CYP1A1 GENE REGULATION AND HUMAN CANCER

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，其表达是 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 在以下水平进行了分析： A.肿瘤性和非肿瘤性肺的一般调节模式。 调控区DNA的寡核苷酸定向诱变（ODM）和 随后的转染实验用一组 人非小细胞肺癌（NSCLC）细胞系。 不同的模式 以及显著不同的CYP 1A 1基因基础（非诱导）水平 表达的特点，从而扩大了观察， 到目前为止，我们已经确定了两类潜在的 可能导致CYP 1A 1基因基础水平升高的改变 在NSCLC中观察到表达。 B。激活子-抑制子相互作用。 我们已经确定了一个CYP 1A 1基因 在通过ODM改变后， 基因表达水平的增加--暗示着 一种抑制剂。 目前正在继续进行工作， 监管要素。 C.反馈调制。 在小鼠肝癌细胞系中， CYP 1A 1基因产物芳烃羟化酶（AHH）被证明是 在CYP 1A 1基因表达中起自身调节作用。 我们 研究在一些NSCLC细胞系中， 观察到的CYP 1A 1基因表达的基础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基因调控区之间的潜在相互作用 以及原癌基因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.

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 implicate 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 following levels: A. General regulatory patterns in neoplastic and non-neoplastic lung. Oligonucleotide directed mutagenesis (ODM) of regulatory region DNA and subsequent transfection experiments are being carried out with a panel of human non-small cell lung cancer (NSCLC) cell lines. Distinct patterns as well as strikingly different basal (non-induced) levels of CYP1A1 gene expression have been characterized, thus extending the observations by McLemore et al. To date, we have identified two potential classes of alteration that may account for the elevated basal levels of CYP1A1 gene expression observed in NSCLC. B. Activator-repressor interactions. We have identified one CYP1A1 gene regulatory element that, upon alteration via ODM, resulted in an increased level of expression of the gene--suggestive of an interaction with a repressor. Work is continuing on the identification of additional regulatory elements. C. Feedback modulation. In 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.