MDM2 PROMOTES THE RAPID DEGRADATION OF P53

The p53 tumour-suppressor protein exerts antiproliferative effects, in cluding growth arrest and apoptosis, in response to various types of s tress'. The activity of p53 is abrogated by mutations that occur frequ ently 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 b inds the transcriptional activation domain of p53 and blocks its abili ty to regulate target genes(3,4) and to exert antiproliferative effect s(4-7). On the other hand, p53 activates the expression of the mdm2 ge ne(1) in an autoregulatory feedback loop(3). The interval between p53 activation and consequent Mdm2 accumulation defines a time window duri ng which p53 exerts its effects(8). We now report that Mdm2 also promo tes the rapid degradation of p53 under conditions in which p53 is othe rwise stabilized. This effect of Mdm2 requires binding of p53; moreove r, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amo unts of Mdm2 strongly repress mutant p53 accumulation in tumour-derive d cells. During recovery from DNA damage, maximal Mdm2 induction coinc ides with rapid p53 loss. We propose that the Mdm2-promoted degradatio n of p53 provides a new mechanism to ensure effective termination of t he p53 signal.