Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway
Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway
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DOI：
10.1074/jbc.m407517200
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发表时间：
2005-01-28
影响因子：
4.8
通讯作者：
Glass, DJ
中科院分区：
文献类型：
--
作者：
Latres, E;Amini, AR;Glass, DJ
骨骼肌的大小受合成代谢（肥厚）和分解代谢（萎缩）过程的调节。我们首先表征了肥大和萎缩的分子标记，并确定了在这两种情况下反向调节的一小部分基因（例如，由肥大的诱变剂胰岛素样生长因子-1 （IGF-1）上调，由萎缩的介质地塞米松下调）。与肥大相反，被鉴定为受萎缩反向调节的基因包括E3泛素连接酶MAFbx（也称为atrogenin -1）。接下来，我们试图研究IGF-1反向调节这些标记物的机制，并发现磷脂酰肌醇3-激酶/Akt/雷帕霉素哺乳动物靶点（PI3K/Akt/mTOR）通路，我们之前认为是肥厚的关键，也需要激活IGF-1介导的转录变化发生。我们最近已经证明IGF1/PI3K/Akt通路可以通过阻断FOXO转录因子的核易位来阻断地塞米松诱导的萎缩诱导的泛素连接酶MuRF1和MAFbx的上调。在目前的研究中，我们证明了IGF1转录调控的另一个步骤发生在mTOR下游，这是独立于FOXO的。因此，Akt/FOXO和Akt/mTOR通路都是IGF-1诱导的转录变化所必需的。
Skeletal muscle size is regulated by anabolic (hypertrophic) and catabolic (atrophic) processes. We first characterized molecular markers of both hypertrophy and atrophy and identified a small subset of genes that are inversely regulated in these two settings (e.g. up-regulated by an inducer of hypertrophy, insulin-like growth factor-1 (IGF-1), and down-regulated by a mediator of atrophy, dexamethasone). The genes identified as being inversely regulated by atrophy, as opposed to hypertrophy, include the E3 ubiquitin ligase MAFbx (also known as atrogin-1). We next sought to investigate the mechanism by which IGF-1 inversely regulates these markers, and found that the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, which we had previously characterized as being critical for hypertrophy, is also required to be active in order for IGF-1-mediated transcriptional changes to occur. We had recently demonstrated that the IGF1/PI3K/Akt pathway can block dexamethasone-induced up-regulation of the atrophy-induced ubiquitin ligases MuRF1 and MAFbx by blocking nuclear translocation of a FOXO transcription factor. In the current study we demonstrate that an additional step of IGF1 transcriptional regulation occurs downstream of mTOR, which is independent of FOXO. Thus both the Akt/FOXO and the Akt/mTOR pathways are required for the transcriptional changes induced by IGF-1.