CDKN2A

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.

Cyclin Dependent Kinase Inhibitor 2A

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.

Cell cycle arrest Source: BHF-UCL
Cellular senescence Source: BHF-UCL
G1/S transition of mitotic cell cycle Source: BHF-UCL
Negative regulation of cell growth Source: BHF-UCL
Negative regulation of cell-matrix adhesion Source: BHF-UCL
Negative regulation of cell population proliferation Source: BHF-UCL
Negative regulation of cyclin-dependent protein serine/threonine kinase activity Source: BHF-UCL
Negative regulation of G1/S transition of mitotic cell cycle Source: Reactome
Negative regulation of NF-kappaB transcription factor activity Source: BHF-UCL
Negative regulation of phosphorylation Source: BHF-UCL
Negative regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of cellular senescence Source: UniProtKB
Positive regulation of macrophage apoptotic process Source: BHF-UCL
Positive regulation of smooth muscle cell apoptotic process Source: BHF-UCL
Ras protein signal transduction Source: BHF-UCL
Regulation of transcription initiation from RNA polymerase II promoter Source: Reactome
Replicative senescence Source: BHF-UCL
Senescence-associated heterochromatin focus assembly Source: UniProtKB

Nucleus; Cytoplasm

The association between cutaneous and uveal melanomas in some families suggests that mutations in CDKN2A may account for a proportion of uveal melanomas. However, CDKN2A mutations are rarely found in uveal melanoma patients.
Melanoma, cutaneous malignant 2 (CMM2): A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites.
Familial atypical multiple mole melanoma-pancreatic carcinoma syndrome (FAMMMPC): An inherited cancer predisposition syndrome characterized by an increased risk of developing malignant melanoma and/or pancreatic cancer. Mutation carriers within families may develop either or both types of cancer.
Melanoma-astrocytoma syndrome (MASTS): Characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.

Phosphorylation seems to increase interaction with CDK4.