FOXO1 Regulates the Expression of 4E-BP1 and Inhibits mTOR Signaling in Mammalian Skeletal Muscle*
FOXO1 Regulates the Expression of 4E-BP1 and Inhibits mTOR Signaling in Mammalian Skeletal Muscle*
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DOI：
10.1074/jbc.m702039200
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发表时间：
2007-07
影响因子：
4.8
通讯作者：
R. Southgate;Bronwyn A Neill;O. Prelovsek;A. El-Osta;Yasutomi Kamei;S. Miura;O. Ezaki;T. Mcloughlin;Wenwei Zhang;T. Unterman;M. Febbraio
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文献类型：
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作者：
R. Southgate;Bronwyn A Neill;O. Prelovsek;A. El-Osta;Yasutomi Kamei;S. Miura;O. Ezaki;T. Mcloughlin;Wenwei Zhang;T. Unterman;M. Febbraio
哺乳动物靶标雷帕霉素(MTOR)受生长因子调控，促进蛋白质合成。在哺乳动物骨骼肌中，Forkhead-O1转录因子(FOXO1)通过激活泛素蛋白连接酶来促进分解代谢。使用稳定表达诱导型FOXO1-ER融合蛋白的C2C12小鼠成肌细胞和在骨骼肌中特异性过表达结构性活性FOXO1的转基因小鼠(FOXO++/+)，我们发现FOXO1抑制mTOR信号和蛋白质合成。活性FOXO1通过与启动子结合，诱导真核细胞起始因子4E结合蛋白1(4E-BP1)的表达。这导致4E-BP1总丰度增加，4E-BP1(Thr-37/46)磷酸化减少。4E-BP1磷酸化的降低与Raptor和mTOR蛋白丰度的降低、Raptor相关的mTOR、下游蛋白p70S6激酶的磷酸化降低以及[14C]苯丙氨酸在蛋白质中的掺入减弱有关。以严重骨骼肌萎缩为特征的FOXO++/+小鼠，其mRNA表达和蛋白质丰度的模式与结构性活跃的FOXO1C2C12肌管相似。这些数据表明，FOXO1可能是合成代谢受损的人类疾病的重要治疗靶点。
The mammalian target of rapamycin (mTOR) is regulated by growth factors to promote protein synthesis. In mammalian skeletal muscle, the Forkhead-O1 transcription factor (FOXO1) promotes catabolism by activating ubiquitin-protein ligases. Using C2C12 mouse myoblasts that stably express inducible FOXO1-ER fusion proteins and transgenic mice that specifically overexpress constitutively active FOXO1 in skeletal muscle (FOXO++/+), we show that FOXO1 inhibits mTOR signaling and protein synthesis. Activation of constitutively active FOXO1 induced the expression of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) mRNA via binding to the promoter. This resulted in an increased total 4E-BP1 abundance and a reduced 4E-BP1 (Thr-37/46) phosphorylation. The reduction in 4E-BP1 phosphorylation was associated with a reduction in the abundance of Raptor and mTOR proteins, Raptor-associated mTOR, reduced phosphorylation of the downstream protein p70S6 kinase, and attenuated incorporation of [14C]phenylalanine into protein. The FOXO++/+ mice, characterized by severe skeletal muscle atrophy, displayed similar patterns of mRNA expression and protein abundance to those observed in the constitutively active FOXO1 C2C12 myotubes. These data suggest that FOXO1 may be an important therapeutic target for human diseases where anabolism is impaired.