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Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1.

http://www.ncbi.nlm.nih.gov/pubmed/18451027

Mad1, a member of the Myc/Max/Mad family, suppresses Myc-mediated transcriptional activity by competing with Myc for heterodimerization with its obligatory partner, Max. The expression of Mad1 suppresses Myc-mediated cell proliferation and transformation. The levels of Mad1 protein are generally low in many human cancers, and Mad1 protein has a very short half-life. However, the mechanism that regulates the turnover of Mad1 protein is poorly understood. In this study, we showed that Mad1 is a substrate of p90 ribosomal kinase (RSK) and p70 S6 kinase (S6K). Both RSK and S6K phosphorylate serine 145 of Mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of Mad1 accelerates the ubiquitination and degradation of Mad1 through the 26S proteasome pathway, which in turn promotes the transcriptional activity of Myc. Our study provides a direct link between the growth factor signaling pathways regulated by PI3 kinase/Akt and MAP kinases with Myc-mediated transcription.

Pubmed ID: 18451027 RIS Download

Mesh terms: Amino Acid Sequence | Amino Acid Substitution | Cell Cycle Proteins | Cell Line, Tumor | Cell Proliferation | Enzyme Activation | Humans | Insulin | Mitogens | Molecular Sequence Data | Nuclear Proteins | Phosphatidylinositol 3-Kinases | Phosphorylation | Phosphoserine | Protein Processing, Post-Translational | Proto-Oncogene Proteins c-akt | Proto-Oncogene Proteins c-myc | Ribosomal Protein S6 Kinases | Ribosomal Protein S6 Kinases, 90-kDa | Serum | Substrate Specificity | Thermodynamics | Transcription, Genetic

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Associated grants

  • Agency: NIA NIH HHS, Id: 5 R37 AG012859

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