CYP1A1 GENE REGULATION AND HUMAN CANCER

CYP1A1 基因调控与人类癌症

• 批准号: 5201408
• 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/5201408
• 关键词: cancer risk; carbopolycyclic compound; chemical carcinogen; chemical carcinogenesis; cytochrome P450; environment related neoplasm /cancer; gender difference; gene expression; gene frequency; genetic markers; genetic polymorphism; genetic regulation; human genetic material tag; human population genetics; human tissue; lung neoplasms; neoplasm /cancer genetics; neoplastic cell; racial /ethnic difference; receptor binding; restriction fragment length polymorphism; tobacco abuse

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 numerous procarcinogenic polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke and other environmental pollutants to highly reactive intermediates. Numerous studies have reported a significant correlation between this phenotype and an enhanced susceptibility to lung cancer in cigarette smokers. 1) Determination of the molecular mechanisms responsible for expression of the human CYP1A1 gene. Induction of CYP1A1 gene expression is mediated through the action of the Ah receptor (AhR). There are at least five candidate binding sites for the AhR within the regulatory region of the CYP1A1 gene, and we have carried out a detailed functional analysis of each. By this procedure we have identified a unique mechanism for the expression of the CYP1A1 gene. 2) Identification of novel polymorphisms of the gene encoding the ligand-binding subunit of the Ah receptor (AhR). We have undertaken the task of identifying polymorphisms within genes associated with the regulation of CYP1A1 gene expression. We recently published the identification of an MspI restriction fragment length polymorphism (RFLP) of the AhR. DNAs from age, race, and sex matched controls and histologically confirmed lung cancer patients were examined to determine the frequency of the newly acquired genetic marker within the two populations. The polymorphic allele was present in 67% of the control population and absent in 33%. In the lung cancer population, the polymorphic allele was present in 53% of the individuals examined and absent in the remaining 47%. We have determined that the absence of the polymorphic allele is a factor associated with increased lung cancer risk (OR 2.45). Preliminary data also suggest that there are gender and race differences in the frequency of the polymorphism. Further characterization of this polymorphism is in progress.

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 CYP1A1基因的产物及其相关的催化活性， 包括芳基（或芳族）烃羟化酶（AHH），是已知的 与许多代谢活化密切相关， 致癌多环芳烃（PAHs），发现于 香烟烟雾和其他环境污染物的高度反应性 中间体的许多研究都报告了一个重要的相关性 这种表型与肺癌易感性增强之间的关系， 吸烟者。 1)确定负责的分子机制 人CYP1A1基因的表达。 CYP1A1基因的诱导 表达通过Ah受体（AhR）的作用介导。 在该区域内存在至少五个AhR的候选结合位点。 CYP1A1基因的调控区，我们已经进行了 详细的功能分析。通过这个过程，我们已经确定了 CYP1A1基因表达的独特机制。 2)鉴定了编码抗肿瘤药物的基因的新多态性， 配体结合亚单位的Ah受体（AhR）。 我们采取了 识别与癌症相关的基因内的多态性的任务 CYP1A1基因表达的调控。我们最近出版了 MspI限制性片段长度多态性鉴定 （RFLP）的AhR。来自年龄、种族和性别匹配的对照组的DNA， 对经组织学证实的肺癌患者进行检查， 新获得的遗传标记的频率在两个 人口。多态性等位基因在67%的对照中存在 人口和缺席的33%。在肺癌人群中， 多态性等位基因存在于53%的个人检查， 剩下的47%没有。我们已经确定， 多态等位基因是与肺癌增加相关的因素 风险（OR 2.45）。初步数据还表明，性别和 多态性频率的种族差异。进一步 该多态性的表征正在进行中。