Nrf2 Protein Translation in Oxidative Stress

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。抗氧化和解毒基因的表达增加有助于细胞存活。虽然诱导氧化应激是多种外源药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期解毒途径主导了氧化剂的基因表达网络。调控II期抗氧化和解毒酶表达的主要开关是转录因子Nrf2。我们发现氧化剂引起内源性Nrf2蛋白的快速翻译。氧化应激下蛋白质翻译的选择性和机制尚不清楚。我们假设“IRES介导氧化诱导的Nrf2蛋白的选择性翻译”。具体目标包括1)。5'UTR内核糖体进入位点（IRES）激活Nrf2蛋白翻译的实验2）. 通过鉴定Nrf2 5'UTR结合蛋白，应用蛋白质组学技术研究应激诱导蛋白翻译的机制。细胞存活是抵御化学毒性的关键一层。因此，研究应激诱导蛋白翻译的机制是了解化学暴露相关疾病病因学的必要任务。公共卫生相关性：本课题拟研究氧化应激诱导Nrf2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.