Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins.
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 pre-initiation 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.
Bouchard
Caroline
C
Institute for Molecular Biology and Tumor Research, Marburg, Germany.
Marquardt
Judith
J
Brás
Alexandra
A
Medema
René H
RH
Eilers
Martin
M
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011905:Genes, ras; D051379:Mice; D041681:NIH 3T3 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism*; D019473:Transcription Factors, TFII / Q000378:metabolism
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D005277:Fenfluramine; C001584:benfluorex; D042925:Positive Transcriptional Elongation Factor B; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt