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Nat Cell Biol. 2008 Feb;10(2):138-48. doi: 10.1038/ncb1676. Epub 2008 Jan 20.

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.

Author information

  • 1Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

Erratum in

  • Nat Cell Biol. 2008 Mar;10(3):370.

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.

Comment in

  • ERK and MDM2 prey on FOXO3a. [Nat Cell Biol. 2008]
PMID:
18204439
[PubMed - indexed for MEDLINE]
PMCID:
PMC2376808
Free PMC Article

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