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FLASH GENE
Symbol CDKN2A contributors: mct/ - updated : 28-02-2015
HGNC name cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
HGNC id 1787
Corresponding disease
CMM2 hereditary malignant melanoma
FAMMMPC familial atypical multiple mole melanoma-pancreatic carcinoma
MNST melanoma-neural system tumor syndrome
Location 9p21.3      Physical location : 21.967.751 - 21.994.490
Synonym name
  • CDK4 inhibitor p16-INK4
  • multiple tumor suppressor 1
  • cell cycle negative regulator beta
  • cyclin-dependent kinase inhibitor p16
  • cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3/4
  • Synonym symbol(s) CDK4I, CDKN2, MTS1, INK4A, P16, P14ARF, ARF, MLM, P14, P19, p19Arf, INK4, TP16, P16INK4, P16INK4A
    DNA
    TYPE functioning gene
    STRUCTURE 26.74 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    Binding site   enhancer   silencer   HRE
    text structure
  • negative regulatory element INK4A transcription silencer element (ITSE ) in the promoter, and positive transcription regulatory element in the GC-rich region (E2F1, E2F3, E2F2 and Sp1-like factors)
  • minimal promoter region required for the transcription factor Sp1 function is mapped at 62 bp upstream of the translation initiation codon ( the region spanning -62 to +1 bp of promoter plays a role in CDKN2A transcription regulation)
  • BMI1-responding element (BRE) within the promoter, and BMI1 bound directly to the BREr of the promoter to repress its expression
  • RB1CC1 activates the expression of CDKN2A through the activation of its promoter
  • MAPPING cloned Y linked N status confirmed
    Map pter - IFNB1 - IFN1@ - D9S736 - MTAP - D9S1749 - D9S974 - D9S1748 - [CDKN2A /D9S942 /D9S1748 ] - D9S1604 - [D9S958 /CDKN2B ] - D9S1870 - D9S171 - D9S265 - D9S126 - D9S259 - D9S975 - D9S976 - D9S978 - cen
    Text see TSG9A
    Physical map
    IFNAP22 9p21 interferon, alpha pseudogene 22 IFNA5 9p22 interferon, alpha 5 KIAA1354 9p22 KIAA1354 protein IFNA6 9p22 interferon, alpha 6 IFNA13 9p22 interferon, alpha 13 IFNA2 9p22 interferon, alpha 2 IFNA8 9p22 interferon, alpha 8 LOC392293 9 similar to Interferon omega-1 precursor (Interferon alpha-II-1) IFNA1 9p22 interferon, alpha 1 LOC392294 9 similar to interferon-alpha IFNT1 9p21.3 interferon tau-1 LOC347217 9p21.3 similar to KH-type splicing regulatory protein (FUSE binding protein 2); KH-type splicing regulatory protein (FUSE-binding protein 2) MTAP 9p22-p21 methylthioadenosine phosphorylase LOC51198 9p21-p22 susceptibility protein NSG-x CDKN2A 9p21.3 cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) CDKN2B 9p21.3 cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) LOC392295 9 similar to ubiquitin A-52 residue ribosomal protein fusion product 1 DMRTA1 9p21.2 DMRT-like family A1
    RNA
    TRANSCRIPTS type messenger
    text
  • two alternative first exon: Alpha and Beta
  • Beta is 12 kb upstream of Alpha
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 - 1267 16.5 156 - 1995 7541708
  • also called P16INK4a or variant 4/isoform 1
  • exons 1A-2-3
  • 3 splicing 1164 - 132 widely 1995 7541708
  • also called variant 4/isoform 4
  • alternative reading frame, starting from exon 1b, deleted in melanoma, neural system tumour sdr
  • exons 1B-2-3
  • also called P14ARF
  • 3 - 1235 12 116 pancreas specific 1995 7541708
    also called p12 or variant 4/isoform 3
    - - 736 - - - 1995 7541708
  • in both methylated and unmethylated cell lines
  • potentially involved in the complex regulation of these critical cell cycle genes
  • - - 1464 - 167 - -
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   moderately
    Digestiveliver   moderately
    Endocrinepancreas   moderately
    Reproductivemale systemprostate  moderately
    Respiratorylung   moderately
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    Lymphoid    
    Nervouscentral   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, interphase, G1
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal 64 AAs encoded by the unique exon 1 (overexpression of the N-terminal half alone is sufficient to activate TP53)
  • four tandemly repeated ankyrin (ANK) motifs
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to rattus Cdkn2a (78.05 pc)
    intraspecies homolog to CDKN2B
    Homologene
    FAMILY
  • CDKN2 cyclin-dependent kinase inhibitor family
  • CATEGORY enzyme , regulatory , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleolus
    text resides predominantly in the nucleolus
    basic FUNCTION
  • inhibitor of CDK4/CDK6 involved in replicative senescence, cell immortalization, and tumor generation
  • involved in an age-dependent increase in cell cycle negative regulation of the corneal endothelial cells (HCEC)
  • may be responsible, at least in part, for the reduced proliferative response observed in HCECs from older donors
  • contributes to the decline in replicative potential of self-renewing cells during aging, angiogenesis and cell senescence and tumor invasion, cell spreading and apoptosis
  • reducing the interaction between E2F4-p130 repressor complex with the promoter of XPC to ensure high level expression of XPC, thus triggering nucleotide excision repair
  • CDKN2A and CDKN2B play a key role in the control of the G1/S transition of the cell cycle
