Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors.
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.
Hribal
Marta L
ML
Russ Berrie Research Pavilion, Rm. 238, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Nakae
Jun
J
Kitamura
Tadahiro
T
Shutter
John R
JR
Accili
Domenico
D
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051379:Mice; D009154:Mutation; D032446:Myoblasts / Q000187:drug effects / Q000502:physiology*; D020033:Protein Isoforms; D020123:Sirolimus / Q000494:pharmacology; D013002:Somatomedins / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D020033:Protein Isoforms; D013002:Somatomedins; D014157:Transcription Factors; D020123:Sirolimus; D000077191:Wortmannin