ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

被引：0
作者：
Jer-Yen Yang
Cong S. Zong
Weiya Xia
Hirohito Yamaguchi
Qingqing Ding
Xiaoming Xie
Jing-Yu Lang
Chien-Chen Lai
Chun-Ju Chang
Wei-Chien Huang
Hsin Huang
Hsu-Ping Kuo
Dung-Fang Lee
Long-Yuan Li
Huang-Chun Lien
Xiaoyun Cheng
King-Jen Chang
Chwan-Deng Hsiao
Fuu-Jen Tsai
Chang-Hai Tsai
Aysegul A. Sahin
William J. Muller
Gordon B. Mills
Dihua Yu
Gabriel N. Hortobagyi
Mien-Chie Hung
机构：
[1] The University of Texas M. D. Anderson Cancer Center,Department of Molecular and Cellular Oncology
[2] Graduate School of Biomedical Sciences,Department of Internal Medicine, Division of Infectious Diseases
[3] The University of Texas,Department of Pathology and College of Medicine
[4] China Medical University Hospital,Department of Surgery
[5] The University of California,Department of Pathology
[6] Asian University,Departments of Medicine and Biochemistry
[7] and Angiogenesis Research Center,Department of Systems Biology
[8] National Taiwan University,Department of Breast Medical Oncology
[9] College of Medicine,undefined
[10] and Angiogenesis Research Center,undefined
[11] National Taiwan University,undefined
[12] Institute of Molecular Biology,undefined
[13] Academia Sinica,undefined
[14] The University of Texas M. D. Anderson Cancer Center,undefined
[15] McGill University,undefined
[16] The University of Texas M. D. Anderson Cancer Center,undefined
[17] The University of Texas M. D. Anderson Cancer Center,undefined
来源：
Nature Cell Biology | 2008年 / 10卷
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摘要：
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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页码：138 / 148
页数：10
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