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Updated: May 4, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis
Tongsen Zheng1,2, Jiabei Wang1,2, Yuhan Zhao1,3
1Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
Abstract:
The tumour suppressor p53 is frequently mutated in tumours. Mutant p53 (Mutp53) proteins often gain new activities in promoting tumorigenesis, defined as gain-of-function (GOF). Mutp53 can accumulate to high levels in tumours, which promotes mutp53 GOF in tumorigenesis. The mechanism of mutp53 accumulation is poorly understood. Here we find that MDM2 isoforms promote mutp53 accumulation in tumours. MDM2 isoform B (MDM2-B), the MDM2 isoform most frequently over-expressed in human tumours, interacts with full-length MDM2 to inhibit MDM2-mediated mutp53 degradation, promoting mutp53 accumulation and GOF in tumorigenesis. Furthermore, MDM2-B overexpression correlates with mutp53 accumulation in human tumours. In mutp53 knock-in mice, a MDM2 isoform similar to human MDM2-B is overexpressed in the majority of tumours, which promotes mutp53 accumulation and tumorigenesis. Thus, overexpression of MDM2 isoforms promotes mutp53 accumulation in tumours, contributing to mutp53 GOF in tumorigenesis. This may be an important mechanism by which MDM2 isoforms promote tumorigenesis.
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