Unlocking the Mdm2-p53 loop - Ubiquitin is the key

For more than a decade, Mdm2 has been believed to regulate p53 primarily through two mechanisms: by masking p53' s access to transcriptional machinery, and by ubiquitinating p53, targeting it for proteasomal degradation. This dogma was recently challenged by data generated from knockin mice in which Mdm2' s RING E3 ubiquitin ligase activity was abrogated by a single point mutation. The RING mutant Mdm2 is fully capable of binding with p53, yet cannot suppress p53 activity, suggesting that Mdm2 cannot block p53 by binding alone without ubiquitination. Data from the RING knockin mice also revealed that endogenous Mdm2 does not, as previously thought, regulate its own stability by self-ubiquitination. In this review, we discuss these findings and their relevance to the field, including potential reasons for the discrepancies between previous data and that generated by our knockin mice, as well as the feasibility of targeting Mdm2' s E3 ubiquitin ligase activity in cancer. We also discuss additional research questions that may be addressed using our mouse model.