Cyclin-dependent kinase inhibitor 2A (CDKN2A) (CDKN2A)

Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a critical tumor suppressor gene located on chromosome 9p21.3 that encodes two distinct proteins, p16INK4a and p14ARF, through the use of alternative reading frames (Wikipedia, NIH). The p16INK4a protein is a potent inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), maintaining the retinoblastoma (Rb) protein in its growth-suppressive state and thereby enforcing cell cycle arrest at the G1 phase (MedlinePlus, Frontiers). The p14ARF protein functions by sequestering MDM2, which prevents the degradation of the p53 tumor suppressor and facilitates p53-mediated apoptosis or senescence in response to oncogenic stress (Wikipedia, NIH). Inactivation of CDKN2A via homozygous deletion, mutation, or epigenetic silencing is one of the most frequent events in human oncogenesis, particularly in melanoma, pancreatic adenocarcinoma, and glioblastoma (Wikipedia, Cancer.gov). While direct restoration of CDKN2A function is not yet clinically routine, the pathway is a major therapeutic focus; CDK4/6 inhibitors like palbociclib and abemaciclib are used to pharmacologically mimic p16INK4a activity, and DNA methyltransferase inhibitors are investigated for their ability to reverse epigenetic silencing of the gene (ResearchGate, NIH).

Other names

p16p16INK4ap14ARFMTS1CDK4ICDKN2CMM2INK4INK4AMLMMTS-1P14P19P19ARFTP16

CDK4/6 inhibition, DNA demethylation, MDM2 inhibition