Nrf2 Protein Translation in Oxidative Stress

氧化应激中的 Nrf2 蛋白翻译

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：多个证据表明哺乳动物细胞中存在针对异生物化学应激的细胞防御。抗氧化剂和解毒基因的表达增加有助于细胞存活。尽管氧化应激的诱导代表了多种类型异种生物的毒性机理中的一个成分，但我们最近的数据表明，II期解毒途径的诱导占主导地位的氧化剂基因表达网络。控制II期抗氧化剂和排毒酶表达的主开关是转录因子NRF2。我们发现氧化剂引起内源性NRF2蛋白的快速翻译。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NRF2蛋白的氧化剂诱导的选择性翻译”。具体目的包括1）。测试氧化剂在5'UTR中由于内部核糖体入口位点（IRES）而打开NRF2蛋白的翻译； 2）。应用蛋白质组学技术来解决应力诱导的蛋白质翻译的机理，通过识别与NRF2 5'UTR结合的蛋白质。细胞存活代表了针对化学毒性的临界防御层。因此，研究应力诱导的蛋白质翻译的机制是理解与化学暴露相关的疾病的病因的必要任务。公共卫生相关性：该提案计划研究氧化应激诱导的NRF2蛋白翻译的机制。