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ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Nature Cell Biology, ISSN: 1465-7392, Vol: 10, Issue: 2, Page: 138-148
2008
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Article Description

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.

Bibliographic Details

Yang, Jer-Yen; Zong, Cong S.; Xia, Weiya; Yamaguchi, Hirohito; Ding, Qingqing; Xie, Xiaoming; Lang, Jing-Yu; Lai, Chien-Chen; Chang, Chun-Ju; Huang, Wei-Chien; Huang, Hsin; Kuo, Hsu-Ping; Lee, Dung-Fang; Li, Long-Yuan; Lien, Huang-Chun; Cheng, Xiaoyun; Chang, King-Jen; Hsiao, Chwan-Deng; Tsai, Fuu-Jen; Tsai, Chang-Hai; Sahin, Aysegul A.; Muller, William J.; Mills, Gordon B.; Yu, Dihua; Hortobagyi, Gabriel N.; Hung, Mien-Chie

Springer Science and Business Media LLC

Biochemistry, Genetics and Molecular Biology

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