Aliases for CDKN2A Gene
- Cyclin Dependent Kinase Inhibitor 2A 2 3 5
- Cyclin-Dependent Kinase Inhibitor 2A (Melanoma, P16, Inhibits CDK4) 2 3
- Cyclin-Dependent Kinase 4 Inhibitor A 3 4
- Cyclin-Dependent Kinase Inhibitor 2A 3 4
- Multiple Tumor Suppressor 1 3 4
- Alternative Reading Frame 3 4
- P16INK4A 3 4
- P14ARF 3 4
- CDKN2 3 4
- CDK4I 3 4
- MTS-1 3 4
- MTS1 3 4
- MLM 3 4
- ARF 3 4
External Ids for CDKN2A Gene
Previous HGNC Symbols for CDKN2A Gene
Previous GeneCards Identifiers for CDKN2A Gene
This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
CDKN2A loss has been shown to be a significant event in a number of cancer types. While no targeted therapeutic has been engaged in clinical trials, the prognostic impact has been studied by a number of meta-analyses. In majority of cases CDKN2A is inactivated by homozygous deletions. One of the mechanisms by which loss of CDKN2A can occur is by hypermethylation of the promoter region for the gene. However, the prognostic impact of promoter hypermethylation has been relatively ambiguous. Many studies have suggesting poorer prognostic outcome for patients with hypermethylation in colorectal, liver, and younger lung cancer patients. This being said, there is still research to be done before this becomes a widely-accepted prognostic indicator. Additionally, CDKN2A (p16) expression is a surrogate marker for HPV infection. As such, CDKN2A expression is prognostic in Oropharyngeal and probably also non-oropharyngeal head and neck squamous cell carcinomas.
GeneCards Summary for CDKN2A Gene
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) is a Protein Coding gene. Diseases associated with CDKN2A include Melanoma-Pancreatic Cancer Syndrome and Melanoma, Cutaneous Malignant 2. Among its related pathways are Metabolism of proteins and ERK Signaling. Gene Ontology (GO) annotations related to this gene include transcription factor binding. An important paralog of this gene is CDKN2B.
UniProtKB/Swiss-Prot Summary for CDKN2A Gene
Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform smARF may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.
Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.