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Chemotherapy induces NEDP1-mediated destabilization of MDM2

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Abstract

MDM2 is an E3 ligase that promotes ubiquitin-mediated destruction of p53. Cellular stresses such as DNA damage can lead to p53 activation due in part to MDM2 destabilization. Here, we show that the stability of MDM2 is regulated by an ubiquitin-like NEDD8 pathway and identify NEDP1 as a chemotherapy-induced isopeptidase that deneddylates MDM2, resulting in MDM2 destabilization concomitant with p53 activation. Concordantly, RNAi-mediated knockdown of endogenous NEDP1 blocked diminution of MDM2 levels and increased chemoresistance of tumor cells. These findings unveil the regulation of MDM2 stability through NEDP1 as a common molecular determinant governing chemotherapy-induced p53-dependent cell death.

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Acknowledgements

We thank Lynn Cheng, Joanne Lau, Roxana Sufan and Ryan Russell for their technical assistance. We thank Drs Uri Tabori and Loretta Lau for helpful discussions. We thank Drs Stephen Meyn and Paul Bradshaw for providing AT reagents. This work was supported by funds from the Canadian Cancer Society Research Institute (CCSRI 018460 to MO and 018054 to MSI). IRW is a recipient of the Hospital for Sick Children Foundation Student Scholarship and the Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship. OR is a recipient of the CIHR Fellowship. MO and MSI are Canada Research Chairs.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    I R Watson, B K Li, O Roche, M Ohh & M S Irwin

  2. Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada

    I R Watson, B K Li, A Blanch & M S Irwin

  3. Department of Paediatrics and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    M S Irwin

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  1. I R Watson
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  2. B K Li
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  3. O Roche
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  4. A Blanch
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  5. M Ohh
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  6. M S Irwin
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Correspondence to M Ohh or M S Irwin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Watson, I., Li, B., Roche, O. et al. Chemotherapy induces NEDP1-mediated destabilization of MDM2. Oncogene 29, 297–304 (2010). https://doi.org/10.1038/onc.2009.314

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