S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover

被引:81
作者
Mieulet, Virginie
Roceri, Mila
Espeillac, Catherine
Sotiropoulos, Athanassia
Ohanna, Mickael
Oorschot, Viola
Klumperman, Judith
Sandri, Marco
Pende, Mario [1 ]
机构
[1] INSERM, U845, F-75015 Paris, France
[2] Univ Paris 05, Unite Mixte Rech Sante, UMR 845, Paris, France
[3] Dulbecco Telethon Inst, Venetian Inst Mol Med, Padua, Italy
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2007年 / 293卷 / 02期
关键词
signal transduction; atrophy; autophagy;
D O I
10.1152/ajpcell.00499.2006
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
A defect in protein turnover underlies multiple forms of cell atrophy. Since S6 kinase (S6K)-deficient cells are small and display a blunted response to nutrient and growth factor availability, we have hypothesized that mutant cell atrophy may be triggered by a change in global protein synthesis. By using mouse genetics and pharmacological inhibitors targeting the mammalian target of rapamycin (mTOR)/S6K pathway, here we evaluate the control of translational target phosphorylation and protein turnover by the mTOR/S6K pathway in skeletal muscle and liver tissues. The phosphorylation of ribosomal protein S6 (rpS6), eukaryotic initiation factor-4B (eIF4B), and eukaryotic elongation factor-2 (eEF2) is predominantly regulated by mTOR in muscle cells. Conversely, in liver, the MAPK and phosphatidylinositol 3-kinase pathways also play an important role, suggesting a tissue-specific control. S6K deletion in muscle mimics the effect of the mTOR inhibitor rapamycin on rpS6 and eIF4B phosphorylation without affecting eEF2 phosphorylation. To gain insight on the functional consequences of these modifications, methionine incorporation and polysomal distribution were assessed in muscle cells. Rates and rapamycin sensitivity of global translation initiation are not altered in S6K-deficient muscle cells. In addition, two major pathways of protein degradation, autophagy and expression of the muscle-specific atrophy-related E3 ubiquitin ligases, are not affected by S6K deletion. Our results do not support a role for global translational control in the growth defect due to S6K deletion, suggesting specific modes of growth control and translational target regulation downstream of mTOR.
引用
收藏
页码:C712 / C722
页数:11
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