Genes Dev.-2021-Humpton-117-32 (1).pdf (9.77 MB)

Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice.

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posted on 12.01.2021, 13:12 by Timothy J Humpton, Koji Nomura, Julia Weber, Helge M Magnussen, Andreas K Hock, Colin Nixon, Sandeep Dhayade, David Stevenson, Danny T Huang, Douglas Strathdee, Karen Blyth, Karen H Vousden
The p53 tumor suppressor protein is a potent activator of proliferative arrest and cell death. In normal cells, this pathway is restrained by p53 protein degradation mediated by the E3-ubiquitin ligase activity of MDM2. Oncogenic stress releases p53 from MDM2 control, so activating the p53 response. However, many tumors that retain wild-type p53 inappropriately maintain the MDM2-p53 regulatory loop in order to continuously suppress p53 activity. We have shown previously that single point mutations in the human MDM2 RING finger domain prevent the interaction of MDM2 with the E2/ubiquitin complex, resulting in the loss of MDM2's E3 activity without preventing p53 binding. Here, we show that an analogous mouse MDM2 mutant (MDM2 I438K) restrains p53 sufficiently for normal growth but exhibits an enhanced stress response in vitro. In vivo, constitutive expression of MDM2 I438K leads to embryonic lethality that is rescued by p53 deletion, suggesting MDM2 I438K is not able to adequately control p53 function through development. However, the switch to I438K expression is tolerated in adult mice, sparing normal cells but allowing for an enhanced p53 response to DNA damage. Viewed as a proof of principle model for therapeutic development, our findings support an approach that would inhibit MDM2 E3 activity without preventing MDM2/p53 binding as a promising avenue for development of compounds to activate p53 in tumors with reduced on-target toxicities.

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Cancer Research UK (Grant ID: C596/A26855, Grant title: CRUK C596/A26855) Crick (Grant ID: 10557, Grant title: Vousden FC001557)

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