Structure and polymorphisms of human aryl hydrocarbon receptor repressor (AhRR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer.
Structure and polymorphisms of human aryl hydrocarbon receptor repressor (AhRR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer.
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DOI：
10.1097/01.fpc.0000054093.48725.79
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发表时间：
2003-06
期刊：
影响因子：
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通讯作者：
S. Cauchi;I. Stücker;S. Cénée;P. Kremers;P. Beaune;L. Massaad-Massade
中科院分区：
文献类型：
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作者：
S. Cauchi;I. Stücker;S. Cénée;P. Kremers;P. Beaune;L. Massaad-Massade
目的 芳烃受体阻遏蛋白 (AhRR) 蛋白可能与 AhR 核易位蛋白 (ARNT) 形成二聚体，并可能与芳烃受体 (AhR) 竞争结合异生素反应元件。其结果是一种负反馈机制，涉及所有受 AhR 转录因子调节的基因的下调，该转录因子正向调节细胞色素 P-4501A1 基因 (CYP1A1) 的表达。方法重建AhRR基因的结构，然后研究该基因（包括启动子）的遗传多态性，并检查这些多态性、CYP1A1诱导性和法国人群肺癌发病率之间的联系。发现了四个多态性，两个位于编码区（609G>C 和 1977G>C），两个位于 5'-非翻译区（-96G>A 和 -869A>T）。在这四种多态性中，只有一种，即609G>C，之前已被描述过。 609G>C 和 1977G>C 分别位于外显子 6 和 12 中，并分别导致 Pro554Ala 和 Asp641His 取代。为了评估这些等位基因变异的频率，对肺癌病例对照研究的 DNA 文库（164 名对照者和 171 名患者）进行了筛选。在对照和患者中，这些多态性以相同的等位基因频率（609C 为 0.40，1977C 为 0.05，-96A 为 0.24，-869T 为 0.17）检测到。统计分析没有显示所有发现的突变与 CYP1A1 诱导性和肺癌发病率之间存在任何关系。结论 没有发现任何多态性在 CYP1A1 诱导或肺癌易感性中起关键作用。
OBJECTIVE The aryl hydrocarbon receptor repressor (AhRR) protein may dimerize with the AhR nuclear translocator (ARNT) and may compete with the aryl hydrocarbon receptor (AhR) to bind the xenobiotic responsive elements. The result is a negative feedback mechanism that involves a down regulation of all genes regulated by the AhR transcription factor which positively regulates the expression of the Cytochrome P-4501A1 gene (CYP1A1). METHODS The structure of the AhRR gene was reconstituted, then the genetic polymorphisms of this gene including the promoter were investigated and the link between these polymorphisms, CYP1A1 inducibility and lung cancer incidence in a French population was examined. Four polymorphisms were found, two in the coding region (609G>C and 1977G>C) and two in the 5'-untranslated region (-96G>A and -869A>T). Among the four polymorphisms, only one, the 609G>C has been previously described. The 609G>C and 1977G>C are localized respectively in exon 6 and 12 and lead to Pro554Ala and Asp641His substitutions, respectively. To evaluate the frequency of these allelic variants, a DNA library of a case-control study of lung cancer (164 controls and 171 patients) was screened. These polymorphisms were detected at the same allele frequency (0.40 for 609C, 0.05 for 1977C, 0.24 for -96A and 0.17 for -869T) in both controls and patients. Statistical analysis did not show any relationship between all the mutations found and CYP1A1 inducibility and lung cancer incidence. CONCLUSION None of the polymorphisms were found to play a key role in CYP1A1 inducibility or in the susceptibility to develop lung cancer.