MDM2 EXPRESSION IS INDUCED BY WILD TYPE-P53 ACTIVITY

We have recently characterized a 95 kDa protein, p95, which exhibits enhanced binding to temperature-sensitive p53 (ts-p53) when cells are shifted down to 32.5-degrees-C, a temperature at which ts-p53 possesses wild-type (wt)-like activities. In the present study we show that p95 is a product of the mdm2 putative proto-oncogene. The enhanced complex formation of mdm2 with ts-p53 in cells maintained at 32.5-degrees-C is due to an elevation in total mdm2 protein levels following the temperature shift. We further demonstrate that the induction of mdm2 expression by wt p53 activity is at the mRNA level. The induction occurs with very rapid kinetics and does not require de novo protein synthesis, suggesting a direct involvement of p53 in the process. Based on these data and on recent findings implicating p53 as a transcription factor, we suggest that the mdm2 gene is a target for activation by wt p53. In view of the ability of mdm2 to act as a specific antagonist of p53 activity, this induction process may serve to tightly autoregulate p53 activity in living cells.