CDKN2A (cyclin dependent kinase 2a / p16)

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

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

Identity

HGNC

CDKN2A

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

1029

ALIAS

ARF,CDK4I,CDKN2,CMM2,INK4,INK4A,MLM,MTS-1,MTS1,P14,P14ARF,P16,P16-INK4A,P16INK4,P16INK4A,P19,P19ARF,TP16

FUSION GENES

Show Gene Fusions

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.

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

Gene ID	Transcript ID	Uniprot
ENSG00000147889	ENST00000304494	P42771
ENSG00000147889	ENST00000304494	K7PML8
ENSG00000147889	ENST00000380151	P42771
ENSG00000147889	ENST00000479692	K7ENC6
ENSG00000147889	ENST00000494262	P42771
ENSG00000147889	ENST00000497750	K7ES20
ENSG00000147889	ENST00000498124	P42771
ENSG00000147889	ENST00000498628	P42771
ENSG00000147889	ENST00000530628	Q8N726
ENSG00000147889	ENST00000578845	P42771
ENSG00000147889	ENST00000579122	J3QRG6
ENSG00000147889	ENST00000579755	Q8N726

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Cell cycle	KEGG	ko04110
p53 signaling pathway	KEGG	ko04115
Pancreatic cancer	KEGG	ko05212
Glioma	KEGG	ko05214
Melanoma	KEGG	ko05218
Bladder cancer	KEGG	ko05219
Chronic myeloid leukemia	KEGG	ko05220
Non-small cell lung cancer	KEGG	ko05223
Cell cycle	KEGG	hsa04110
p53 signaling pathway	KEGG	hsa04115
Pathways in cancer	KEGG	hsa05200
Pancreatic cancer	KEGG	hsa05212
Glioma	KEGG	hsa05214
Melanoma	KEGG	hsa05218
Bladder cancer	KEGG	hsa05219
Chronic myeloid leukemia	KEGG	hsa05220
Non-small cell lung cancer	KEGG	hsa05223
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Viral carcinogenesis	KEGG	hsa05203
Viral carcinogenesis	KEGG	ko05203
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
SUMOylation	REACTOME	R-HSA-2990846
SUMO E3 ligases SUMOylate target proteins	REACTOME	R-HSA-3108232
SUMOylation of DNA damage response and repair proteins	REACTOME	R-HSA-3108214
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle, Mitotic	REACTOME	R-HSA-69278
Mitotic G1-G1/S phases	REACTOME	R-HSA-453279
G1 Phase	REACTOME	R-HSA-69236
Cyclin D associated events in G1	REACTOME	R-HSA-69231
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular Senescence	REACTOME	R-HSA-2559583
Oncogene Induced Senescence	REACTOME	R-HSA-2559585
Oxidative Stress Induced Senescence	REACTOME	R-HSA-2559580
Senescence-Associated Secretory Phenotype (SASP)	REACTOME	R-HSA-2559582
SUMOylation of transcription factors	REACTOME	R-HSA-3232118
Regulation of TP53 Activity	REACTOME	R-HSA-5633007
Regulation of TP53 Expression and Degradation	REACTOME	R-HSA-6806003
Regulation of TP53 Degradation	REACTOME	R-HSA-6804757
Platinum drug resistance	KEGG	ko01524
Endocrine resistance	KEGG	ko01522
Platinum drug resistance	KEGG	hsa01524
Endocrine resistance	KEGG	hsa01522

Protein levels (Protein atlas)

Not detected

Low

Medium

High

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