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The Arsenic Stress Signaling Code of Yeast

酵母的砷应激信号编码

基本信息

批准号：
10442468
负责人：
DAVID E. LEVIN
金额：
$ 43.89万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442468
关键词：
Air Arsenates Arsenic Arsenicals Arsenites Binding Biochemical Cardiovascular Diseases Cell membrane Cell surface Cells Cellular Metabolic Process Chronic Code Cysteine Diabetes Mellitus Disease Environment Enzymes Event Evolution Exposure to Food Food Contamination Genetic Glycerol Health Hypertension Iron Lead MAP Kinase Gene MEKKs MEKs Malignant Neoplasms Mammals Metabolic Metabolic Biotransformation Metabolism Modeling Modification Molecular Nature Osmolar Concentration Osmotic Shocks Output Oxidative Regulation Oxidative Stress Pathway interactions Post-Translational Protein Processing Production Protein Kinase Protein Tyrosine Phosphatase Protein phosphatase Proteins Reactive Oxygen Species Regulation Replication Initiation Role Route Signal Transduction Signaling Molecule Source Specificity Stress Substrate Specificity Sulfhydryl Compounds Testing Toxic effect Toxin Tyrosine Water Yeasts anthropogenesis aqueous base behavior influence biological adaptation to stress cancer therapy cancer type carcinogenicity cell behavior chemotherapeutic agent effective therapy exposed human population geochemistry ground water inorganic phosphate interest nervous system disorder novel novel strategies protein activation protein function response stress activated protein kinase stressor

项目摘要

Project Summary Arsenic is the most prevalent toxin in the environment. This natural metalloid enters the biosphere from geochemical sources and, to a lesser degree, from anthropogenic sources. Human exposure to arsenic is mainly through food, water and air, and contamination of groundwater poses a worldwide health problem. Inorganic aqueous arsenic exists mainly as oxyanions of trivalent arsenite [As(III)] and pentavalent arsenate [As(V)]. As(V) is much less toxic than As(III), which is thiol reactive and binds covalently to cysteine residues in proteins. Chronic exposure to inorganic arsenic is associated with cardiovascular disease and hypertension, diabetes mellitus, neurological disorders, and various forms of cancer. It has been proposed that both direct modification of biomolecules by As(III) and reactive oxygen species (ROS) generated by arsenicals are responsible for its toxicity and carcinogenicity. Despite these health effects, As(III) is used as a highly effective treatment for certain types of cancers. Therefore, it is important to understand the cellular responses mobilized by arsenic-induced stress. Both As(V) and As(III) exposure stimulate the yeast stress-activated MAPK (SAPK) Hog1, whose activity is critically important for the cellular response to arsenic. We are interested in two general questions. First, how do diverse stressors activate a small number of SAPKs? We have found that many stressors activate yeast SAPKs by intracellular routes that interface with SAPK pathways in atypical ways, rather than signaling from the cell surface, which may influence the behavior of the SAPK. Second, how does the cell mobilize coherent, stress-specific outputs from an activated SAPK? This proposal centers on the cellular responses to arsenic exposure. We have developed evidence that both As(III) and its methylated metabolite, MAs(III), are important signaling molecules that allow cells to mobilize protective, stress-specific responses through modification of specific cysteine residues in target proteins. We refer to this as an arsenic stress signaling code. Aim1 extends our recent findings that cells respond differently to As(V) and As(III) exposure. We propose to understand the mechanistic bases of distinct regulatory events driven by these stressors. We will identify key targets of arsenic modification for the regulation of the glycerol channel Fps1 [the major port of entry for As(III)], and test the role of newly discovered arsenic modifications of proteins involved in the regulation of the oxidative stress response and replication initiation. Aim 2 is to understand how Hog1 activated by As(III) drives stress-specific outputs. This aim extends our recent finding that Hog1 itself is modified by arsenic and that this modification is important for its role in the response to As(III). Using mass spectral approaches, we will determine the Hog1 phosphorylome in response to As(III) and As(V) and establish whether Hog1 target specificity is altered by arsenylation. Aim 3 is to delineate the novel pathway by which As(V) activates Hog1 and to determine its significance for As(V) entry to cells. Completion of these aims will establish a novel paradigm centered on the regulatory nature of protein arsenylation.

项目总结