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Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

Oncogene volume 26, pages 7355–7362 (2007)Cite this article

Abstract

The 14-3-3σ, upregulated by p53 in response to DNA damage, can have a positive-feedback impact driving p53 activities and is a human cancer epithelial marker downregulated in various tumors. However, the precise roles of 14-3-3σ during tumorigenesis are not well characterized. Here, we show that 14-3-3σ is a critical regulator of murine double minute oncogene (MDM2). 14-3-3σ interacts with MDM2 at the RING domain. The C-terminal region of 14-3-3σ binds to MDM2 very efficiently. Importantly, 14-3-3σ overexpression leads to destabilization of MDM2 through enhancing MDM2 self-ubiquitination and accelerating turnover rate. Conversely, loss of 14-3-3σ results in a significant increase in MDM2 protein. Moreover, live-cell images indicated that 14-3-3σ can affect the location of MDM2 from the nucleus to the cytoplasm, and that MDM2-mediated cytoplasmic localization of p53 can be reversed by the presence of 14-3-3σ. Significantly, we further showed that 14-3-3σ causes MDM2 downregulation, thereby stabilizing p53 and inhibiting tumor growth in animal tumors. Also, 14-3-3σ blocks MDM2-mediated retinoblastoma degradation and p53 NEDDylation. Our results provide evidence that 14-3-3σ is a pivotal MDM2 regulator involved in blocking a variety of activities of MDM2.

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Acknowledgements

We thank Drs Vogelstein, Zhang, Kamitani, Shenoy, Wahl and Maki for valuable reagents, and Bill Spohn for live-cell imaging help. This work was supported in part by the NIHRO1CA (089266) and Cancer Center Core Grant (CA16672).

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H-Y Yang, Y-Y Wen, Y-l Lin, L Pham, C-H Su & M-H Lee

  2. Programs in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    Y-Y Wen, C-H Su & M-H Lee

  3. Programs in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    M-H Lee

  4. Department of Pathophysiology, Zhongshan University, Guangzhou, China

    H Yang

  5. H Lee Moffitt Cancer Center, Tampa, FL, USA

    J Chen

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  1. H-Y Yang
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Correspondence to M-H Lee.

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Yang, HY., Wen, YY., Lin, Yl. et al. Roles for negative cell regulator 14-3-3σ in control of MDM2 activities. Oncogene 26, 7355–7362 (2007). https://doi.org/10.1038/sj.onc.1210540

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