The p53 and Rb pathways. p53 activity is predominantly regulated at the protein level. In the unstressed state, p53 is rapidly degraded by MDM2; a process which is inhibited by ARF. Also, p53 can be stabilized by N-terminal serine phosphorylation in response to genotoxic stresses, and this phosphorylation inhibits its interaction with MDM2. p53 activation potently induces either growth arrest or apoptosis depending on cellular context. The antiproliferative activity of p53 in part results from p21 expression, which is a p53 transcriptional target. Rb is inactivated by phosphorylation as a result of the cyclin-dependent kinases CDK4 and CDK6. Hypophosphorylated Rb binds E2F and represses proliferation. CDK activity is inhibited by both p16^INK4a and p21.