A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network

Summary chanisms by which Mdm2 and Mdm4 (MdmX) regulate p53 remain controversial. We generated a mouse encoding p53 lacking the proline-rich domain (p53ΔP). p53ΔP exhibited increased sensitivity to Mdm2-dependent degradation and decreased transactivation capacity, correlating with deficient cell cycle arrest and reduced apoptotic responses. p53ΔP induced lethality in Mdm2−/− embryos, but not in Mdm4−/− embryos. Mdm4 loss did not alter Mdm2 stability but significantly increased p53ΔP transactivation to partially restore cycle control. In contrast, decreasing Mdm2 levels increased p53ΔP levels without altering p53ΔP transactivation. Thus, Mdm4 regulates p53 activity, while Mdm2 mainly controls p53 stability. Furthermore, Mdm4 loss dramatically improved p53ΔP-mediated suppression of oncogene-induced tumors, emphasizing the importance of targeting Mdm4 in chemotherapies designed to activate p53.