MDM2 suppresses p73 function without promoting p73 degradation

The newly identified p53 homolog p73 can mimic the transcriptional activati on function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo a nd in vitro. Wild-type but not mutant MDM2, expressed in human p53 null ost eosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driv en by the MDM2 promoter-derived p53RE motif as measured in transient-transf ection and chloramphenicol acetyltransferase assays and also inhibited p73- induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 d id not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73 alpha and p73 beta stimulated the expres sion of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activ ated by p73 and, in turn, negatively regulates the function of this activat or through a mechanism distinct from that used for p53 inactivation.