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

作为信号因子的氨基酸和转导其信息的分子网络

• 批准号: 12460054
• 负责人: KATO Hisanori
• 金额: $ 8.9万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12460054/
• 关键词: amino acid; transcription factor; IGF binding protein; DNA microarray; insulin receptor; mTOR; leucine; translation factor; IGF結合タンパク質; フォークヘッド; 翻訳制御因子; エチオニン; インスリンレセプター; 翻訳開始因子; インスリン; IGFBP-1; 糖尿病; USF; HNF-3

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.

研究了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基因上，结果表明：1）亮氨酸通过对渥曼青霉素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)一些转录因子的核定位在该效应中起重要作用。一些转录因子被确定在氨基酸和蛋白质营养的影响中发挥作用。他们包括HNF-3家族成员，FoxOs，其基因表达被证明是在营养和激素因素的调节下。上游调控因子也被发现是氨基酸效应的介质。III型胶原基因对氨基酸状态，特别是谷氨酰胺高度敏感，其作用依赖于ATP的合成。此外，通过DNA微阵列分析，详尽地研究了响应于膳食蛋白质平衡的基因，并获得了响应基因的全局图。还揭示了蛋白质营养不良通过减少IRS-1的丝氨酸磷酸化和通过增加IRS-2基因的表达来增强胰岛素受体的信号传导机制。一系列关于翻译调节的分析表明，eIF-4 E的调节是亮氨酸调节作用的关键点。我们的体内实验已经清楚地表明，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方式影响eIF-4 E，并且乙烯利通过降低ATP水平和降低mTOR活性来抑制转录。