CDKN2a, cyclin dependent kinase 2a / p16

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CDKN2a, cyclin dependent kinase 2a / p16

Identity

Other names CDKN2a

p16

INK4

p16- INK4a

TP16

CDK4I

MTS1

HGNC CDKN2A

Location 9p21.3

Location_base_pair Starts at 21957751 and ends at 21965038 bp from pter ( according to hg18-Mar_2006).

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.

Protein

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 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 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 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 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.

External links

	Nomenclature
HGNC	CDKN2A 1787
Entrez_Gene	CDKN2A 1029 cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
	Cards
Atlas	CDKN2aID146
GeneCards	CDKN2A
Ensembl	ENSG00000147889 [Gene_View] CDKN2A [Vega]
Genatlas	CDKN2A
	Genomic and cartography
GoldenPath	CDKN2A - 9p21.3 chr9:21957751-21965038 - 9p21 [Description] (hg18-Mar_2006)
Ensembl	CDKN2A - 9p21 [CytoView]
NCBI	Mapview
OMIM	151623 Disease map [OMIM]
OMIM	155601 Disease map [OMIM]
OMIM	155755 Disease map [OMIM]
OMIM	600160 Disease map [OMIM]
OMIM	606719 Disease map [OMIM]
HomoloGene	CDKN2A
	Gene and transcription
Genbank	AF115544 [ ENTREZ ]
Genbank	AI859822 [ ENTREZ ]
Genbank	AJ844636 [ ENTREZ ]
Genbank	AL582909 [ ENTREZ ]
Genbank	BC015960 [ ENTREZ ]
RefSeq	NM_000077 [ SRS ] NM_000077 [ ENTREZ ]
RefSeq	NM_058195 [ SRS ] NM_058195 [ ENTREZ ]
RefSeq	NM_058197 [ SRS ] NM_058197 [ ENTREZ ]
RefSeq	AC_000052 [ SRS ] AC_000052 [ ENTREZ ]
RefSeq	AC_000141 [ SRS ] AC_000141 [ ENTREZ ]
RefSeq	NC_000009 [ SRS ] NC_000009 [ ENTREZ ]
RefSeq	NG_007485 [ SRS ] NG_007485 [ ENTREZ ]
RefSeq	NT_008413 [ SRS ] NT_008413 [ ENTREZ ]
RefSeq	NW_001839149 [ SRS ] NW_001839149 [ ENTREZ ]
RefSeq	NW_924062 [ SRS ] NW_924062 [ ENTREZ ]
CCDS	CDKN2A CCDS - NCBI
AceView	CDKN2A AceView - NCBI
Unigene	Hs.512599 [ SRS ] Hs.512599 [ NCBI ]
Fast-db	3514 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P42771 [ SRS] P42771 [ EXPASY ] P42771 [ INTERPRO ] P42771 [ UNIPROT ] P42771 [ VarSplice FASTA ]
Prosite	PS50297 ANK_REP_REGION [ SRS ] PS50297 ANK_REP_REGION [ Expasy ]
Prosite	PS50088 ANK_REPEAT [ SRS ] PS50088 ANK_REPEAT [ Expasy ]
Interpro	IPR002110 ANK [ SRS ] IPR002110 ANK [ EBI ]
CluSTr	P42771
Pfam	PF00023 Ank [ SRS ] PF00023 Ank [ Sanger ] pfam00023 [ NCBI-CDD ]
Smart	SM00248 ANK [EMBL]
Blocks	P42771
PDB	1A5E [ SRS ] 1A5E [ PdbSum ], 1A5E [ IMB ] 1A5E [ RSDB ]
PDB	1BI7 [ SRS ] 1BI7 [ PdbSum ], 1BI7 [ IMB ] 1BI7 [ RSDB ]
PDB	1DC2 [ SRS ] 1DC2 [ PdbSum ], 1DC2 [ IMB ] 1DC2 [ RSDB ]
PDB	2A5E [ SRS ] 2A5E [ PdbSum ], 2A5E [ IMB ] 2A5E [ RSDB ]
HPRD	02542
	Protein Interaction databases
DIP	P42771
IntAct	P42771
	Polymorphism : SNP, mutations, diseases
OMIM	151623 [ map ]
OMIM	155601 [ map ]
OMIM	155755 [ map ]
OMIM	600160 [ map ]
OMIM	606719 [ map ]
GENETests	151623
GENETests	155601
GENETests	155755
GENETests	600160
GENETests	606719
SNP	CDKN2A [dbSNP-NCBI]
SNP	NM_000077 [SNP-NCI]
SNP	NM_058195 [SNP-NCI]
SNP	NM_058197 [SNP-NCI]
SNP	CDKN2A [GeneSNPs - Utah] CDKN2A] [HGBASE - SRS]
HAPMAP	CDKN2A [HAPMAP]
COSMIC	CDKN2A [Somatic mutation (COSMIC-CGP-Sanger)]
TICdb	CDKN2A [Translocation breakpoints In Cancer]
HGMD	CDKN2A
Genetic Association	CDKN2A
CDC HuGE	CDKN2A
