Regulation of p53 and Checkpoint Signaling by Chromium(VI)

项目摘要 流行病学研究已确定六价铬[Cr（VI）]为人类致癌物 在不同国家的职业暴露人群中。这种有毒金属的存在 许多超级基金网站和许多州的饮用水也引起了公众的极大关注。 关于癌症和其他与环境接触有关的健康风险的健康问题， Cr（VI）。通过饮用水摄入Cr（VI）， 小鼠小肠。将这些动物数据低剂量外推至环境风险， 人类需要了解Cr（VI）的致癌作用机制，这表明 使用特定的外推模型。Cr（VI）生成的Cr-DNA加合物最丰富 DNA损伤的形式，但这些加合物是弱的DNA扭曲，不诱导经典的DNA 损害反应。这个项目将调查一个假设上的一个主要作用的DNA修复产品 最初形成的Cr-DNA损伤在基因毒性应激的非典型分支的激活中 发信号。我们还将研究控制反应的生化过程， 应激敏感转录因子p53和Cr-DNA损伤的保护性G1检查点。的 这项工作的完成有望为不寻常的遗传特征提供机械解释 铬（VI）诱导的肺肿瘤和改善人类风险评估。

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.