Mdm2 and mdmX prevent ASPP1 and ASPP2 from stimulating p53 without targeting p53 for degradation.

Using various mutants of p53 and mdm2, we demonstrate here that both the DNA binding and transactivation function of p53 are required for ASPP1 and ASPP2 to stimulate the apoptotic functions of p53. Mdm2 and mdmx prevent ASPP1 and ASPP2 from stimulating the apoptotic function of p53 by binding and inhibiting the transcriptional activity of p53. Importantly, mdm2 and mdmx can prevent the stimulatory effects of ASPP1 and ASPP2 without targeting p53 for degradation. These data provide a novel mechanism by which mdm2 and mdmx act as potent inhibitors of p53.