Nrf2 Protein Translation in Oxidative Stress

描述（由申请人提供）：多条证据表明哺乳动物细胞中存在针对异生物质化学应激的细胞防御。抗氧化和解毒基因的表达增加有助于细胞存活。虽然氧化应激的诱导代表了许多类型的外源性物质的毒性机制中的一个组成部分，但我们最近的数据表明，诱导II期解毒途径主导了氧化剂的基因表达网络。控制II相抗氧化剂和解毒酶表达的主开关是转录因子Nrf 2。我们发现氧化剂引起内源性Nrf 2蛋白的快速翻译。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Nrf 2蛋白的选择性翻译”。具体目标包括1）。测试氧化剂由于5 'UTR中的内部核糖体进入位点（IRES）而开启Nrf 2蛋白翻译; 2）。应用蛋白质组学技术，通过鉴定与Nrf 2 5 'UTR结合的蛋白质，研究胁迫诱导蛋白质翻译的机制。细胞存活是抵抗化学毒性的关键防御层。因此，研究应激诱导蛋白质翻译的机制对于理解化学暴露相关疾病的病因学是一项迫切的任务。公共卫生相关性：该提案计划研究氧化应激诱导Nrf 2蛋白翻译的机制。

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.