CYP1A1 GENE REGULATION AND HUMAN CANCER

我们实验室的一个主要目标是阐明 人细胞色素P450，CYP 1A 1在肺癌发生中的作用蛋白质产物 CYP 1A 1基因及其相关催化活性，包括芳基 (or芳香族）烃羟化酶（AHH），已知与 与许多致癌原的代谢活化有关， 多环芳烃（PAHs）在香烟烟雾和其他 环境污染物转化为高活性中间体。水平升高 许多研究表明，AHH活性是一种重要的 肺癌的病因学危险因素。我们的调查 重点阐明CYP 1A 1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之间的差异。 A.我们对人CYP 1A 1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显示， 该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 该元件对基因的整体表达仅贡献约30%。 这些数据得到了蛋白质/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。这项工作 代表了第一次努力的特点，监管要素 的人CYP 1A 1基因和确定的作用，每个在 成人肺中基因表达的调节。 B。CYP 1A 1基因表达的个体间差异可能是由于 编码CYP 1A 1的基因内的遗传差异的结果 转录调节蛋白。我们已经确认了至少两个 限制性片段长度多态性（RFLP）基因编码 CYP 1A 1基因的主要转录激活因子，芳香族 碳氢化合物（Ah）受体。年龄、种族和性别匹配的对照组和 经组织学证实的肺癌患者目前正在接受 检查以确定这些新获得的遗传基因的频率 两个群体中的标记。 这些项目的重要性在于阐明了 遗传决定因素和化学致癌物在 肺癌发生结果将有诊断和预防 应用.

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.