P300 MDM2 COMPLEXES PARTICIPATE IN MDM2-MEDIATED P53 DEGRADATION/

Control of p53 turnover is critical to p53 function. E1A binding to p3 00/CBP translates into enhanced p53 stability, implying that these coa ctivator proteins normally operate in p53 turnover control. In this re gard, the p300 C/H1 region serves as a specific in vivo binding site f or both p53 and MDM2, a naturally occurring p53 destabilizer. Moreover , most of the endogenous MDM2 is bound to p300, and genetic analysis i mplies that specific interactions of p53 and MDM2 with p300 C/H1 are i mportant steps in the MDM2-directed turnover of p53. A specific role f or p300 in endogenous p53 degradation is underscored by the p53-stabil izing effect of overproducing the p300 C/H1 domain. Taken together, th e data indicate that specific interactions between p300/CBP C/H1, p53, and MDM2 are intimately involved in the MDM2-mediated control of p53 abundance.