	General knowledge
Family Browser	CDKN2A [UCSC Family Browser]
SOURCE	NM_000077
SOURCE	NM_058195
SOURCE	NM_058197
SMD	Hs.512599
SAGE	Hs.512599
GO	cell cycle checkpoint [Amigo] cell cycle checkpoint
GO	G1/S transition of mitotic cell cycle [Amigo] G1/S transition of mitotic cell cycle
GO	negative regulation of cell-matrix adhesion [Amigo] negative regulation of cell-matrix adhesion
GO	DNA binding [Amigo] DNA binding
GO	cyclin-dependent protein kinase inhibitor activity [Amigo] cyclin-dependent protein kinase inhibitor activity
GO	protein binding [Amigo] protein binding
GO	nucleus [Amigo] nucleus
GO	nucleus [Amigo] nucleus
GO	nucleoplasm [Amigo] nucleoplasm
GO	nucleolus [Amigo] nucleolus
GO	cytoplasm [Amigo] cytoplasm
GO	DNA fragmentation during apoptosis [Amigo] DNA fragmentation during apoptosis
GO	transcription [Amigo] transcription
GO	regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA-dependent
GO	rRNA processing [Amigo] rRNA processing
GO	negative regulation of protein kinase activity [Amigo] negative regulation of protein kinase activity
GO	apoptosis [Amigo] apoptosis
GO	induction of apoptosis [Amigo] induction of apoptosis
GO	induction of apoptosis [Amigo] induction of apoptosis
GO	caspase activation [Amigo] caspase activation
GO	cell cycle arrest [Amigo] cell cycle arrest
GO	negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation
GO	apoptotic mitochondrial changes [Amigo] apoptotic mitochondrial changes
GO	senescence [Amigo] senescence
GO	regulation of G2/M transition of mitotic cell cycle [Amigo] regulation of G2/M transition of mitotic cell cycle
GO	protein kinase binding [Amigo] protein kinase binding
GO	negative regulation of cell growth [Amigo] negative regulation of cell growth
GO	negative regulation of B cell proliferation [Amigo] negative regulation of B cell proliferation
GO	regulation of protein stability [Amigo] regulation of protein stability
GO	negative regulation of NF-kappaB transcription factor activity [Amigo] negative regulation of NF-kappaB transcription factor activity
GO	negative regulation of immature T cell proliferation in the thymus [Amigo] negative regulation of immature T cell proliferation in the thymus
GO	negative regulation of phosphorylation [Amigo] negative regulation of phosphorylation
GO	negative regulation of cyclin-dependent protein kinase activity [Amigo] negative regulation of cyclin-dependent protein kinase activity
GO	negative regulation of cell cycle [Amigo] negative regulation of cell cycle
GO	somatic stem cell division [Amigo] somatic stem cell division
GO	NF-kappaB binding [Amigo] NF-kappaB binding
GO	negative regulation of ubiquitin-protein ligase activity [Amigo] negative regulation of ubiquitin-protein ligase activity
GO	ubiquitin-protein ligase inhibitor activity [Amigo] ubiquitin-protein ligase inhibitor activity
BIOCARTA	Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]
BIOCARTA	Cyclins and Cell Cycle Regulation [Genes]
BIOCARTA	CTCF: First Multivalent Nuclear Factor [Genes]
BIOCARTA	Cell Cycle: G1/S Check Point [Genes]
KEGG	Cell cycle
PubGene	CDKN2A
TreeFam	CDKN2A
CTD	1029 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	CDKN2A Related clones (RZPD - Berlin)
	PubMed
PubMed	499 Pubmed reference(s) in Entrez

Bibliography

Cytogenetic analysis of melanocytes from premalignant nevi and melanomas.

