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Retinoblastoma protein modulates gankyrin–MDM2 in regulation of p53 stability and chemosensitivity in cancer cells

Oncogene volume 27, pages 4034–4043 (2008)Cite this article

Abstract

MDM2 is a key ubiquitin E3 ligase for p53 and its activity is critically regulated by a set of modulators, including ARF, p300, YY1 and recently by gankyrin, an oncoprotein frequently overexpressed in human heptocellular carcinomas. We have previously shown that MDM2 binds to and promotes retinoblastoma protein (Rb) degradation. Here we show that Rb inhibits MDM2 E3 ligase activity resulting in stabilization of p53. In addition, we demonstrated that Rb inhibits MDM2-mediated p53 ubiquitination in a gankyrin-dependent manner and the Rb–gankyrin interaction is critical for Rb-induced p53 stabilization. Furthermore, acute ablation of Rb facilitates gankyrin-mediated p53 destabilization, and desensitizes cancer cells for chemotherapy-induced apoptosis. These results indicate that Rb antagonizes gankyrin to inhibit MDM2-mediate p53 ubiquitination in cancer cells and suggest that the status of both p53 and Rb is important for efficacy of cancer chemotherapy.

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Acknowledgements

We thank Dr Yang Shi, Dr Nick Dyson and Dr Steve Grossman for plasmids. We are grateful to many stimulating discussions from members of Xiao's group. This work was supported by NIH grants CA79804 and GM70017 to ZX X.

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Author notes

  1. C-Y Chen

    Present address: 6Current address: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.,

Authors and Affiliations

  1. Department of Medicine, Graduate Program in Molecular Medicine, Boston University School of Medicine, Boston, MA, USA

    W Qiu & Z-Xj Xiao

  2. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    W Qiu, J Wu, E M Walsh & Z-Xj Xiao

  3. Department of Medicine, The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA

    Y Zhang

  4. Department of Pathology, Boston University School of Medicine, Boston, MA, USA

    C-Y Chen

  5. Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Shogoin Kawaharacho, Sakyo-Ku, Kyoto, Japan

    J Fujita

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  1. W Qiu
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Correspondence to Z-Xj Xiao.

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Qiu, W., Wu, J., Walsh, E. et al. Retinoblastoma protein modulates gankyrin–MDM2 in regulation of p53 stability and chemosensitivity in cancer cells. Oncogene 27, 4034–4043 (2008). https://doi.org/10.1038/onc.2008.43

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