CYP1A1 GENE REGULATION AND HUMAN CANCER

CYP1A1 基因调控与人类癌症

• 批准号: 3774739
• 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/3774739
• 关键词: carbopolycyclic compound; chemical carcinogenesis; clone cells; cytochrome P450; gene expression; gene interaction; genetic regulation; human tissue; isozymes; lung neoplasms; mutant; protooncogene; regulatory gene; site directed mutagenesis; tobacco abuse; transcription factor

The cytochrome P450 isoenzyme CYP1A1 is intimately involved in the metabolic activation of pulmonary procarcinogens and its expression is induced by components found in tobacco smoke condensate. The CYP1A1 gene has been implicated as a risk factor in the etiology of lung cancer in heavy cigarette smokers. The role of human CYP1A1 in lung carcinogenesis was analyzed at the level of: A. General regulatory patterns in neoplastic and non-neoplastic lung. Oligonucleotide directed mutagenesis (ODM) of numerous potential transcriptional elements within the regulatory region of the human CYP1A1 gene was carried out. Using a panel of well characterized human non-small cell lung cancer (NSCLC) cell lines, we have identified a unique pattern of expression of the CYP1A1 gene that requires interaction with two copies of the transcriptional activator known as the aromatic hydrocarbon receptor at two widely separated DNA regulatory elements. B. Activator-repressor interactions. Elucidation of the pattern of expression of the human CYP1A1 gene involving two transcriptional activators has stimulated additional studies on the potential role of a transcriptional repressor or "silencer." C. Feedback modulation. In certain mutant murine derived hepatoma cell lines, the CYP1A1 gene product, aromatic hydrocarbon hydroxylase (AHH) was shown to play an autoregulatory role in CYP1A1 gene expression. We are investigating the possibility that, in some NSCLC lines, the elevated basal levels of CYP1A1 gene expression observed may be due to a similar mechanism. D. Proto-oncogene interaction. Preliminary studies have identified a potential interaction between the regulatory region of the CYP1A1 gene and the proto-oncogenes c-fos and c-jun. The significance of the project is to elucidate the interactive role of genetically determined factors and chemical carcinogens in pulmonary carcinogenesis. The results will have diagnostic and prevention applications.

细胞色素P450同工酶CYP 1A 1密切参与细胞色素P450的合成。 代谢活化的肺前致癌物及其表达， 由烟草烟雾冷凝物中的成分引起。 cyp 1a 1基因 在肺癌的病因学中被认为是一个危险因素， 烟瘾很大。 人细胞色素P450 1A 1在肺癌发生中的作用 在以下层面进行了分析： A.肿瘤性和非肿瘤性肺的一般调节模式。 寡核苷酸定向诱变（ODM）的许多潜在的 人CYP 1A 1调控区内的转录元件 基因进行了。 使用一组充分表征的人类非小细胞肺癌细胞， 细胞肺癌（NSCLC）细胞系，我们已经确定了一种独特的模式， CYP 1A 1基因的表达需要与两个拷贝的 被称为芳香烃受体的转录激活因子， 两个相距甚远的DNA调控元件。 B。激活-抑制相互作用。 的模式阐明 涉及两个转录的人CYP 1A 1基因的表达 激活剂刺激了对潜在作用的进一步研究， 转录阻遏物或“沉默物”。" C.反馈调制。 在某些突变型小鼠肝癌细胞中， 细胞色素P450 1A 1基因产物芳烃羟化酶（AHH）， 显示在CYP 1A 1基因表达中起自动调节作用。 我们 研究在某些NSCLC细胞系中， 观察到的CYP 1A 1基因表达水平可能是由于类似的 机制 D.原癌基因相互作用 初步研究发现， CYP 1A 1基因调控区与 原癌基因c-fos和c-jun。 该项目的意义在于阐明 遗传因素和化学致癌物 致癌作用 结果将有诊断和预防 应用.