Stress response, p97, and Nrf2 in arsenic-mediated toxicity

砷介导的毒性中的应激反应、p97 和 Nrf2

• 批准号: 9186452
• 负责人: Eli Chapman
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186452
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Air; Alpha Cell; Amaze; Antioxidants; Arsenic; Arsenicals; Arsenites; Autophagocytosis; Autophagosome; Binding; Biochemical; Biochemistry; Biological; Carcinogens; Cardiovascular system; Cell Cycle; Cell Survival; Cell physiology; Cells; Cellular Stress Response; Chronic; Complex; Coupled; Developing Countries; Diabetes Mellitus; Disease; Elements; Endoplasmic Reticulum; Enzymatic Biochemistry; Exposure to; Foot Diseases; Genes; Growth; Health; Heat-Shock Response; Homeostasis; Human; Impairment; In Vitro; Inclusion Body Myopathy with Early-Onset Paget Disease; Lead; Link; Lysosomes; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Measures; Mediating; Membrane Proteins; Metabolic Diseases; Modeling; Molecular; Mus; Names; Oxidation-Reduction; Oxidative Stress; Oxides; Pathologic; Pathology; Pathway interactions; Proteins; Quality Control; Recombinants; Regulation; Reporting; Research; Response Elements; Risk; Series; Skin; Societies; Soil; Source; Specificity; System; Toxic effect; Transgenes; Transgenic Mice; Ubiquitin; Up-Regulation; Variant; Vascular Diseases; Work; autosomal dominant mutation; biological adaptation to stress; contaminated drinking water; contaminated water; epidemiology study; in vivo; macromolecular assembly; metaplastic cell transformation; mouse model; multicatalytic endopeptidase complex; mutant; p97 ATPase; pollutant; prevent; programs; public health relevance; reconstitution; response; stress protein; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Arsenic and its arsenical derivatives are estimated to effect greater than 200 million people worldwide. Exposure to arsenicals comes from a number of sources such as contaminated drinking water, soil or as an airborne pollutant. Various epidemiological studies have linked chronic arsenic exposure to a number of disease states including cancer of the lungs, bladder, or skin; metabolic diseases such as diabetes; cardiovascular and other vascular diseases; and skin problems such as 'black foot disease'. In addition to the epidemiological studies there has been a great deal of effort to understand the mechanisms of pathology, but to date many questions along these lines remain obfuscated. Part of the problem with understanding arsenic toxicity is the sheer number of cellular systems that arsenic alters. For instance arsenic leads to oxidative stress, compromise of protein quality control, heat-shock response, and cell-cycle alterations to name a few. Work from our lab has identified a crucial link in the effects of arsenic on cells. Chronic treatment with low levels of arsenite (one of the oxides of arsenic) leads to a compromise of autophagy, a major protein quality control pathway. This breach comes at the step of autophagosome/lysosome fusion, leading to a build-up of autophagosomes and high levels of the autophagy specificity factor, p62. Critically, p62 contains a recognition element for Keap1, which is a substrate recognition factor in the Cul3-Keap1-Rbx1 E3 ubiquitin ligase complex. This E3 complex normally maintains a low level of the oxidative stress responsive transcription factor, Nrf2. In the presence of excess p62, Keap1 is occupied, allowing for constitutive, high level expression of Nrf2 and subsequent activation of antioxidant response element regulated genes. This high-level expression confers a growth advantage on the cells and can lead to diseases such as cancer. Despite these mechanistic leaps, it remains the mechanism by which arsenite interferes with autophagy is unknown. In the present research program we propose the hypothesis that arsenicals interfere with the AAA+ protein quality control machine, p97. This provides a critical link between arsenic and autophagy as well as other protein quality control mechanisms. To probe the detailed mechanistic underpinnings of this arsenic-mediated breach we will use an array of detailed mechanistic enzymology studies, coupled with cellular biochemistry, and in vivo studies. These efforts will be greatly aided by the multi-PI team we have assembled.

描述（由申请人提供）：据估计，砷及其砷衍生物在全球范围内影响超过2亿人。接触砷的人来自许多来源，例如受污染的饮用水，土壤或空气污染物。各种流行病学研究已将慢性砷暴露与许多疾病状态联系起来，包括肺癌，膀胱或皮肤。代谢疾病，例如糖尿病；心血管和其他血管疾病；和皮肤问题，例如“黑足病”。除了流行病学研究外，还花了很多努力来了解病理学的机制，但迄今为止，沿着这些线路的许多问题仍然令人困惑。理解砷毒性的部分问题是砷改变了大量的细胞系统。例如，砷导致氧化应激，蛋白质质量控​​制的损害，热震反应和细胞周期改变，仅举几例。我们实验室的工作确定了砷对细胞的影响的关键联系。低水平的砷（砷的氧化物之一）的慢性治疗导致自噬的妥协，自噬是一种主要的蛋白质质量控​​制途径。这种漏洞是在自噬体/溶酶体融合的步骤中，导致自噬体和高水平的自噬特异性因子p62堆积。至关重要的是，p62包含KEAP1的识别元素，Keap1是CUL3-KEAP1-RBX1 E3泛素连接酶复合物中的底物识别因子。该E3复合物通常保持低水平的氧化应激反应转录因子NRF2。在存在多余的p62的情况下，KEAP1被占据，允许NRF2的组成型高水平表达以及随后的抗氧化反应元件调节基因的激活。这种高级表达赋予细胞上的生长优势，并可能导致癌症等疾病。尽管有这些机械飞跃，但它仍然是砷干扰自噬的机制。在本研究计划中，我们提出了一个假设，即砷会干扰AAA+蛋白质质量控​​制机P97。这提供了砷和自噬与其他蛋白质质量控​​制机制之间的关键联系。为了探究这种砷介导的破坏的详细机械基础，我们将使用一系列详细的机械酶学研究，再加上细胞生物化学和体内研究。我们组装的多个PI团队将极大地帮助这些努力。