A potential mechanism for differential regulation of p53 transcriptional activity by wild-type Mdm2 and Mdm2^C462A.

<p>A) Heterodimerization between wild-type Mdm2 and Mdmx is necessary for inhibiting the p53-p300 interaction and suppressing p300-mediated acetylation of p53, reducing p53 activity. B) Absence of Mdm2 permits p300-p53 interaction, allowing p300-mediated acetylation of p53, and thereby enhancing p53 transcriptional activity compared to that in Mdm2-positive cells. C) Mdm2^C462A cannot heterodimerize with Mdmx and, therefore, fails to inhibit the p53-p300 interaction, allowing enhanced p300-mediated acetylation and activation of p53. In addition, monomeric Mdm2 (such as RING mutant Mdm2^C462A) promotes p300-p53 binding to further enhance p300-mediated p53 acetylation beyond that which occurs in Mdm2-null cells.