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Published 18 August 2003. doi:10.1083/jcb.200212107
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© The Rockefeller University Press, 0021-9525/2003/8/535 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 535-541

Report

 Regulation of insulin-like growth factor–dependent myoblast differentiation by Foxo forkhead transcription factors

Marta L. Hribal1, Jun Nakae1, Tadahiro Kitamura1, John R. Shutter2 and Domenico Accili1

1 Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032
2 Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320

Address correspondence to Domenico Accili, Russ Berrie Research Pavilion, Rm. 238, 1150 St. Nicholas Ave., New York, NY 10032. Tel.: (212) 851-5332. Fax: (212) 851-5331. email: da230{at}columbia.edu

Insulin-like growth factors promote myoblast differentiation through phosphoinositol 3-kinase and Akt signaling. Akt substrates required for myogenic differentiation are unknown. Forkhead transcription factors of the forkhead box gene, group O (Foxo) subfamily are phosphorylated in an insulin-responsive manner by phosphatidylinositol 3-kinase–dependent kinases. Phosphorylation leads to nuclear exclusion and inactivation. We show that a constitutively active Foxo1 mutant inhibits differentiation of C2C12 cells and prevents myotube differentiation induced by constitutively active Akt. In contrast, a transcriptionally inactive mutant Foxo1 partially rescues inhibition of C2C12 differentiation mediated by wortmannin, but not by rapamycin, and is able to induce aggregation-independent myogenic conversion of teratocarcinoma cells. Inhibition of Foxo expression by siRNA resulted in more efficient differentiation, associated with increased myosin expression. These observations indicate that Foxo proteins are key effectors of Akt-dependent myogenesis.

Key Words: myogenesis; growth factors; insulin signaling; phosphorylation; serine kinases

Abbreviations used in this paper: Foxo, forkhead box gene, group O; IGF, insulin-like growth factor; MyHC, myosin heavy chain; PI 3-kinase, phosphatidylinositol 3-kinase; RD, rhabdomyosarcoma-derived.


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