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

Nature Communications volume 4, Article number: 2996 (2013) | Download Citation

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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Acknowledgements

W.H. is supported by National Institutes of Health (NIH) Grant 1R01CA160558-01, Department of Defence Grant W81XWH-10-1-0435, the Ellison Foundation, and the New Investigator Award of Rutgers Cancer Institute of New Jersey. Z.F. is supported by NIH Grant 1R01CA143204-01. We thank Dr Arnold Levine and Dr Mushui Dai for helpful discussion.

Author information

Author notes

    • Tongsen Zheng
    • , Jiabei Wang
    •  & Yuhan Zhao

    These authors contributed equally to this work

Affiliations

  1. Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08903, USA

    • Tongsen Zheng
    • , Jiabei Wang
    • , Yuhan Zhao
    • , Haiyang Yu
    •  & Wenwei Hu
  2. Key laboratory of Hepatosplenic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150086, China

    • Tongsen Zheng
    • , Jiabei Wang
    •  & Lianxin Liu
  3. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08903, USA

    • Yuhan Zhao
    • , Cen Zhang
    • , Meihua Lin
    • , Xiaowen Wang
    • , Haiyang Yu
    • , Zhaohui Feng
    •  & Wenwei Hu
  4. Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey 08903, USA

    • Wenwei Hu

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Contributions

W.H., L.L. and Z.F. directed the project. Z.F.and W.H. designed the experiments. T.Z., J.W., Y.Z., C.Z., M.L., X.W., H. Y., L.L., Z.F. and W.H. performed the experiments. Z.F., L.L. W.H. analysed the data. Z.F. and W.H. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lianxin Liu or Zhaohui Feng or Wenwei Hu.

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DOI

https://doi.org/10.1038/ncomms3996

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