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

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.

Pubmed ID: 18204439


  • Yang JY
  • Zong CS
  • Xia W
  • Yamaguchi H
  • Ding Q
  • Xie X
  • Lang JY
  • Lai CC
  • Chang CJ
  • Huang WC
  • Huang H
  • Kuo HP
  • Lee DF
  • Li LY
  • Lien HC
  • Cheng X
  • Chang KJ
  • Hsiao CD
  • Tsai FJ
  • Tsai CH
  • Sahin AA
  • Muller WJ
  • Mills GB
  • Yu D
  • Hortobagyi GN
  • Hung MC


Nature cell biology

Publication Data

February 4, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA116199
  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: P01 CA 099031
  • Agency: NCI NIH HHS, Id: P01 CA099031
  • Agency: NCI NIH HHS, Id: P01 CA099031-01
  • Agency: NCI NIH HHS, Id: P01 CA099031-010001
  • Agency: NCI NIH HHS, Id: P50 CA116199-01
  • Agency: NCI NIH HHS, Id: R01 CA109311

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Down-Regulation
  • Extracellular Signal-Regulated MAP Kinases
  • Female
  • Forkhead Transcription Factors
  • Humans
  • Mass Spectrometry
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2
  • Serine
  • Signal Transduction
  • Transplantation, Heterologous