Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis

Tongsen Zheng, Jiabei Wang, Yuhan Zhao, Cen Zhang, Meihua Lin, Xiaowen Wang, Haiyang Yu, Lianxin Liu (), Zhaohui Feng () and Wenwei Hu ()
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Tongsen Zheng: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Jiabei Wang: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Yuhan Zhao: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Cen Zhang: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Meihua Lin: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Xiaowen Wang: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Haiyang Yu: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Lianxin Liu: Key laboratory of Hepatosplenic Surgery, The First Affiliated Hospital of Harbin Medical University
Zhaohui Feng: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey
Wenwei Hu: Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3996

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