CYP1A1 GENE REGULATION AND HUMAN CANCER

CYP1A1 基因调控与人类癌症

• 批准号: 3752561
• 负责人: J E JONES
• 金额: --
• 依托单位: DIVISION OF CANCER PREVENTION AND CONTROL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752561
• 关键词: carbopolycyclic compound; chemical carcinogen; chemical carcinogenesis; cytochrome P450; gel mobility shift assay; gene expression; genetic markers; genetic polymorphism; genetic regulation; genetic regulatory element; human genetic material tag; human tissue; lung neoplasms; neoplasm /cancer genetics; neoplastic cell; reporter genes; restriction fragment length polymorphism; site directed mutagenesis; tissue /cell culture; tobacco abuse; transcription factor

A major goal of our laboratory has been the elucidation of the role of the human cytochrome P450, CYP1A1, in lung carcinogenesis. The protein product of the CYP1A1 gene and its associated catalytic activities, including aryl (or aromatic) hydrocarbon hydroxylase (AHH), are known to be intimately associated with the metabolic activation of many of the procarcinogenic polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke and other environmental pollutants to highly reactive intermediates. Elevated levels of AHH activity have been implicated in numerous studies as a significant risk factor in the etiology of lung cancer. Our investigations have been focused upon elucidating the mechanisms by which CYP1A1 gene expression is regulated and to establish a functional relationship between deviations from normal patterns of expression and lung cancer. A. Our studies of the regulation of expression of the human CYP1A1 gene using oligonucleotide directed mutagenesis and reporter gene expression in non-small cell lung cancer derived cell lines reveal that transcriptional activation of the gene is mediated through two widely separated DNA regulatory elements. This activation appears to be synergistic, as each element contributes roughly only 30% to the overall expression of the gene. These data are supported by gel mobility shift analyses of protein/DNA interactions at each site under control and inducing conditions. This work represents the first effort at characterization of the regulatory elements of the human CYP1A1 gene and the determination of the role for each in the regulation of expression of the gene in the adult lung. B. Interindividual variability in CYP1A1 gene expression may arise as a result of genetic differences within the genes encoding CYP1A1 transcriptional regulatory proteins. We have identified at least two restriction fragment length polymorphisms (RFLPs) within the gene encoding the major transcriptional activator of the CYP1A1 gene, the aromatic hydrocarbon (Ah) receptor. DNA from age, race, and sex matched control and histologically confirmed lung cancer patients is presently under examination to determine the frequency of these newly acquired genetic markers within the two populations. The significance of these projects is the elucidation of the interactive role of genetically determined factors and chemical carcinogens in pulmonary carcinogenesis. The results will have diagnostic and prevention applications.

我们实验室的一个主要目标是阐明 人细胞色素 P450、CYP1A1 在肺癌发生中的作用。蛋白质产品 CYP1A1 基因及其相关催化活性，包括芳基 （或芳香族）烃羟化酶（AHH），已知与 与许多致癌物质的代谢激活有关 香烟烟雾和其他烟雾中发现的多环芳烃 (PAH) 环境污染物转化为高活性中间体。水平提高 许多研究表明 AHH 活性是一种重要的 肺癌病因学中的危险因素。我们的调查已 重点阐明 CYP1A1 基因表达的机制 调节并建立偏差之间的函数关系 正常表达模式和肺癌。 A. 我们对人类 CYP1A1 基因表达调控的研究 使用寡核苷酸定向诱变和报告基因表达 非小细胞肺癌衍生细胞系揭示转录 基因的激活是通过两个广泛分离的DNA介导的 监管要素。这种激活似乎是协同作用的，因为每个 元素对基因整体表达的贡献大约只有 30%。 这些数据得到蛋白质/DNA 凝胶迁移率变化分析的支持 在控制和诱导条件下每个位点的相互作用。这部作品 代表了监管要素特征的首次尝试 人类 CYP1A1 基因的研究以及每个基因在 成人肺中基因表达的调节。 B. CYP1A1 基因表达的个体差异可能是由于 编码 CYP1A1 的基因内遗传差异的结果 转录调节蛋白。我们已经确定了至少两个 基因编码内的限制性片段长度多态性 (RFLP) CYP1A1 基因的主要转录激活因子 碳氢化合物（Ah）受体。来自年龄、种族和性别的 DNA 匹配控制和 经组织学证实的肺癌患者目前正在接受治疗 检查以确定这些新获得的遗传的频率 两个群体内的标记。 这些项目的意义在于阐明了互动性 遗传决定因素和化学致癌物的作用 肺癌发生。结果将具有诊断和预防作用 应用程序。