Cowan JM, Halaban R, Francke U

Journal of the National Cancer Institute. 1988 ; 80 (14) : 1159-1164.

PMID 3166071

A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.

Serrano M, Hannon GJ, Beach D

Nature. 1993 ; 366 (6456) : 704-707.

PMID 8259215

A cell cycle regulator potentially involved in genesis of many tumor types.

Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH

Science (New York, N.Y.). 1994 ; 264 (5157) : 436-440.

PMID 8153634

Germline p16 mutations in familial melanoma.

Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC

Nature genetics. 1994 ; 8 (1) : 15-21.

PMID 7987387

Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.

Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ

Genes, chromosomes & cancer. 1995 ; 14 (3) : 189-195.

PMID 8589035

Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.

Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W

Nature genetics. 1995 ; 11 (2) : 210-212.

PMID 7550353

Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition.

Koh J, Enders GH, Dynlacht BD, Harlow E

Nature. 1995 ; 375 (6531) : 506-510.

PMID 7777061

Methylation and p16: suppressing the suppressor.

Little M, Wainwright B

Nature medicine. 1995 ; 1 (7) : 633-634.

PMID 7585141

5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.

Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D

Nature medicine. 1995 ; 1 (7) : 686-692.

PMID 7585152

Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.

Quelle DE, Zindy F, Ashmun RA, Sherr CJ

Cell. 1995 ; 83 (6) : 993-1000.

PMID 8521522

Complex structure and regulation of the P16 (MTS1) locus.

Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A

Cancer research. 1995 ; 55 (14) : 2988-2994.

PMID 7606716

Role of the INK4a locus in tumor suppression and cell mortality.

Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA

Cell. 1996 ; 85 (1) : 27-37.

PMID 8620534

The CDKN2A (p16) gene and human cancer.

Foulkes WD, Flanders TY, Pollock PM, Hayward NK

Molecular medicine (Cambridge, Mass.). 1997 ; 3 (1) : 5-20.

PMID 9132280

Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF.

Quelle DE, Cheng M, Ashmun RA, Sherr CJ

Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (2) : 669-673.

PMID 9012842

Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice.

Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A

Nature. 2001 ; 413 (6851) : 83-86.

PMID 11544530

Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.

Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA

Nature. 2001 ; 413 (6851) : 86-91.

PMID 11544531

The INK4a/ARF locus and melanoma.

Sharpless E, Chin L

Oncogene. 2003 ; 22 (20) : 3092-3098.

PMID 12789286

FAMMM syndrome: pathogenesis and management.

Czajkowski R, Placek W, Drewa G, Czajkowska A, Ucha��ska G

Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2004 ; 30 (2 Pt 2) : 291-296.

PMID 14871223

Ink4a/Arf expression is a biomarker of aging.

Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE

The Journal of clinical investigation. 2004 ; 114 (9) : 1299-1307.

PMID 15520862

Oncogenic activity of Cdc6 through repression of the INK4/ARF locus.

Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M

Nature. 2006 ; 440 (7084) : 702-706.

PMID 16572177

p16INK4a induces an age-dependent decline in islet regenerative potential.

Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE

Nature. 2006 ; 443 (7110) : 453-457.

PMID 16957737

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Search in all EBI NCBI

Contributor(s)

Written 08-2004 Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire

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

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

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

Citation

This paper should be referenced as such :
Saffroy R, Lemoine A, Debuire B . CDKN2a, cyclin dependent kinase 2a / p16. Atlas Genet Cytogenet Oncol Haematol. August 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/CDKN2aID146.html

Saffroy R, Lemoine A, Debuire B . CDKN2a, cyclin dependent kinase 2a / p16. Atlas Genet Cytogenet Oncol Haematol. August 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/CDKN2aID146.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Dec 6 17:54:38 2008

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us
jlhuret@AtlasGeneticsOncology.org.

Other names	CDKN2a
	p16
	INK4
	p16- INK4a
	TP16
	CDK4I
	MTS1
HGNC	CDKN2A
Location	9p21.3
Location_base_pair	Starts at 21957751 and ends at 21965038 bp from pter ( according to hg18-Mar_2006).

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.

Entity	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	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	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	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.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	08-2004	Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
		Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France
Updated	08-2007	Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
		Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France