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  • The EMBO Journal (2004) 23, 2830 - 2840
  • doi:10.1038/sj.emboj.7600279

Published online: 8 July 2004

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

Caroline Bouchard1,a, Judith Marquardt1,a, Alexandra Brás2,a, René H Medema2 and Martin Eilers1

  1. Institute for Molecular Biology and Tumor Research, Marburg, Germany
  2. Dutch Cancer Institute (NKI-H8), Plesmanlaan, Amsterdam, Netherlands

Correspondence to:

Martin Eilers, Inst. f. Molekularbiologie & Tumorf., Universität Marburg, Emil-Mannkopff-Str. 2, 35033 Marburg, Germany. Tel.: +49 6421 286 6410/6768; Fax: +49 6421 286 5196; E-mail: eilers@imt.uni-marburg.de

aThese authors contributed equally to this work

Received 29 January 2004; Accepted 25 May 2004

Myc synergizes with Ras and PI3-kinase in cell transformation, yet the molecular basis for this behavior is poorly understood. We now show that Myc recruits TFIIH, P-TEFb and Mediator to the cyclin D2 and other target promoters, while the PI3-kinase pathway controls formation of the preinitiation complex and loading of RNA polymerase II. The PI3-kinase pathway involves Akt-mediated phosphorylation of FoxO transcription factors. In a nonphosphorylated state, FoxO factors inhibit induction of multiple Myc target genes, Myc-induced cell proliferation and transformation by Myc and Ras. Abrogation of FoxO function enables Myc to activate target genes in the absence of PI3-kinase activity and to induce foci formation in primary cells in the absence of oncogenic Ras. We suggest that the cooperativity between Myc and Ras is at least in part due to the fact that Myc and FoxO proteins control distinct steps in the activation of an overlapping set of critical target genes.

  • Keywords:

    • cyclin D2,
    • FoxO,
    • Myc,
    • Ras,
    • PI3-kinase