ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

被引：555

作者：

Yang, Jer-Yen ^{[1
,2
]}

Zong, Cong S. ^{[1
]}

Xia, Weiya ^{[1
]}

Yamaguchi, Hirohito ^{[1
]}

Ding, Qingqing ^{[1
]}

Xie, Xiaoming ^{[1
]}

Lang, Jing-Yu ^{[1
]}

Lai, Chien-Chen ^{[3
]}

Chang, Chun-Ju ^{[1
]}

Huang, Wei-Chien ^{[1
]}

Huang, Hsin ^{[1
,4
]}

Kuo, Hsu-Ping ^{[1
,2
]}

Lee, Dung-Fang ^{[1
,2
]}

Li, Long-Yuan ^{[3
,5
]}

Lien, Huang-Chun ^{[6
]}

Cheng, Xiaoyun ^{[1
,2
]}

Chang, King-Jen ^{[7
,8
]}

Hsiao, Chwan-Deng ^{[9
]}

Tsai, Fuu-Jen ^{[3
]}

Tsai, Chang-Hai ^{[3
,5
]}

Sahin, Aysegul A. ^{[10
]}

Muller, William J. ^{[11
,12
]}

Mills, Gordon B. ^{[13
]}

Yu, Dihua ^{[1
,2
]}

Hortobagyi, Gabriel N. ^{[14
]}

Hung, Mien-Chie ^{[1
,2
,3
,5
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA

[3] China Med Univ Hosp, Taichung 404, Taiwan

[4] Univ Calif Davis, Dept Internal Med, Div Infect Dis, Sacramento, CA 95817 USA

[5] Asian Univ, Taichung 413, Taiwan

[6] Natl Taiwan Univ, Dept Pathol, Taipei 106, Taiwan

[7] Natl Taiwan Univ, Coll Med, Dept Surg, Taipei 106, Taiwan

[8] Natl Taiwan Univ, Angiogenesis Res Ctr, Taipei 106, Taiwan

[9] Acad Sinica, Inst Mol Biol, Taipei 115, Taiwan

[10] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[11] McGill Univ, Dept Med, Montreal, PQ H3A 1A1, Canada

[12] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A1, Canada

[13] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA

来源：

NATURE CELL BIOLOGY | 2008年 / 10卷 / 02期

关键词：

D O I：

10.1038/ncb1676

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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.

引用

页码：138 / U22

页数：17

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