p53 regulation by post-translational modification and nuclear retention inresponse to diverse stresses

p53 activation by diverse stresses involves post-translational modification s that alter its structure and result in its nuclear accumulation. We will discuss several unresolved topics regarding p53 regulation which are curren tly under investigation. DNA damage is perhaps the best-studied stress whic h activates p53, and recent data implicate phosphorylation at N-terminal se rine residues as critical in this process. We discuss recent data regarding the potential kinases which modify p53 and the possible role of the result ing phosphorylation events. By contrast, much less is understood about agen ts which disrupt the mitotic spindle, The cell cycle phase, induction signa l, and biochemical mechanism of the reversible arrest induced by microtubul e disruption are currently under investigation. Finally, a key event in res ponse to any genotoxic stress is the accumulation of p53 in the nucleus. Th e factors which determine the steady state level of p53 are starting to be elucidated, but the mechanisms responsible for nuclear accumulation and nuc lear export remain controversial. We discuss new studies revealing a mechan ism for nuclear retention of p53, and the potential contributions of MDM2 t o this process.