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

• DOI: 10.1038/ncomms3996
• Publication Date: 2013-12-20T11:40:23Z
• Authors: Tongsen Zheng; Jiabei Wang; Yuhan Zhao; Cen Zhang; Meihua Lin; Xiaowen Wang; Haiyang Yu; Lianxin Liu; Zhaohui Feng; Wenwei Hu
• Keywords: Male; 0301 basic medicine; Mice, Inbred BALB C; Carcinogenesis; Ubiquitin; Proto-Oncogene Proteins c-mdm2; Article; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Mutation; Animals; Humans; Protein Isoforms; Neoplasm Invasiveness; Neoplasm Metastasis; Tumor Suppressor Protein p53; Colorectal Neoplasms; Neoplasm Transplantation; Protein Binding

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.