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

Proc Natl Acad Sci U S A. 2008 May 6;105(18):6584-9. doi: 10.1073/pnas.0802785105. Epub 2008 May 1.

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • Humans
  • Insulin / pharmacology
  • Mitogens / pharmacology
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Processing, Post-Translational* / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Ribosomal Protein S6 Kinases / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Serum
  • Substrate Specificity / drug effects
  • Thermodynamics
  • Transcription, Genetic* / drug effects

Substances

  • Cell Cycle Proteins
  • Insulin
  • MAD1L1 protein, human
  • Mitogens
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Phosphoserine
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa