CDKN2A

The CDKN2A gene, also known as cyclin-dependent kinase inhibitor 2A, is located on human chromosome 9p21.3. This gene plays a crucial role in cell cycle regulation and acts as a tumor suppressor. It produces multiple protein isoforms through alternative splicing and the use of different start codons, including p16INK4a and p14ARF.

The p16INK4a protein inhibits cyclin-dependent kinases CDK4 and CDK6, which are involved in the progression of the cell cycle from the G1 phase to the S phase. By preventing phosphorylation of the retinoblastoma protein (Rb), p16INK4a halts cell division and promotes cell senescence.

The p14ARF protein acts as a tumor suppressor by stabilizing the p53 protein. It does this by inhibiting Mdm2, an E3 ubiquitin ligase that targets p53 for degradation. Stabilized p53 can then trigger cell cycle arrest or apoptosis in response to cellular damage.

Mutations or deletions in the CDKN2A gene are frequently observed in various cancers, including melanoma, pancreatic cancer, and lung cancer. These alterations lead to the loss of its tumor-suppressive functions, allowing for uncontrolled cell proliferation and tumor development. Germline mutations in CDKN2A are associated with an increased risk of developing melanoma and other cancers, highlighting its importance in inherited cancer predisposition syndromes.