Regulation and Function of the Original p53- Inducible p21 Gene

P21 is a well known regulator of cell cycle progression through its inhibitory actions on Cyclin dependent kinases, (Cdk)/cyclin complexes, and DNA replication via its binding to proliferating cell nuclear antigen (PCNA). p21 also has a role in many diverse cellular processes including modulation of apoptosis, regulation of Rho Kinase and modification of cytoskeletal structures, as well as cellular senescence and differentiation.1–6 Due to its multiple and wide ranging effects on key cellular processes, intracellular p21 levels are tightly regulated. p53 is a major transcriptional regulator of p21, and p53-dependent transcription of p21 in response to DNA damage is well characterized. However, p53-independent transcriptional pathways also exist.7 More recently, post-translational mechanisms that influence p21 steady state levels have been identified, including modulation of p21 binding interactions, phosphorylation status, subcellular localization, and trafficking to the proteasome. Post-translational regulation of p21, particularly at its COOH terminus has a significant impact on p21 stability and abundance and therefore is an important determinant of intracellular p21 concentration.