Translational Control by Nutrients

营养素的翻译控制

• 批准号: 7603043
• 负责人: MARIA HATZOGLOU
• 金额: $ 31.04万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603043
• 关键词: Amino Acid Transporter; Amino Acids; Be++ element; Beryllium; Binding; Catabolism; Cationic Amino Acid Transporter 1; Cell Cycle Arrest; Cell Maintenance; Cell Survival; Cell membrane; Cells; Cellular Stress; Chloramphenicol; Complex; Cytoplasmic Granules; Elements; Embryo; Essential Amino Acids; Felis catus; Fibroblasts; Firefly Luciferases; Fractionation; Genes; Genetic Transcription; Initiator Codon; Kinetics; Knockout Mice; Light; Literature; Mammalian Cell; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Names; Nutrient; Open Reading Frames; Peptide Initiation Factors; Peptide Leader Sequences; Phosphorylation; Physiological; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Prokaryotic Initiation Factor-2; Protein Binding; Protein Biosynthesis; Proteins; RNA; RNA Interference; RNA, Transfer, Met; Recruitment Activity; Regulation; Regulatory Element; Reporting; Research Personnel; Ribosomes; Role; Signal Pathway; Signal Transduction; Starvation; Stress; Structure; System; Testing; Translating; Translation Initiation; Translations; Untranslated Regions; Viral; Y protein; aminoacid biosynthesis; arginyllysine; attenuation; cell growth; extracellular; novel; programs; protein complex; response

DESCRIPTION (provided by applicant): The studies in this proposal will determine the molecular mechanisms that induce a mammalian amino acid transporter gene during the cellular stress of amino acid limitation and the physiological significance of this process. Amino acids are essential nutrients for cell growth and maintenance. Transfer of amino acids across the plasma membrane is mediated by proteins that recognize, bind and transport these amino acids from the extracellular medium into the cell and vice versa. The essential cationic amino acids, arginine and lysine, are mainly transported via the cat-1 (cationic amino acid transporter 1) protein of the Y+ system. Mammalian cells have developed an adaptive response to changes in amino acid availability. When the amino acid supply is limited, protein synthesis decreases and there are increases in catabolism of cellular proteins, amino acid biosynthesis, and amino acid transport across the plasma membrane. Together these responses provide the amino acids that are essential for cell survival. A significant part of this adaptive response is the increased expression of the cat-1 gene. We discovered a novel mechanism used for the synthesis of the cat-1 protein during limited amino acid supply, when global protein synthesis is inhibited. This involves translation initiation via an internal ribosomal entry sequence (IRES), with common features with both viral (IRES-mediated) and bacterial (translation within a leader peptide) protein synthesis pointing to the evolutionary conserved mechanisms in amino acid metabolism. Our hypothesis is that the IRES is activated by the binding of translation initiation factors and IRES-specific proteins (ITAFs) which recruit the ribosome and position it at the correct translation initiation codon. The proposed studies aim to identify these proteins and characterize how they activate the IRES. This is the first report on the regulation of the activity of the IRES by nutrients.

描述(申请人提供)：本提案中的研究将确定在氨基酸限制的细胞应激过程中诱导哺乳动物氨基酸转运蛋白基因的分子机制以及这一过程的生理意义。氨基酸是细胞生长和维持所必需的营养物质。氨基酸通过质膜的转移是由蛋白质介导的，这些蛋白质识别、结合并将这些氨基酸从细胞外介质输送到细胞内，反之亦然。必需的阳离子氨基酸精氨酸和赖氨酸主要通过Y+系统的CAT-1(阳离子氨基酸转运体1)蛋白运输。哺乳动物细胞已经发展出对氨基酸可获得性变化的适应性反应。当氨基酸供应有限时，蛋白质合成减少，细胞蛋白质分解代谢、氨基酸生物合成和跨质膜转运增加。这些反应共同提供了细胞生存所必需的氨基酸。这种适应性反应的一个重要部分是CAT-1基因表达的增加。我们发现了一种新的机制，用于在有限的氨基酸供应期间合成CAT-1蛋白质，而此时全球蛋白质合成受到抑制。这涉及到通过内部核糖体进入序列(IRES)启动翻译，具有病毒(IRES介导的)和细菌(前导肽内翻译)蛋白质合成的共同特征，表明氨基酸代谢中的进化保守机制。我们的假设是，IRES是由翻译起始因子和IRES特异性蛋白(ITAFs)结合激活的，ITAFs招募核糖体并将其定位在正确的翻译起始密码子上。拟议的研究旨在识别这些蛋白质并表征它们是如何激活IRES的。这是有关营养物质对IRES活性调节的第一份报告。