Translational Control by Nutrients

营养素的翻译控制

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：该提案中的研究将确定在氨基酸限制的细胞应激期间诱导哺乳动物氨基酸转运蛋白基因的分子机制以及该过程的生理意义。氨基酸是细胞生长和维持的必需营养素。氨基酸在质膜上的转移是由蛋白质介导的，这些蛋白质识别，结合和将这些氨基酸从细胞外培养基中转移到细胞中，反之亦然。基本的阳离子氨基酸（精氨酸和赖氨酸）主要通过Y+系统的CAT-1（阳离子氨基酸转运蛋白1）运输。哺乳动物细胞对氨基酸可用性的变化产生了适应性反应。当氨基酸供应受到限制时，蛋白质合成降低，并且细胞蛋白，氨基酸生物合成和氨基酸在整个质膜上的分解代谢增加。这些反应共同提供了对细胞存活至关重要的氨基酸。这种适应性反应的重要部分是CAT-1基因的表达增加。当抑制全球蛋白质合成时，我们发现了一种用于在有限的氨基酸供应期间合成CAT-1蛋白的新型机制。这涉及通过内部核糖体入口序列（IRES）进行翻译起始，具有病毒式（IRES介导的）和细菌（在铅肽中的翻译）蛋白质合成的常见特征，表明在氨基酸代谢中的进化保守机制。我们的假设是，IRES被翻译起始因子和IRES特异性蛋白（ITAFS）的结合激活，这些因子和IRES特异性蛋白（ITAFS）募集核糖体并将其定位在正确的翻译起始密码子上。拟议的研究旨在鉴定这些蛋白质并表征它们如何激活IRES。这是关于营养素对IRES活性调节的第一个报告。