Regulation of p53 and Checkpoint Signaling by Chromium(VI)

Chromium(VI) 对 p53 和检查点信号传导的调节

• 批准号: 10057383
• 负责人: Anatoly Zhitkovich
• 金额: $ 36.56万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057383
• 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/antagonist; male; novel; preservation; promoter; respiratory; response; superfund site; toxic metal; transcription factor

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.

项目摘要 六价铬[Cr（VI）]通过流行病学研究牢固地确定为人类致癌 在来自不同国家的职业群体中。这种有毒金属的存在 许多州的众多超级基金站点以及许多州的饮用水也兴建了大量公众 与环境暴露有关的癌症和其他健康风险的健康问题 CR（VI）。通过饮用水摄入CR（VI）产生了明确的致癌证据 小肠小鼠。这些动物数据的低剂量外推到环境风险 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CR-DNA加合物是最丰富的 DNA损伤的形式，但这些加合物是弱的双链延伸，并且不会诱导经典的DNA 损坏反应。该项目将研究关于DNA修复产品的主要作用的假设 最初形成的CR-DNA损伤在遗传毒性应激的非宗教分支的激活中 信号。我们还将研究有关响应能力的生化过程 应力敏感的转录因子p53和CR-DNA损伤的保护性G1检查点。这 这项工作的完成有望为不寻常的遗传特征提供机械解释 CR（VI）诱导的肺肿瘤并改善人类风险评估。