  • is a modulator of transcription and apoptosis through controlling the expression of two major transcription regulators, HNRNPD and E2F1
  • age-dependent increases of CDKN2A, restrict proliferation of pancreatic beta-cells and other tissues with ageing
  • is a regulator of the ubiquitin system
  • is involved with regulation of several key processes mediated by the ubiquitin system
  • CELLULAR PROCESS cell cycle, checkpoint
    nucleotide, repair, nucleotide excision repair
    PHYSIOLOGICAL PROCESS
    text inducer of cell cycle arrest at G1 and G2/M checkpoint, blocking them from phosphorylating RB1 and preventing exit from G1 phase of the cell cycle
    PATHWAY
    metabolism
    signaling signal transduction
  • RB pathway
  • novel NMI-mediated, transcription-independent CDKN2A induction pathway in response to cellular stresses
  • a component
  • heterodimer with CDK4 or CDK6
  • INTERACTION
    DNA binding
    RNA
    small molecule
    protein
  • sequestering SUMO1-conjugated MDM2 (UBL1) in the nucleus
  • preventing binding to TP53 and/or RB1 which results in p53 activation and cell cycle arrest
  • p14ARF cooperatively activating TP53 with CARF
  • functional link between CDKN2A and ING1
  • expression levels of CDKN2A, CDKN2B, and CDKN2BAS are positively correlated
  • CDKN2A-ZNF420 interaction could be induced or enhanced in response to oncogene activation
  • elevated CDKN2A competed with TP53 to bind to ZNF420, therefore disrupted the ZNF420-TP53 interaction
  • TRADD shuttles dynamically from the cytoplasm into the nucleus to modulate the interaction between CDKN2A and its E3 ubiquitin ligase TRIP12, thereby promoting CDKN2A stability and tumour suppression
  • by binding to the RING domain of RNF2, CDKN2A disrupts RNF2 homodimerization, providing a potential mechanism for its effect on RNF2 self-ubiquitination
  • DLC1 inactivation cooperates with downregulation of CDKN2B and CDKN2A, leading to neoplastic transformation and poor prognosis in cancer
  • MKRN1 functions as a novel E3 ligase of CDKN2A and potentially regulates cellular senescence and tumorigenesis in gastric cancer
  • EEF1A2 as a novel interacting partner CDKN2A, and interaction of CDKN2A with EEF1A2, and subsequent downregulation of the expression and function of EEF1A2 is a novel mechanism explaining the anti-proliferative effects of CDKN2A
  • CARM1 represses replicative senescence by methylating ELAVL1 and thereby enhancing ELAVL1 ability to regulate the turnover of CCNA1, CCNB1, FOS, SIRT1, and CDKN2A mRNAs (
  • CDKN2A stabilizes the CDKN1A mRNA through negative regulation of the mRNA decay-promoting HNRNPD protein
  • control of CD8 T cell proliferation and terminal differentiation by active STAT5B and CDKN2A/CDKN2B
  • CDKN2A plays a previously unrecognized role in downregulating KL expression during ageing
  • VHL/CDKN2A interaction is specifically mediated by the 53 residue long pVHL30 N-terminal region, suggesting that this N-terminus acts as a further VHL interaction interface
  • cell & other
    REGULATION
    repressed by transcriptionally by ID1
    ASSOCIATED DISORDERS
    corresponding disease(s) MNST , CMM2 , FAMMMPC
    related resource Cyclin-dependent kinase inhibitor A
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   deletion    
    in osteosarcomas and Ewing sarcomas, and in cutaneous large cells lymphoma (marker of apparition and progression), homozygously deleted in any neuroblastomas and in bladder cancer
    tumoral   LOH    
    in esophageal squamous cell carcinoma (concomitant loss of RB or not) and in hepatocellular carcinoma
    tumoral       loss of function
    inactivated by hypermethylation in non small cell lung carcinoma of non-smoker, in melanoma and in pancreas carcinoma
    tumoral       gain of function
    activated by hypomethylation in breast cancer
    tumoral       loss of function
    loss of function or deletion in ovarian granulosa cell
    tumoral   deletion    
    -mutated or deleted in non in small cell lung carcinoma of smoker,in squamous cell carcinoma of the skin and esophagus, in vulval squamous neoplasia and in colorectal cancer
    tumoral germinal mutation deletion    
    in melanoma
    tumoral   deletion    
    with hypermethylation of CpG islands, in acute lymphoblastic leukemia (ALL)
    tumoral   deletion    
    minimal common deleted region removing CDKN2A exon 1 and CDKN2B exon 2 in diffuse large B-cell lymphomas
    tumoral     --low  
    by promoter methylation may be closely implicated in the pathogenesis of multiple myeloma (MM)
    Susceptibility
  • to multiple myeloma, familial uveal and cutaneous melanoma, breast cancer
  • to pancreatic cancer
  • to myocardial infarction
  • to acute lymphoblastic leukemia
  • to type 2 diabetes
  • Variant & Polymorphism SNP , other
  • germline mutation implicated in the susceptibility to multiple myeloma and in familial uveal
  • variant A148T predisposing to breast cancer and cutaneous melanoma
  • common variation (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk
  • increasing the risk of myocardial infarction
  • significant contribution of CDKN2A/B gene rs10811661 to type 2 diabetes
  • Candidate gene
  • for sensitive detection in plasma or serum of cancer (bladder, breast, colorectal, gastric, liver, lung) by DNA methylation markers
  • Marker
    Therapy target
    ANIMAL & CELL MODELS