Mdm2 promotes the rapid degradation of p53

Abstract

The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress¹. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins^1,2. The Mdm2 oncoprotein is a potent inhibitor of p53 (ref. 3). Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes^3,4 and to exert antiproliferative effects^4–7. On the other hand, p53 activates the expression of the mdm2 gene¹ in an autoregulatory feedback loop³. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects⁸. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.