MDM2 and MDMX bind and stabilize the p53-related protein p73

The p53 gene encodes one of the most important tumor suppressors in human cells and undergoes frequent mutational inactivation in cancers. MDM2, a transcriptional target of p53, binds p53 and can both inhibit p53-mediated transcription [1,2] and target p53 for proteasome-mediated proteolysis [3,4], A close relative of p53, p73, has recently been identified [5,6]. Here, we report that, like p53, p73 alpha and the alternative transcription product p73 beta also bind MDM2, Interaction between MDM2 and p53 represents a key step in the regulation of p53, as MDM2 promotes the degradation of p53. In striking contrast to p53, the half-life of p73 was found to be increased by binding to MDM2, Like MDM2, the MDM2-related protein MDMX also bound p73 and stabilized the level of p73, Moreover, the growth suppression functions of p73 and the induction of endogenous p21, a major mediator of the p53-dependent growth arrest pathway, were enhanced in the presence of MDM2, These differences between the regulation of p53 and p73 by MDM2/MDMX may highlight a physiological difference in their action.