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 RIS Download
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 Box Protein O3 | 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