Nrf2 Protein Translation in Oxidative Stress

氧化应激中的 Nrf2 蛋白翻译

• 批准号: 7896415
• 负责人: QIN M CHEN
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896415
• 关键词: 5' Untranslated Regions; Address; Antioxidants; Apoptosis; Automobile Driving; BIRC4 gene; Binding; Binding Proteins; Biotin; Cell Survival; Cells; Chemical Exposure; Chemicals; Code; Computer Simulation; DNA; Data; Disease; Dose; Drug Metabolic Detoxication; Electrophoretic Mobility Shift Assay; Enzymes; Etiology; Firefly Luciferases; GC Rich Sequence; Gene Expression; Genes; Genetic Transcription; Human; Hydrogen Peroxide; In Vitro; Internal Ribosome Entry Site; Label; Mammalian Cell; Mediating; Messenger RNA; Mus; Mutate; NF-E2-related factor 2; Nucleotides; Oxidants; Oxidative Stress; Oxidative Stress Induction; Pathway interactions; Phase; Play; Polyribosomes; Process; Protein Binding; Proteins; Proteomics; RNA; Rattus; Renilla Luciferases; Reporter; Resistance; Response Elements; Ribosomes; Role; Site; Stress; Stress-Induced Protein; Stretching; Structure; Structure-Activity Relationship; Technology; Testing; Toxic Environmental Substances; Toxic effect; Toxicogenomics; Trans-Activators; Transcript; Transcription Process; Translating; Translational Research; Translations; Work; Xenobiotics; base; infancy; novel; promoter; public health relevance; stem; transcription factor

DESCRIPTION (provided by applicant): Multiple lines of evidence point to the existence of cellular defense against xenobiotic chemical stress in mammalian cells. Increased expression of antioxidant and detoxification genes contributes to cell survival. While induction of oxidative stress represents one component in the mechanism of toxicity of many types of xenobiotics, our recent data suggest that induction of Phase II detoxification pathway dominates the gene expression network of oxidants. A master switch controlling the expression of Phase II antioxidant and detoxification enzymes is the transcription factor Nrf2. We found that oxidants cause rapid translation of endogenous Nrf2 protein. Little is known about the selectivity and mechanisms of protein translation under oxidative stress. We hypothesize that "IRES mediates oxidant induced selective translation of Nrf2 protein". The Specific Aims include 1). Test that oxidants turn on Nrf2 protein translation due to Internal Ribosomal Entry Site (IRES) in the 5'UTR; 2). Apply proteomic technology to address the mechanism of stress induced protein translation by identifying the proteins bound to Nrf2 5'UTR. Cell survival represents a critical layer of defense against chemical toxicity. Therefore studying the mechanism of stress induced protein translation is an imperative task for understanding the etiology of diseases associated with chemical exposure. PUBLIC HEALTH RELEVANCE: This proposal plans to study the mechanism of oxidative stress induced Nrf2 protein translation.

描述（由申请人提供）：多种证据表明哺乳动物细胞中存在针对外源化学应激的细胞防御。抗氧化和解毒基因表达的增加有助于细胞存活。虽然氧化应激的诱导代表了多种外源物质毒性机制中的一个组成部分，但我们最近的数据表明，第二阶段解毒途径的诱导主导了氧化剂的基因表达网络。控制 II 期抗氧化和解毒酶表达的主开关是转录因子 Nrf2。我们发现氧化剂会导致内源性 Nrf2 蛋白快速翻译。关于氧化应激下蛋白质翻译的选择性和机制知之甚少。我们假设“IRES 介导氧化剂诱导的 Nrf2 蛋白选择性翻译”。具体目标包括 1)。测试氧化剂是否由于 5'UTR 中的内部核糖体进入位点 (IRES) 而开启 Nrf2 蛋白翻译； 2）。应用蛋白质组学技术通过鉴定与 Nrf2 5'UTR 结合的蛋白质来解决应激诱导的蛋白质翻译机制。细胞存活是抵御化学毒性的关键防御层。因此，研究应激诱导的蛋白质翻译机制是了解与化学暴露相关的疾病病因学的当务之急。公共健康相关性：该提案计划研究氧化应激诱导 Nrf2 蛋白翻译的机制。