Forkhead transcription factor FoxO1 transduces insulin-like growth factor's signal to p27Kip1 in primary skeletal muscle satellite cells
✍ Scribed by Shuichi Machida; Espen E. Spangenburg; Frank W. Booth
- Book ID
- 102309955
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 234 KB
- Volume
- 196
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
The insulin‐like growth factor I (IGF‐I) stimulates muscle satellite cell proliferation. Chakravarthy et al., (2000, J Biol Chem 275:35942–35952.) previously found that IGF‐I‐stimulated proliferation of primary satellite cells was associated with the activation of phosphatidylinositol 3′‐kinase (PI3K)/Akt and the downregulation of a cell‐cycle inhibitor p27^__Kip__1^. To understand mechanisms by which IGF‐I signals the downregulation of p27^__Kip__1^ in rat skeletal satellite cells, the role of Forkhead transcription factor FoxO1 in transcriptional activity of p27^__Kip__1^ was examined. When primary rat satellite cells were transfected with a p27^__Kip__1^ promoter–reporter gene construct, IGF‐I (100 ng/ml) inhibited specific p27^__Kip__1^ promoter activity. Addition of LY294002, an inhibitor of PI3K, reversed the IGF‐I‐mediated downregulation of p27^__Kip__1^ promoter activity. Co‐transfection of wild type (WT) FoxO1 into satellite cells increased p27^__Kip__1^ promoter activity in the absence of IGF‐I supplementation. Addition of IGF‐I reversed the induction of p27^__Kip__1^ promoter activity by WT FoxO1. When a mutated FoxO1 (without Thr^24^, Ser^256^, and Ser^316^ Akt phosphorylation sites) was used, IGF‐I was no longer able to reverse the FoxO1 induced stimulation of p27^__Kip__1^ promoter activity that had been seen when WT FoxO1 was present. When the satellite cells were treated with IGF‐I, phosphorylation of Akt‐Ser^473^ and FoxO1‐Ser^256^ was increased. In addition, when the cells were pre‐incubated with LY294002 before IGF‐I stimulation, the phosphorylation of Akt‐Ser^473^ and FoxO1‐Ser^256^ was inhibited, implying that phosphorylation of Akt and FoxO1 was downstream of IGF‐I‐induced PI3K signaling. However, IGF‐I did not induce phosphorylation of FoxO1 on residues Thr^24^ and Ser^316^. These results suggested that IGF‐I induced the phosphorylation of Ser^256^ and inactivated FoxO1 thereby downregulating the activation of the p27^__Kip__1^ promoter. Thus, inactivation of FoxO1 by IGF‐I plays a critical role in rat skeletal satellite cell proliferation through regulation of p27^__Kip__1^ expression. J. Cell. Physiol. 196: 523–531, 2003. © 2003 Wiley‐Liss, Inc.