease
Malignant melanoma arises de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites.
Oncogenesis
Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait. CDKN2a has been identified as a major susceptibility gene for melanoma. However this gene accounts for a minority of familial melanoma. P16 is functionally inactivated by mutations or deletions, however, because many such mutations occur in exon 2, they can potentially also affect the alternative reading frame (ARF) protein.
Entity name
Familial atypical multiple mole melanoma carcinoma syndrome (FAMMM)
Disease
Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer.
Oncogenesis
FAMMM syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Germline mutations in the p16-INK4a gene were found in approximately 40% of the FAMMM syndrome.
Entity name
Sporadic cancer
Disease
Defects in CDKN2a are involved in tumor formation in a wide range of tissues.
Prognosis
Aberrant p16 expression is associated with more aggressive behavior.
Oncogenesis
LOH on 9p21 is one of the most frequent genetic alterations identified in human cancer. However, point mutations of p16 on the other chromosome are relatively rare. Promoter methylation appears as the commonest mechanism of p16 gene inactivation.
Entity name
Aging
Note
Expression of p16 increases markedly with aging in many human tissues. This finding has led to the proposal that p16 expression could be used as a biomarker of physiologic, as opposed to chronologic, age. It was suggested that an age-induced increase in p16 expression contributes to the decline of replicative potential of certain self-renewing compartments with aging.

Bibliography

Pubmed IDLast YearTitleAuthors
85890351995Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.Bartsch D et al
75503531995Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.Cairns P et al
31660711988Cytogenetic analysis of melanocytes from premalignant nevi and melanomas.Cowan JM et al
148712232004FAMMM syndrome: pathogenesis and management.Czajkowski R et al
91322801997The CDKN2A (p16) gene and human cancer.Foulkes WD et al
165721772006Oncogenic activity of Cdc6 through repression of the INK4/ARF locus.Gonzalez S et al
79873871994Germline p16 mutations in familial melanoma.Hussussian CJ et al
81536341994A cell cycle regulator potentially involved in genesis of many tumor types.Kamb A et al
77770611995Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition.Koh J et al
115445302001Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice.Krimpenfort P et al
169577372006p16INK4a induces an age-dependent decline in islet regenerative potential.Krishnamurthy J et al
75851411995Methylation and p16: suppressing the suppressor.Little M et al
758515219955' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.Merlo A et al
90128421997Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF.Quelle DE et al
85215221995Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.Quelle DE et al
82592151993A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.Serrano M et al
86205341996Role of the INK4a locus in tumor suppression and cell mortality.Serrano M et al
127892862003The INK4a/ARF locus and melanoma.Sharpless E et al
115445312001Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.Sharpless NE et al
76067161995Complex structure and regulation of the P16 (MTS1) locus.Stone S et al

Other Information

Locus ID:

NCBI: 1029
MIM: 600160
HGNC: 1787
Ensembl: ENSG00000147889

Variants:

dbSNP: 1029
ClinVar: 1029
TCGA: ENSG00000147889
COSMIC: CDKN2A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000147889ENST00000304494P42771
ENSG00000147889ENST00000304494K7PML8
ENSG00000147889ENST00000380151P42771
ENSG00000147889ENST00000479692K7ENC6
ENSG00000147889ENST00000494262P42771
ENSG00000147889ENST00000497750K7ES20
ENSG00000147889ENST00000498124P42771
ENSG00000147889ENST00000498628P42771
ENSG00000147889ENST00000530628Q8N726
ENSG00000147889ENST00000578845P42771
ENSG00000147889ENST00000579122J3QRG6
ENSG00000147889ENST00000579755Q8N726

Expression (GTEx)

0
5
10
15
20

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
p53 signaling pathwayKEGGko04115
Pancreatic cancerKEGGko05212
GliomaKEGGko05214
MelanomaKEGGko05218
Bladder cancerKEGGko05219
Chronic myeloid leukemiaKEGGko05220
Non-small cell lung cancerKEGGko05223
Cell cycleKEGGhsa04110
p53 signaling pathwayKEGGhsa04115
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
GliomaKEGGhsa05214
MelanomaKEGGhsa05218
Bladder cancerKEGGhsa05219
Chronic myeloid leukemiaKEGGhsa05220
Non-small cell lung cancerKEGGhsa05223
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1 PhaseREACTOMER-HSA-69236
Cyclin D associated events in G1REACTOMER-HSA-69231
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
SUMOylation of transcription factorsREACTOMER-HSA-3232118
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
Endocrine resistanceKEGGhsa01522

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA446155Precursor Cell Lymphoblastic Leukemia-LymphomaDiseaseMultilinkAnnotationassociated26104880

References

Pubmed IDYearTitleCitations
174632462007Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.1137
174632482007A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.1102
174632492007Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.887
201773972010Genomic instability--an evolving hallmark of cancer.633
174786812007A common allele on chromosome 9 associated with coronary heart disease.586
174786792007A common variant on chromosome 9p21 affects the risk of myocardial infarction.561
173444142007The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.350
195783672009Genome-wide association study identifies five susceptibility loci for glioma.340
211519602010Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk.311
190203232008Genotype score in addition to common risk factors for prediction of type 2 diabetes.304

Citation

Raphael Saffroy ; Antoinette Lemoine ; Brigitte Debuire

CDKN2A (cyclin dependent kinase 2a / p16)

Atlas Genet Cytogenet Oncol Haematol. 2007-08-01

Online version: http://atlasgeneticsoncology.org/gene/146/cdkn2a

Historical Card

2004-08-01 CDKN2A (cyclin dependent kinase 2a / p16) by  Raphael Saffroy,Antoinette Lemoine,Brigitte Debuire 

Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France