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CDKN2A (cyclin dependent kinase 2a / p16)

Identity

Other namesCDKN2a
p16
INK4
p16- INK4a
TP16
CDK4I
MTS1
HGNC (Hugo) CDKN2A
LocusID (NCBI) 1029
Location 9p21.3
Location_base_pair Starts at 21967751 and ends at 21975132 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics

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 (Hugo)CDKN2A   1787
Cards
AtlasCDKN2aID146
Entrez_Gene (NCBI)CDKN2A  1029  cyclin-dependent kinase inhibitor 2A
GeneCards (Weizmann)CDKN2A
Ensembl (Hinxton)ENSG00000147889 [Gene_View]  chr9:21967751-21975132 [Contig_View]  CDKN2A [Vega]
ICGC DataPortalENSG00000147889
cBioPortalCDKN2A
AceView (NCBI)CDKN2A
Genatlas (Paris)CDKN2A
WikiGenes1029
SOURCE (Princeton)NM_000077 NM_001195132 NM_058195 NM_058196 NM_058197
Genomic and cartography
GoldenPath (UCSC)CDKN2A  -  9p21.3   chr9:21967751-21975132 -  9p21   [Description]    (hg19-Feb_2009)
EnsemblCDKN2A - 9p21 [CytoView]
Mapping of homologs : NCBICDKN2A [Mapview]
OMIM155601   155755   600160   606719   
Gene and transcription
Genbank (Entrez)AF115544 AI859822 AJ844636 AL582909 BC015960
RefSeq transcript (Entrez)NM_000077 NM_001195132 NM_058195 NM_058196 NM_058197
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NG_007485 NT_008413 NW_001839149 NW_004929342
Consensus coding sequences : CCDS (NCBI)CDKN2A
Cluster EST : UnigeneHs.512599 [ NCBI ]
CGAP (NCI)Hs.512599
Alternative Splicing : Fast-db (Paris)GSHG0030724
Alternative Splicing GalleryENSG00000147889
Gene ExpressionCDKN2A [ NCBI-GEO ]     CDKN2A [ SEEK ]   CDKN2A [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8N726 (Uniprot)
NextProtQ8N726  [Medical]
With graphics : InterProQ8N726
Splice isoforms : SwissVarQ8N726 (Swissvar)
Domains : Interpro (EBI)Cyclin_kinase-Inhib_2A [organisation]  
Related proteins : CluSTrQ8N726
Domain families : Pfam (Sanger)P19Arf_N (PF07392)   
Domain families : Pfam (NCBI)pfam07392   
DMDM Disease mutations1029
Blocks (Seattle)Q8N726
Human Protein AtlasENSG00000147889 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ8N726
HPRD02542
IPIIPI00942408   IPI00030733   IPI00478390   IPI00001560   
Protein Interaction databases
DIP (DOE-UCLA)Q8N726
IntAct (EBI)Q8N726
FunCoupENSG00000147889
BioGRIDCDKN2A
InParanoidQ8N726
Interologous Interaction database Q8N726
IntegromeDBCDKN2A
STRING (EMBL)CDKN2A
Ontologies - Pathways
Ontology : AmiGOcell cycle checkpoint  G1/S transition of mitotic cell cycle  protein polyubiquitination  mitotic cell cycle  negative regulation of cell-matrix adhesion  p53 binding  DNA binding  cyclin-dependent protein serine/threonine kinase inhibitor activity  protein binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytoplasm  mitochondrion  cytosol  transcription, DNA-templated  rRNA processing  negative regulation of protein kinase activity  activation of cysteine-type endopeptidase activity involved in apoptotic process  cell cycle arrest  cell cycle arrest  Ras protein signal transduction  transcription factor binding  negative regulation of cell proliferation  negative regulation of cell proliferation  apoptotic mitochondrial changes  regulation of G2/M transition of mitotic cell cycle  nuclear body  protein kinase binding  negative regulation of cell growth  negative regulation of B cell proliferation  regulation of protein stability  protein destabilization  negative regulation of NF-kappaB transcription factor activity  negative regulation of immature T cell proliferation in thymus  positive regulation of protein sumoylation  positive regulation of smooth muscle cell apoptotic process  senescence-associated heterochromatin focus  senescence-associated heterochromatin focus assembly  negative regulation of phosphorylation  protein complex  positive regulation of DNA damage response, signal transduction by p53 class mediator  poly(A) RNA binding  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  regulation of protein export from nucleus  somatic stem cell division  protein stabilization  NF-kappaB binding  negative regulation of ubiquitin-protein transferase activity  ubiquitin-protein transferase inhibitor activity  protein K63-linked ubiquitination  positive regulation of cell cycle arrest  cellular senescence  replicative senescence  MDM2/MDM4 family protein binding  regulation of apoptotic DNA fragmentation  positive regulation of macrophage apoptotic process  positive regulation of cellular senescence  
