Open AccessMDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53
Author(s) -
Alyssa Klein,
Lynn Biderman,
David Tong,
Bita Alaghebandan,
Sakina A. Plumber,
Helen S. Mueller,
Anne van Vlimmeren,
Chen Katz,
Carol Prives
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2102420118
Subject(s) - mdmx , cell cycle , cell cycle checkpoint , mdm2 , biology , e2f , ubiquitin ligase , microbiology and biotechnology , cancer research , cdc25a , cell growth , cell cycle protein , carcinogenesis , cell , apoptosis , ubiquitin , cancer , genetics , gene
The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2-Murine Double Minute X (MDM2-MDMX) heterodimer. The role of MDM2-MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.