ONCOPROTEIN MDM2 CONCEALS THE ACTIVATION DOMAIN OF TUMOR SUPPRESSOR-P53

THE tumour-suppressor gene p53 is inactivated in most human malignanci es1 either by missense mutations1 or by binding to oncogenic proteins2 -4. In human soft tissue sarcomas, inactivation apparently results fro m MDM2 gene amplification4. MDM2 is an oncogene product5,6 that may fu nction by binding to p53 and inhibiting its ability to activate transc ription3 . Here we show that, when expressed in Saccharomyces cerevisi ae, human MDM2 inhibits human p53's ability to stimulate transcription by binding to a region that nearly coincides with the p53 acidic acti vation domain. The isolated p53 activation domain fused to another DNA -binding protein is also inactivated by MDM2, confirming that MDM2 can inhibit p53 function by concealing the activation domain of p53 from the cellular transcription machinery.