Downregulation of MDM2 stabilizes p53 by inhibiting p53 ubiquitination in response to specific alkylating agents

p53 is stabilized in response to DNA damaging stress. This stabilization is thought to result from phosphorylation in the N-terminus of p53, which inh ibits p53:MDM2 binding, and prevents MDM2 from promoting p53 ubiquitination . In this report, the DNA alkylating agents mitomycin C (MMC) and methylmet hane sulfonate (MMS), as well as UV radiation. stabilized p53 in a manner i ndependent of phosphorylation in p53 N-terminus. This stabilization coincid ed with decreased levels of MDM2 mRNA and protein, and a corresponding decr ease in p53 ubiquitination, Importantly, MDM2 overexpression inhibited the stabilization of p53 and decrease in ubiquitination following MMC, MMS, and UV treatment. This indicates that down-regulation of MDM2 contributes to t he stabilization of p53 in response to these agents. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rig hts reserved.