p16INK4a (CDKN2A)
p16^INK4a, encoded by CDKN2A, is a cyclin-dependent kinase inhibitor that blocks the CDK4/6 kinases, keeping RB active and arresting the cell cycle in G1.
Function
p16 binds CDK4 and CDK6 and prevents their activation by cyclin D, so RB stays hypophosphorylated and E2F stays repressed - the G1/S transition stays closed. The CDKN2A locus is unusual in encoding two unrelated proteins from the same stretch of DNA using alternative reading frames: p16^INK4a and p14ARF, with p16 acting on the RB axis and ARF on the p53 axis via MDM2. p16 expression rises steeply with age in most human tissues, and the accumulated p16-positive cells are the hallmark of cellular senescence in vivo.
In cancer
CDKN2A is among the most frequently inactivated loci in human cancer - deleted, methylated, or point-mutated in melanoma, pancreatic cancer, glioma, and many others. Germline CDKN2A mutations cause familial atypical mole and melanoma syndrome. Because the locus contains two suppressors on one stretch of DNA, a single deletion disables both the RB and p53 arms of the checkpoint, which is one reason the locus is hit so often.
Notes
- Human gene symbol: CDKN2A; UniProt P42771 (p16); 156 amino acids; four ankyrin repeats.
- p16 is a clinical biomarker of senescent cell burden and the target of the CDK4/6 inhibitor drug class.