Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage.

The principal regulator of p53 stability is HDM2, an E3 ligase mediating p53 degradation via the ubiquitin-26S proteasome pathway. Until recently, the accepted model held that p53 degradation occurs exclusively on cytoplasmic proteasomes, with an absolute requirement for nuclear export of p53 via the CRM1 pathway. However, 26S proteasomes are abundant in cytosol and nucleus.

Analysis of nuclear and cytoplasmic degradation of p53 in cells after stress.

Until recently, the accepted model held that p53 degradation occurs exclusively on cytoplasmic proteasomes and, hence, has an absolute requirement for nuclear export of p53 via the CRM1 pathway. However, proteasomes are abundant in both cytosol and nucleus. We recently analyzed HDM2-mediated degradation of endogenous p53 in the presence of various CRM1 blockers.

DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors.

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH(2) terminally truncated isoform.