Regulation of p53 and Checkpoint Signaling by Chromium(VI)

项目摘要 流行病学研究证实六价铬[Cr(VI)]是人类致癌物质 在来自不同国家的职业暴露群体中。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筹集了大量的公众资金 对癌症的健康担忧和与环境暴露有关的其他健康风险 铬(VI)。通过饮用水摄取铬(VI)对人体有明显的致癌作用 小鼠的小肠。这些动物数据对环境风险的低剂量外推 人类需要了解铬(VI)致癌作用的机制，这决定了 使用特定的外推模型。铬(VI)生成最丰富的铬-DNA加合物 DNA损伤的一种形式，但这些加合物是弱双链扭曲的，不会诱导典型的DNA 破坏反应。这个项目将调查关于DNA修复产物主要作用的假说。 最初形成的铬-DNA损伤在基因毒性应激的非典型分支激活中的作用 发信号。我们还将研究控制生物反应的生化过程。 应激敏感的转录因子P53和对铬-DNA损伤的保护性G1检查点。这个 这项工作的完成有望为不寻常的遗传特征提供机械解释 减少铬(VI)诱发的肺肿瘤，并改善人类风险评估。

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.