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Regulation of p53 and Checkpoint Signaling by Chromium(VI)

Chromium(VI) 对 p53 和检查点信号传导的调节

基本信息

批准号：
10306386
负责人：
Anatoly Zhitkovich
金额：
$ 36.56万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306386
关键词：
Abbreviations Base Excision Repairs Binding Biochemical Process Biological Assay CDKN2A gene CDT1 Gene Carcinogens Cell Cycle Cells Chromium Country DNA DNA Adducts DNA Damage DNA Double Strand Break DNA Repair Data Dose Environmental Exposure Environmental Pollution Environmental Risk Factor Excision Exposure to Female G1 Arrest G1 Phase Gene Expression Genetic Genetic Suppression Genetic Transcription Genotoxic Stress Glutathione Health Human Individual Industrialization Ingestion Knowledge Laboratory Animals Licensing Factor Lung Neoplasms MDM2 gene Maintenance Malignant Neoplasms Metabolism Metals Mismatch Repair Modeling Mus Mutation National Toxicology Program Non-linear Models Nucleotide Excision Repair Occupational Exposure Occupations Proteins Public Health Regulation Replication Initiation Replication Licensing Risk Risk Assessment Rodent Role Signal Transduction Small Intestines Source Specificity Squamous Cell Lung Carcinoma Stress TP53 gene Testing Tissues Tobacco smoke Transactivation Up-Regulation Water Work Workplace adduct animal data ascorbate biological adaptation to stress cancer cell cancer risk cancer type carcinogenicity cell transformation chromium hexavalent ion cytotoxicity drinking water epidemiology study genome integrity genotoxicity improved in vivo inhibitor male novel preservation promoter respiratory response superfund site toxic metal transcription factor

项目摘要

Project Summary Hexavalent chromium [Cr(VI)] is firmly established as a human carcinogen by epidemiological studies in occupationally exposed groups from different countries. The presence of this toxic metal at numerous Superfund sites and in drinking water across many states has also raised significant public health concerns regarding cancer and other health risks associated with environmental exposures to Cr(VI). Ingestion of Cr(VI) through drinking water produced clear evidence of carcinogenicity in the small intestine of mice. The low-dose extrapolation of these animal data to environmental risks in humans requires knowledge of the mechanism of the carcinogenic action for Cr(VI), which dictates the use of specific extrapolation models. Cr(VI) generates Cr-DNA adducts as the most abundant form of DNA damage but these adducts are weakly duplex-distorting and do not induce classic DNA damage responses. This project will investigate a hypothesis on a major role of DNA repair products of the initially formed Cr-DNA damage in the activation of noncanonical branches of genotoxic stress signaling. We will also examine the biochemical processes governing the responsiveness of the stress-sensitive transcription factor p53 and a protective G1 checkpoint to Cr-DNA damage. The completion of this work is expected to provide mechanistic explanations for unusual genetic features of Cr(VI)-induced lung tumors and improve human risk assessment.

项目概要流行病学研究明确六价铬 [Cr(VI)] 是人类致癌物来自不同国家的职业暴露群体。这种有毒金属的存在众多超级基金站点和许多州的饮用水也筹集了大量公众资金有关癌症和与环境暴露相关的其他健康风险的健康问题六价铬。通过饮用水摄入 Cr(VI) 产生了明显的致癌性证据小鼠的小肠。这些动物数据对环境风险的低剂量外推人类需要了解 Cr(VI) 的致癌作用机制，这决定了使用特定的外推模型。 Cr(VI) 生成最丰富的 Cr-DNA 加合物 DNA 损伤的形式，但这些加合物是弱双链体扭曲并且不会诱导经典 DNA 损害反应。该项目将研究 DNA 修复产品主要作用的假设基因毒性应激非规范分支激活中最初形成的 Cr-DNA 损伤的影响发信号。我们还将检查控制反应性的生化过程应激敏感转录因子 p53 和针对 Cr-DNA 损伤的保护性 G1 检查点。这这项工作的完成预计将为不寻常的遗传特征提供机制解释 Cr(VI) 诱发的肺部肿瘤并改善人类风险评估。