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.
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
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
Nat. Cell Biol.
Date: Feb. 01, 2008
PubMed ID: 18204439
View in: Pubmed Google Scholar
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