2021 Theses Doctoral

A p53-independent role for MDM2-MDMX in cell cycle progression

Klein, Alyssa Michelle

Mutation or loss of p53 is the most common genetic lesion in human cancers, with simultaneous loss-of-function and gain-of-function pro-oncogenic effects. Because of its critical importance in several processes, including cell cycle arrest and apoptosis, p53 is highly regulated by multiple mechanisms, most certifiably by the MDM2-MDMX heterodimer. The role of MDM2-MDMX in cell cycle regulation through inhibition of p53 has been well-established. In this thesis, I report that loss of either endogenous MDM2 or MDMX, or specifically blocking E3 ligase activity of the heterocomplex, causes a cell cycle arrest independent of p53 expression or mutational status. This arrest is not mediated by activation of the pRb family, but instead is correlated with reduction in E2F1, E2F3, and p73 levels—the latter of which is a p53 family member known to be involved in cell cycle arrest. Remarkably, direct ablation of endogenous p73 produces a similar effect on cell cycle and reduces E2F levels as downregulation of MDM2- MDMX. These data indicate that MDM2 and MDMX, working at least in part as a hetero- complex, play a p53-independent role in cell cycle progression by promoting the activity of E2F family members and p73, making it a potential target of interest in cancers that lack wild-type p53.