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

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

Authors

  • Zhu J
  • Blenis J
  • Yuan J

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 6, 2008

Associated Grants

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

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