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ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Nature Cell Biology volume 10, pages 138–148 (2008)Cite this article

Abstract

The RAS–ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS–ERK and MDM2.

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Figure 1: Erk suppresses FOXO3a stability and induces its nuclear exclusion.
Figure 2: Erk interacts with and phosphorylates FOXO3a in vitro and in vivo.
Figure 3: MDM2 is required for Erk-mediated FOXO3a degradation.
Figure 4: Phosphorylation of FOXO3a by Erk facilitates MDM2-mediated FOXO3a degradation through an ubiquitin-proteasome pathway.
Figure 5: FOXO3a3A, but not FOXO3a3D, inhibits tumorigenesis and induces apoptosis.
Figure 6: ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.

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Acknowledgements

We thank: P. P. Pandolfi, D.-H. Yan, J. Chen, T. Sakai, P. Coffer and A. Toker for providing expression plasmids; G. Lozano for the knockout MEF cells; M. C.-H. Hu for the p-FOXO3a (644) antibodies; Y. Wei, J.-M. Hsu, S. Zhang, J.-F. Lee and C.-T. Chen for technical support; W. Kaelin, M. Van Dyke and D. Sarbasov for critical comments on the manuscript; and J. C. Cheng and the Department of Scientific Publications, M. D. Anderson Cancer Center for editing the manuscript. This work was supported by National Institutes of Health (NIH) grant P01 CA 099031, MDACC SPORE in Breast Cancer CA116199 and The University of Texas M. D. Anderson Cancer Center support grant CA16672, and was partially supported by the National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Foundation, Breast Cancer Research Foundation grant and Kadoorie Charitable Foundations.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Jer-Yen Yang, Cong S. Zong, Weiya Xia, Hirohito Yamaguchi, Qingqing Ding, Xiaoming Xie, Jing-Yu Lang, Chun-Ju Chang, Wei-Chien Huang, Hsu-Ping Kuo, Dung-Fang Lee, Xiaoyun Cheng, Dihua Yu & Mien-Chie Hung

  2. Graduate School of Biomedical Sciences, The University of Texas, Houston, 77030, TX, USA

    Jer-Yen Yang, Hsu-Ping Kuo, Dung-Fang Lee, Xiaoyun Cheng, Dihua Yu & Mien-Chie Hung

  3. China Medical University Hospital, Taichung, 404, Taiwan

    Chien-Chen Lai, Long-Yuan Li, Fuu-Jen Tsai, Chang-Hai Tsai & Mien-Chie Hung

  4. Department of Internal Medicine, Division of Infectious Diseases, The University of California, Davis, 95817, CA, USA

    Hsin Huang

  5. Asian University, Taichung, 413, Taiwan

    Long-Yuan Li, Chang-Hai Tsai & Mien-Chie Hung

  6. Department of Pathology and College of Medicine, and Angiogenesis Research Center, National Taiwan University, Taipei, 106, Taiwan

    Huang-Chun Lien

  7. Department of Surgery, College of Medicine, and Angiogenesis Research Center, National Taiwan University, Taipei, 106, Taiwan

    King-Jen Chang

  8. Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan

    Chwan-Deng Hsiao

  9. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Aysegul A. Sahin

  10. Departments of Medicine and Biochemistry, McGill University, Montreal, H3A 1A1, Quebec, Canada

    William J. Muller

  11. Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Gordon B. Mills

  12. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Gabriel N. Hortobagyi

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Contributions

J.-Y.Y. and M.-C.H. designed the experiments and wrote the manuscript. M.-C.H. supervised the research. J.-Y.Y. and C.S.Z. performed most of the experiments. W.X. performed the immunohistochemistry staining and contributed to the results shown in Tables 1 and 2. X.X. and J.-Y.L. performed the animal experiments. H.Y., Q.D., C.-J.C., W.-C.W., H.-P.K., D.-F.L., L.-Y.L., H.-C.L. and X.C. assisted with experiments for the revision of the manuscript. C.-C.L., F.-J.T. and C.-H.T were responsible for the LC-MC/MS data. H.H. performed the statistical analysis. All authors contributed to discussions of the manuscript.

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Correspondence to Mien-Chie Hung.

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Yang, JY., Zong, C., Xia, W. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10, 138–148 (2008). https://doi.org/10.1038/ncb1676

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