Inactivation of Mdm2 restores apoptosis proficiency of cooperativity mutant p53 in vivo

<i>TP53</i> mutations are found in 50% of all cancers and mutated <i>TP53</i> status is considered poor for treatment. However, some <i>TP53</i> mutations exhibit only partial loss-of-function (LOF), meaning they retain residual transcriptional and non-transcriptional activities that are potentially beneficial for therapy. Earlier we have characterized a knock-in mouse model for the partial LOF mutant <i>Trp53^E177R</i> (p53RR). Reduced DNA binding cooperativity of this mutant led to the loss of p53-dependent apoptosis, while p53 functions in cell cycle control, senescence, metabolism, and antioxidant defense remained intact. Concomitantly, tumor suppression was evident but strongly compromised compared to wild-type mice. Here we used the <i>Trp53^E177R</i> mouse as a model to investigate whether residual functions of mutant p53 can be engaged to induce cell death, which is considered the most desirable outcome of tumor therapy. We made use of <i>Mdm2</i> knock-out in developing embryos as a sensitive tool for detecting remaining p53 activities. Genetic ablation of <i>Mdm2</i> led to embryonic lethality in <i>Trp53^E177R/E177R</i> homozygotes at days 9.5–11.5. This effect was not rescued by concomitant p21-knockout, indicating its independence of p21-mediated cell cycle arrest. Instead, immunohistochemical analysis showed widespread apoptosis in tissues of defective embryos accompanied by persistent accumulation of p53RR protein. This led to partial restoration of the mutant’s proficiency in transcriptional induction of the pro-apoptotic genes <i>Bbc3</i> (Puma) and <i>Bax</i>. These data indicate that increased quantity can compensate for qualitative defects of p53 mutants and suggest that Mdm2-targeting (potentially in combination with other drugs) might be effective against cells bearing p53 partial LOF mutants.