Article abstract
Nature Cell Biology 10, 138 - 148 (2008)
Published online: 20 January 2008 | doi:10.1038/ncb1676
There is an Erratum (March 2008) associated with this Article.
ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation
Jer-Yen Yang1,2, Cong S. Zong1, Weiya Xia1, Hirohito Yamaguchi1, Qingqing Ding1, Xiaoming Xie1, Jing-Yu Lang1, Chien-Chen Lai3, Chun-Ju Chang1, Wei-Chien Huang1, Hsin Huang4, Hsu-Ping Kuo1,2, Dung-Fang Lee1,2, Long-Yuan Li3,5, Huang-Chun Lien6, Xiaoyun Cheng1,2, King-Jen Chang7, Chwan-Deng Hsiao8, Fuu-Jen Tsai3, Chang-Hai Tsai3,5, Aysegul A. Sahin9, William J. Muller10, Gordon B. Mills11, Dihua Yu1,2, Gabriel N. Hortobagyi12 & Mien-Chie Hung1,2,3,5
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.
- Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
- Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
- China Medical University Hospital, Taichung 404, Taiwan.
- Department of Internal Medicine, Division of Infectious Diseases, The University of California, Davis, CA 95817, USA.
- Asian University, Taichung 413, Taiwan.
- Department of Pathology and College of Medicine, and Angiogenesis Research Center, National Taiwan University, Taipei 106, Taiwan.
- Department of Surgery, College of Medicine, and Angiogenesis Research Center, National Taiwan University, Taipei 106, Taiwan.
- Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
- Departments of Medicine and Biochemistry, McGill University, Montreal, Quebec, H3A 1A1, Canada.
- Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Correspondence to: Mien-Chie Hung1,2,3,5 e-mail: mhung@mdanderson.org
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