PRIVES LABORATORY
MDM2, MDMX and p53 protein stability

Research programme 03

MDM2, MDMX and p53 protein stability

We study the regulatory circuitry that keeps wild-type p53 low in unstressed cells while permitting mutant p53 to accumulate in tumours.

Central question

How do MDM2 and MDMX distinguish normal from mutant p53, and can their regulatory interfaces be redirected therapeutically?

MDM2 and MDMX form a central negative-regulatory system for p53. The laboratory examines the biochemical interactions and ubiquitin-ligase mechanisms that govern p53 stability and activity.

The same circuitry behaves differently in mutant-p53 tumours. Understanding how mutant proteins inhibit or escape MDM2 can reveal strategies to destabilise oncogenic p53 while preserving normal stress responses.

p53 immunohistochemistry and fluorescence microscopy showing nuclear and cytoplasmic p53 accumulation and localisation in intestinal tumour cells. Figure 2, Oncogene (2017). Reused unchanged under CC BY 4.0.
p53 immunohistochemistry and fluorescence microscopy showing nuclear and cytoplasmic p53 accumulation and localisation in intestinal tumour cells. Figure 2, Oncogene (2017). Reused unchanged under CC BY 4.0.

Approaches

Ubiquitination and degradation assaysProtein-domain mappingBiophysical interaction studiesChemical and genetic perturbationTumour-cell response profiling

Selected work

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death (2023)Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers (2018)The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain (2015)
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