The physiology of p16(INK4A)-mediated G1 proliferative arrest

Abstract

Phosphorylation of the product of the retinoblastoma susceptibility gene (Rb) physiologically inactivates its growth-suppressive properties. Rb phosphorylation is mediated by cyclin-dependent kinases (CDKs), whose activity is enhanced by cyclins and inhibited by CDK inhibitors. p16(INK4A) is a member of a family of inhibitors specific for CDK4 and CDK6. p16(INK4A) is deleted and inactivated in a wide variety of human malignancies, including familial melanomas and pancreatic carcinoma syndromes, indicating that it is an authentic human tumor suppressor. Although one mechanism for its tumor suppression may be prevention of Rb phosphorylation, thereby causing G1 arrest, many normal cell types express p16(INK4A), and are still able to traverse the cell cycle. In a search for other mechanisms, we have found that p16(INK4A) is required for p53-independent G1 arrest in response to DNA-damaging agents, including topoisomerase I and II inhibitors. Thus, like other tumor suppressors, p16(INK4A) plays an essential role in a DNA-damage checkpoint that leads to cell cycle arrest.