P16INK4a

p16INK4A is a tumor suppressor protein encoded by the CDKN2A gene in humans. It is commonly referred to as p16 and is produced from the INK4A transcript within the CDKN2A locus on chromosome 9p21. The locus also gives rise to another tumor suppressor, p14ARF (p19 in mice), via an alternative reading frame. p16INK4A is a relatively small protein, typically described as around 150 amino acids, and is part of the INK4 family of cyclin-dependent kinase inhibitors.

Function and mechanism: p16INK4A binds selectively to cyclin-dependent kinases 4 and 6 (CDK4/CDK6), inhibiting their kinase activity. This prevents phosphorylation of the retinoblastoma (Rb) protein, keeping Rb active and enforcing a G1 cell cycle arrest. Through this action, p16INK4A acts as a brake on cell proliferation and contributes to cellular senescence and protection against oncogenic transformation. The protein is predominantly localized in the nucleus, with reports of cytoplasmic distribution in some contexts.

Clinical and biological significance: In many cancers, p16INK4A is inactivated by homozygous deletions, point mutations, or epigenetic silencing of CDKN2A. Loss of p16INK4A function is a frequent event in melanoma, pancreatic cancer, glioblastoma, and other malignancies, and germline mutations in CDKN2A confer predisposition to familial melanoma. Conversely, expression of p16INK4A increases during replicative and oncogene-induced senescence, serving as a biomarker of cellular aging.

Therapeutic context: The p16INK4A pathway is functionally related to CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib, which target the same cell cycle axis. p16INK4A status can influence prognosis and therapeutic response in certain cancers.