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

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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.