CDKN2A (cyclin dependent kinase 2a / p16)
2007-08-01 Raphael Saffroy , Antoinette Lemoine , Brigitte Debuire AffiliationLaboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France
Identity
HGNC
LOCATION
9p21.3
IMAGE
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
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
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.
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 8589035 | 1995 | Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. | Bartsch D et al |
| 7550353 | 1995 | Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. | Cairns P et al |
| 3166071 | 1988 | Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. | Cowan JM et al |
| 14871223 | 2004 | FAMMM syndrome: pathogenesis and management. | Czajkowski R et al |
| 9132280 | 1997 | The CDKN2A (p16) gene and human cancer. | Foulkes WD et al |
| 16572177 | 2006 | Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. | Gonzalez S et al |
| 7987387 | 1994 | Germline p16 mutations in familial melanoma. | Hussussian CJ et al |
| 8153634 | 1994 | A cell cycle regulator potentially involved in genesis of many tumor types. | Kamb A et al |
| 7777061 | 1995 | Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. | Koh J et al |
| 11544530 | 2001 | Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. | Krimpenfort P et al |
| 16957737 | 2006 | p16INK4a induces an age-dependent decline in islet regenerative potential. | Krishnamurthy J et al |
| 7585141 | 1995 | Methylation and p16: suppressing the suppressor. | Little M et al |
| 7585152 | 1995 | 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. | Merlo A et al |
| 9012842 | 1997 | Cancer-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 |
| 8521522 | 1995 | Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. | Quelle DE et al |
| 8259215 | 1993 | A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. | Serrano M et al |
| 8620534 | 1996 | Role of the INK4a locus in tumor suppression and cell mortality. | Serrano M et al |
| 12789286 | 2003 | The INK4a/ARF locus and melanoma. | Sharpless E et al |
| 11544531 | 2001 | Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. | Sharpless NE et al |
| 7606716 | 1995 | Complex 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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA446155 | Precursor Cell Lymphoblastic Leukemia-Lymphoma | Disease | MultilinkAnnotation | associated | 26104880 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37211840 | 2024 | LncRNA CAI2 Contributes to Poor Prognosis of Glioma through the PI3K-Akt Signaling Pathway. | 0 |
| 37578068 | 2024 | ARID5B, IKZF1, GATA3, CEBPE, and CDKN2A germline polymorphisms and predisposition to childhood acute lymphoblastic leukemia. | 0 |
| 37861207 | 2024 | Human papillomavirus and p16(INK4a) in oropharyngeal squamous cell carcinomas: A systematic review and meta-analysis. | 0 |
| 37924530 | 2024 | Prognosis of CDKN2A germline mutation in patients with familial melanoma: a systematic review and meta-analysis. | 0 |
| 38097874 | 2024 | FISH analysis reveals CDKN2A and IFNA14 co-deletion is heterogeneous and is a prominent feature of glioblastoma. | 0 |
| 38265748 | 2024 | CDKN2A/B deletion in IDH-mutant astrocytomas: An evaluation by Fluorescence in-situ hybridization. | 0 |
| 38421707 | 2024 | METTL14-Mediated m6a Modification of CDKN2A Promotes the Development of Retinoblastoma by Inhibiting the p53 Pathway. | 1 |
| 38438773 | 2024 | CDKN2A promoter methylation enhances self-renewal of glioblastoma stem cells and confers resistance to carmustine. | 1 |
| 38441530 | 2024 | PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation. | 0 |
| 38457226 | 2024 | Treatments, prognostic factors, and genetic heterogeneity in advanced cholangiocarcinoma: A multicenter real-world study. | 1 |
| 38500158 | 2024 | HPV related p16(INK4A) and HSV in benign and potentially malignant oral mucosa pathologies. | 0 |
| 38546068 | 2024 | High P16INK4A Expression, Keratinizing Features, and Surgical Margin-Free Status are Associated with Improved Survival in Patients with Oral Squamous Cell Carcinomas. | 0 |
| 38626341 | 2024 | De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression. | 0 |
| 38627195 | 2024 | iChIP-SILAC analysis identifies epigenetic regulators of CpG methylation of the p16(INK4A) gene. | 0 |
| 38630911 | 2024 | Uterine Inflammatory Myofibroblastic Tumors: p16 as a Surrogate for CDKN2A Deletion and Predictor of Aggressive Behavior. | 0 |
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-(cyclin-dependent-kinase-2a-p16)
Historical Card
2004-08-01 CDKN2A (cyclin dependent kinase 2a / p16) by Raphael Saffroy,Antoinette Lemoine,Brigitte Debuire Affiliation
Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France
