Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1 Academic Article uri icon

Overview

MeSH Major

  • Cell Cycle Proteins
  • Nuclear Proteins
  • Phosphatidylinositol 3-Kinases
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-myc
  • Transcription, Genetic

abstract

  • 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.

publication date

  • May 6, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2373325

Digital Object Identifier (DOI)

  • 10.1073/pnas.0802785105

PubMed ID

  • 18451027

Additional Document Info

start page

  • 6584

end page

  • 9

volume

  • 105

number

  • 18