Myc-induced Proliferation and Transformation Require Akt-mediated Phosphorylation of FoxO Proteins

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2004 Jul 9

PMID 15241468

Citations 111

Authors

Caroline Bouchard

Judith Marquardt

Alexandra Bras

Rene H Medema

Martin Eilers

Affiliations

Soon will be listed here.

Abstract

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.

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References

Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers W . A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell. 2002; 2(1):81-91. DOI: 10.1016/s1535-6108(02)00086-7. View

Nikiforov M, Chandriani S, Park J, Kotenko I, Matheos D, Johnsson A . TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins. Mol Cell Biol. 2002; 22(14):5054-63. PMC: 139788. DOI: 10.1128/MCB.22.14.5054-5063.2002. View

Eberhardy S, Farnham P . Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J Biol Chem. 2002; 277(42):40156-62. DOI: 10.1074/jbc.M207441200. View

Knoepfler P, Cheng P, Eisenman R . N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002; 16(20):2699-712. PMC: 187459. DOI: 10.1101/gad.1021202. View

Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops G, Lam E . Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol. 2002; 22(22):7842-52. PMC: 134724. DOI: 10.1128/MCB.22.22.7842-7852.2002. View

Basu S, Totty N, Irwin M, Sudol M, Downward J . Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003; 11(1):11-23. DOI: 10.1016/s1097-2765(02)00776-1. View

Wei W, Jobling W, Chen W, Hahn W, Sedivy J . Abolition of cyclin-dependent kinase inhibitor p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol Cell Biol. 2003; 23(8):2859-70. PMC: 152557. DOI: 10.1128/MCB.23.8.2859-2870.2003. View

Orsulic S, Li Y, Soslow R, Gutkind J, Varmus H . Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell. 2002; 1(1):53-62. PMC: 2267863. DOI: 10.1016/s1535-6108(01)00002-2. View

Matsushime H, Roussel M, Ashmun R, Sherr C . Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991; 65(4):701-13. DOI: 10.1016/0092-8674(91)90101-4. View

10.

Brockman J, Scherer D, McKinsey T, Hall S, Qi X, Lee W . Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol. 1995; 15(5):2809-18. PMC: 230512. DOI: 10.1128/MCB.15.5.2809. View

11.

Sicinski P, Donaher J, Geng Y, Parker S, Gardner H, Park M . Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature. 1996; 384(6608):470-4. DOI: 10.1038/384470a0. View

12.

Alessi D, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P . Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996; 15(23):6541-51. PMC: 452479. View

13.

Rodriguez-Viciana P, Warne P, Khwaja A, Marte B, Pappin D, Das P . Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997; 89(3):457-67. DOI: 10.1016/s0092-8674(00)80226-3. View

14.

Leone G, DeGregori J, Sears R, Jakoi L, Nevins J . Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature. 1997; 387(6631):422-6. DOI: 10.1038/387422a0. View

15.

Mateyak M, Obaya A, Adachi S, Sedivy J . Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ. 1997; 8(10):1039-48. View

16.

Datta S, Dudek H, Tao X, Masters S, Fu H, Gotoh Y . Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997; 91(2):231-41. DOI: 10.1016/s0092-8674(00)80405-5. View

17.

Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. DOI: 10.1016/s0092-8674(00)80595-4. View

18.

Bouchard C, Thieke K, Maier A, Saffrich R, Ansorge W, Reed S . Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J. 1999; 18(19):5321-33. PMC: 1171602. DOI: 10.1093/emboj/18.19.5321. View

19.

Orian A, van Steensel B, Delrow J, Bussemaker H, Li L, Sawado T . Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 2003; 17(9):1101-14. PMC: 196053. DOI: 10.1101/gad.1066903. View

20.

Fernandez P, Frank S, Wang L, Schroeder M, Liu S, Greene J . Genomic targets of the human c-Myc protein. Genes Dev. 2003; 17(9):1115-29. PMC: 196049. DOI: 10.1101/gad.1067003. View