Ontology : EGO-EBIcell cycle checkpoint  G1/S transition of mitotic cell cycle  protein polyubiquitination  mitotic cell cycle  negative regulation of cell-matrix adhesion  p53 binding  DNA binding  cyclin-dependent protein serine/threonine kinase inhibitor activity  protein binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytoplasm  mitochondrion  cytosol  transcription, DNA-templated  rRNA processing  negative regulation of protein kinase activity  activation of cysteine-type endopeptidase activity involved in apoptotic process  cell cycle arrest  cell cycle arrest  Ras protein signal transduction  transcription factor binding  negative regulation of cell proliferation  negative regulation of cell proliferation  apoptotic mitochondrial changes  regulation of G2/M transition of mitotic cell cycle  nuclear body  protein kinase binding  negative regulation of cell growth  negative regulation of B cell proliferation  regulation of protein stability  protein destabilization  negative regulation of NF-kappaB transcription factor activity  negative regulation of immature T cell proliferation in thymus  positive regulation of protein sumoylation  positive regulation of smooth muscle cell apoptotic process  senescence-associated heterochromatin focus  senescence-associated heterochromatin focus assembly  negative regulation of phosphorylation  protein complex  positive regulation of DNA damage response, signal transduction by p53 class mediator  poly(A) RNA binding  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  regulation of protein export from nucleus  somatic stem cell division  protein stabilization  NF-kappaB binding  negative regulation of ubiquitin-protein transferase activity  ubiquitin-protein transferase inhibitor activity  protein K63-linked ubiquitination  positive regulation of cell cycle arrest  cellular senescence  replicative senescence  MDM2/MDM4 family protein binding  regulation of apoptotic DNA fragmentation  positive regulation of macrophage apoptotic process  positive regulation of cellular senescence  
Pathways : BIOCARTATumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]    Cyclins and Cell Cycle Regulation [Genes]    CTCF: First Multivalent Nuclear Factor [Genes]    Cell Cycle: G1/S Check Point [Genes]   
Pathways : KEGGCell cycle    p53 signaling pathway    HTLV-I infection    Pathways in cancer    Viral carcinogenesis    MicroRNAs in cancer    Pancreatic cancer    Glioma    Melanoma    Bladder cancer    Chronic myeloid leukemia    Non-small cell lung cancer   
Protein Interaction DatabaseCDKN2A
Wikipedia pathwaysCDKN2A
Gene fusion - rearrangments
Rearrangement : TICdb- [-]  -  CDKN2A [4q12]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CDKN2A
snp3D : Map Gene to Disease1029
SNP (GeneSNP Utah)CDKN2A
SNP : HGBaseCDKN2A
Genetic variants : HAPMAPCDKN2A
Exome VariantCDKN2A
1000_GenomesCDKN2A 
ICGC programENSG00000147889 
Cancer Gene: CensusCDKN2A 
Somatic Mutations in Cancer : COSMICCDKN2A 
CONAN: Copy Number AnalysisCDKN2A 
Mutations and Diseases : HGMDCDKN2A
Genomic VariantsCDKN2A  CDKN2A [DGVbeta]
dbVarCDKN2A
ClinVarCDKN2A
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM155601    155755    600160    606719   
MedgenCDKN2A
GENETestsCDKN2A
Disease Genetic AssociationCDKN2A
Huge Navigator CDKN2A [HugePedia]  CDKN2A [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneCDKN2A
Homology/Alignments : Family Browser (UCSC)CDKN2A
Phylogenetic Trees/Animal Genes : TreeFamCDKN2A
Chemical/Protein Interactions : CTD1029
Chemical/Pharm GKB GenePA106
Drug Sensitivity CDKN2A
Clinical trialCDKN2A
Cancer Resource (Charite)ENSG00000147889
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=CDKN2A
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineCDKN2A
iHOPCDKN2A
OncoSearchCDKN2A

Bibliography

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Contributor(s)

Written08-2004Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France
Updated08-2007Raphael 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. 2008;12(2):89-90.
Free online version   Free pdf version   [Bibliographic record ]
History of this paper:
Saffroy, R ; Lemoine, A ; Debuire, B. CDKN2a (cyclin dependent kinase 2a / p16). Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):89-90.
http://documents.irevues.inist.fr/bitstream/2042/38488/1/08-2007-CDKN2aID146.pdf
URL : http://AtlasGeneticsOncology.org/Genes/CDKN2aID146.html

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indexed on : Wed Jul 30 14:25:16 CEST 2014

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