由芳烃受体-芳烃受体核转运蛋白异二聚体介导的大鼠CYP1A2基因的一种新型诱导机制。

A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer.

作者信息

Sogawa Kazuhiro, Numayama-Tsuruta Keiko, Takahashi Tomohiro, Matsushita Natsuki, Miura Chisa, Nikawa Jun-ichi, Gotoh Osamu, Kikuchi Yasuo, Fujii-Kuriyama Yoshiaki

机构信息

Department of Biomolecular Science, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.

出版信息

Biochem Biophys Res Commun. 2004 Jun 4;318(3):746-55. doi: 10.1016/j.bbrc.2004.04.090.

DOI:10.1016/j.bbrc.2004.04.090

PMID:15144902

Abstract

We have identified an enhancer responsible for induction by 3-methylcholanthrene in the upstream region of the CYP1A2 gene. The enhancer does not contain the invariant core sequence of XREs that are binding sites for the Ah receptor (AhR) and Arnt heterodimer. The enhancer did not show any inducible expression in Hepa-1-derived cell lines, C4 and C12, deficient of Arnt and AhR, respectively. On the other hand, bacterially expressed AhR-Arnt heterodimer could not bind to the enhancer. Mutational analysis of the enhancer revealed that a repeated sequence separated by six nucleotides is important for expression. A factor binding specifically to the enhancer was found by using gel shift assays. Bacterially expressed AhR-Arnt heterodimer interacted with the factor. A dominant negative mutant of the AhR to XRE activated the enhancer. Collectively, these results demonstrate that a novel induction mechanism is present in which the AhR-Arnt heterodimer functions as a coactivator.

摘要

我们已在CYP1A2基因上游区域鉴定出一个负责由3 - 甲基胆蒽诱导的增强子。该增强子不包含作为芳烃受体（AhR）和芳烃受体核转运蛋白（Arnt）异二聚体结合位点的XREs的不变核心序列。该增强子在分别缺乏Arnt和AhR的Hepa - 1衍生细胞系C4和C12中未显示出任何诱导性表达。另一方面，细菌表达的AhR - Arnt异二聚体无法与该增强子结合。对该增强子的突变分析表明，由六个核苷酸隔开的重复序列对表达很重要。通过凝胶迁移试验发现了一种与该增强子特异性结合的因子。细菌表达的AhR - Arnt异二聚体与该因子相互作用。AhR针对XRE的显性负性突变体激活了该增强子。总体而言，这些结果表明存在一种新的诱导机制，其中AhR - Arnt异二聚体作为共激活因子发挥作用。