CELLULAR RESPONSE TO NONMUTAGENIC CARCINOGENS

描述：本应用程序的目标是探索分子基础 与长期接触苯系物有关的长期致癌效应 砷。砷是一大类毒素的代表， 未检测到明显诱变作用的致癌物。的确有, 然而，细胞对砷暴露的反应包括增加 多种细胞的转录和翻译后产物 基因，其中一些是已知的，许多仍然是未知的。 了解细胞对慢性砷的适应机制 曝光是此应用程序的主要关注点。针对这一目标，提出 实验集中在砷诱导的One转录的表达 因子CHOP(C/EBP同源蛋白)。罗恩博士的团队已经做了大量的工作 之前对这一因素的分析，他们假设它起到了 早期主开关在诱导其他基因表达中的作用， 砷诱导的生长调节剂。通过这样做，砍掉链接，通过它的目标 基因、砷暴露于细胞复制的变化可能解释 砷和类似的毒素是如何导致癌症形成的。基于 他关于CHOP的中心角色的假设，调查者发展了三个 目的包括：1)培育具有CHOP等位基因的小鼠 基因被敲除，2)定义表型的差异 在正常小鼠和CHOP缺陷小鼠之间以及分离的细胞之间 暴露在已知会导致CHOP的有毒物质如砷中，以及3) 分离和鉴定一系列基因的成员，这些基因是由 对砷有反应的排骨。这些基因被称为CHOP依赖基因， 砷诱导的基因。通过识别这组基因，他希望成为 能够更好地解释慢性砷暴露如何促进癌症 发展。 总而言之，研究人员计划开发出排骨基因敲除小鼠，到那时 这样做，可以进行一系列合乎逻辑的实验，这将有助于澄清 CHOP转录因子特异性激活哪些基因 在接触了砷之后。通过识别这些基因，研究人员 希望解释像砷这样的非诱变毒素如何有助于 细胞转化。

DESCRIPTION: The goal of this application is to explore the molecular basis for the long-term carcinogenic effects associated with chronic exposure to arsenic. Arsenic is representative of a broad class of toxins and carcinogens for which no discernible mutagenesis is detectable. There is, however, a cellular response to arsenic exposure that consists of increased transcription and post-translational product for a variety of cellular genes, some of which are known, and many of which remain unidentified. Understanding the mechanism of this cellular adaptation to chronic arsenic exposure is a primary focus of this application. Toward this goal, proposed experiments focus upon the arsenic-induced expression of one transcription factor, CHOP (C/EBP Homology Protein). Dr. Ron's group has done substantial previous analysis of this factor, and they hypothesize that it plays the role of an early master switch in acting to induce the expression of other, arsenic-induced growth regulators. By so doing, CHOP links, via its target genes, arsenic exposure to changes in cellular replication that may explain how arsenic and similar toxins contribute to cancer formation. Based upon his hypothesis of the central role for CHOP, the investigator develops three aims, which include: 1) to develop mice in which both alleles of the CHOP gene have been knocked out, 2) to define the differences in phenotype between normal and CHOP-deficient mice and isolated cells when they are exposed to toxins like arsenic that are known to induce CHOP, and 3) to isolate and identify members of the battery of genes that are induced by CHOP in response to arsenic. These genes are referred to as CHOP-dependent, arsenic-induced genes. By identifying this battery of genes, he hopes to be able to better explain how chronic arsenic exposure serves to promote cancer development. In summary, the investigator plans to develop CHOP knockout mice, and by so doing, enable a logical series of experiments that will serve to clarify what genes are activated specifically by the CHOP transcription factor following arsenic exposure. By identifying these genes, the investigator hopes to explain how non-mutagenic toxins like arsenic can contribute to cell transformation.