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)：多条证据表明哺乳动物细胞中存在抵抗外来化学应激的细胞防御系统。抗氧化和解毒基因的表达增加有助于细胞存活。虽然诱导氧化应激是许多类型外源生物毒性机制的一个组成部分，但我们最近的数据表明，诱导II相解毒途径主导着氧化剂的基因表达网络。控制第二阶段抗氧化酶和解毒酶表达的主开关是转录因子Nrf2。我们发现，氧化剂导致内源性Nrf2蛋白的快速翻译。对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介导了氧化剂诱导的Nrf2蛋白的选择性翻译。具体目标包括1)。检测氧化剂是否由于5‘非编码区中的内部核糖体进入位点(IRES)而打开Nrf2蛋白翻译；2)。应用蛋白质组学技术，通过鉴定与Nrf2 5‘非编码区结合的蛋白质来研究应激诱导蛋白质翻译的机制。细胞存活是抵御化学毒性的关键一层。因此，研究应激诱导蛋白质翻译的机制是了解化学物质暴露相关疾病的病因学的迫切任务。公共卫生相关性：该提案计划研究氧化应激诱导Nrf2蛋白翻译的机制。