期刊
NATURE CELL BIOLOGY
卷 10, 期 2, 页码 138-U22出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1676
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- NCI NIH HHS [P30 CA016672, P01 CA099031, CA16672, P50 CA116199-01, P01 CA099031-01, CA116199, P01 CA099031-010001, P50 CA116199, P01 CA 099031, R01 CA109311] Funding Source: Medline
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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