Amino Acids as Signaling Factors and the Molecular Network Transducing Their Information

氨基酸调节基因表达的机制主要集中在胰岛素样生长因子结合蛋白-1基因，结果表明：1)亮氨酸通过对Wortmannin和雷帕霉素敏感的途径调节该基因的转录。2)亮氨酸在细胞内被识别。3)某些转录因子的核定位在这一效应中起重要作用。已鉴定出一些转录因子在氨基酸和蛋白质营养的影响中起作用。他们包括Foxos的HNF-3家族成员，其基因表达被证明受到营养和激素因素的调节。上游调控因素也被发现是氨基酸效应的中介。III型胶原基因对氨基酸状态特别是谷氨酰胺高度敏感，这种作用依赖于ATP的合成。此外，通过DNA微阵列分析对响应膳食蛋白质平衡的基因进行了详尽的研究，获得了响应基因的全局图像。研究还表明，蛋白质营养不良通过减少IRS-1丝氨酸磷酸化和增加IRS-2基因的表达来增强胰岛素受体的信号机制。一系列关于翻译调控的分析表明，eIF-4E的调控是亮氨酸调控作用的关键。我们的体内实验表明，亮氨酸的作用是通过mTOR磷酸化介导的，色氨酸以肝脏特异性的方式影响eIF-4E，而乙硫氨酸通过降低ATP水平和降低mTOR活性来抑制转录。

The mechanism whereby amino acids regulate gene expression was studied with a major focus on the gene for insulin-like growth factor binding protein-1, and the results indicate that ; 1) Leucine regulates transcription of this gene via a pathway sensitive to wortmannin and rapamycin. 2) Leucine is recognized inside the cells. 3) Nuclear localization of some transcription factors is important in the effect. Some transcription factors were identified that play roles in the effects of amino acids and protein nutrition. They included family members of HNF-3, of FoxOs, the gene expression of which turned out to be under the regulation of nutritional and hormonal factors. Upstream regulatory factors were also found mediators of the amino acid effect. The type III collagen gene is highly responsive to amino acid status, especially to glutamine, the effect being dependent on ATP synthesis. In addition, genes that respond to the balance of dietary protein were exhaustively investigated by DNA microarray analyzes and a global picture of responsive genes was obtained. It was also revealed that protein malnutrition potentiates signaling machinery of the insulin receptor by reducing serine phosphorylation of IRS-1 and by increasing the expression of the IRS-2 gene. Series of analyzes regarding to translational regulation have shown that regulation of eIF-4E stands for as the key point of the regulatory role of leucine. Our in vivo experiments have made it clear that, the effect of leucine was mediated by mTOR phosphorylation, tryptophan affect on eIF-4E on a liver specific manner, and that ethionine suppresses transcription through a reduced level of ATP and lowered mTOR activity.