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Wu, AL, Kim, JH, Zhang, C, Unterman, TG and Chen, J (2008) Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components. Endocrinology 149:1407-14


The forkhead transcription factor forkhead box protein O1 (FoxO1), a downstream target of phosphatidylinositol 3-kinase/Akt signaling, has been reported to suppress skeletal myocyte differentiation, but the mechanism by which FoxO1 regulates myogenesis is not fully understood. We have previously demonstrated that a nutrient-sensing mammalian target of rapamycin (mTOR) pathway controls the autocrine production of IGF-II and the subsequent phosphatidylinositol 3-kinase/Akt signaling downstream of IGF-II in myogenesis. Here we report a regulatory loop connecting FoxO1 to the mTOR pathway. Inducible activation of a FoxO1 active mutant in the C2C12 mouse myoblasts blocks myogenic differentiation at an early stage and meanwhile leads to proteasome-dependent degradation of a specific subset of components in the mTOR signaling network, including mTOR, raptor, tuberous sclerosis complex 2, and S6 protein kinase 1. This function of FoxO1 requires new protein synthesis, consistent with the idea that a transcriptional target of FoxO1 may be responsible for the degradation of mTOR. We further show that active FoxO1 inhibits IGF-II expression at the transcriptional activation level, through the modulation of mTOR protein levels. Moreover, the addition of exogenous IGF-II fully rescues myocyte differentiation from FoxO inhibition. Taken together, we propose that the mTOR-IGF-II pathway is a major mediator of FoxO's inhibitory function in skeletal myogenesis.


PubMed PMC2275355 Online version:10.1210/en.2007-1470


Animals; Cell Differentiation/genetics; Cell Differentiation/physiology; Cell Line; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Insulin-Like Growth Factor II/genetics; Insulin-Like Growth Factor II/metabolism; Mice; Muscle Development/genetics; Muscle Development/physiology; Myoblasts, Skeletal/metabolism; Myoblasts, Skeletal/pathology; Proteasome Endopeptidase Complex/metabolism; Protein Kinases/genetics; Protein Kinases/metabolism; Signal Transduction/genetics; Signal Transduction/physiology; TOR Serine-Threonine Kinases; Transcription, Genetic/genetics; Transcription, Genetic/physiology



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0005634: nucleus



Figure 1A shows staining of C2C12 cells expressing FoxO1-3A-ER. The cells were immunostained using anti-ER and DAPI nuclear staining. The control showed some overlap of areas showing staining for FoxO1-3A-ER and DAPI(nuclear stain), but when the cells were treated with 4-HT, there was more overlap of FoxO1-3A-ER and DAPI stained areas. This suggests after treatment with 4-HT, FoxO1-3A-ER was located in the nucleus.

CACAO 9240


GO:0048523: negative regulation of cellular process



Figure 2A shows the effect on the production of raptor by the FOX01 when exposed to 4-HT versus when not. The figure shows that over time the production of raptor decreased when exposed to 4-HT versus not.

CACAO 9469

See also


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