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Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins

Caroline Bouchard1, Judith Marquardt, Alexandra Brás

  • 1Institute for Molecular Biology and Tumor Research, Marburg, Germany.

The EMBO Journal
|July 9, 2004
PubMed

Insights

Myc and PI3-kinase cooperate in cell transformation by distinct mechanisms. Myc recruits transcription factors, while PI3-kinase regulates RNA polymerase II loading via FoxO phosphorylation, impacting gene activation and cell growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Myc and PI3-kinase signaling pathways are crucial for cell transformation.
  • The molecular mechanisms underlying the synergy between Myc and PI3-kinase remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular basis of Myc and PI3-kinase cooperation in cell transformation.
  • To investigate the roles of FoxO transcription factors in mediating this synergy.

Main Methods:

  • Analysis of gene promoter recruitment of transcription factors (TFIIH, P-TEFb, Mediator).
  • Investigation of pre-initiation complex formation and RNA polymerase II loading.
  • Study of Akt-mediated phosphorylation of FoxO transcription factors and its functional consequences.

Main Results:

  • Myc recruits essential transcription machinery to target gene promoters.
  • PI3-kinase pathway controls pre-initiation complex assembly and RNA polymerase II loading.
  • Non-phosphorylated FoxO inhibits Myc target gene induction, proliferation, and transformation.
  • Abrogating FoxO function allows Myc to drive target gene activation and cell transformation independently of PI3-kinase or oncogenic Ras.

Conclusions:

  • Myc and FoxO proteins regulate distinct steps in the activation of overlapping target genes.
  • This distinct regulation contributes to the cooperative effects of Myc and Ras in cell transformation.
  • The PI3-kinase/Akt/FoxO axis is a key modulator of Myc's oncogenic functions.

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