3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor α
3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor α
复制标题
DOI：
10.1158/0008-5472.can-05-3132
复制
发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Safe, S
中科院分区：
文献类型：
--
作者：
Abdelrahim, M;Ariazi, E;Safe, S
3-甲基胆蒽（3 MC）是一种芳香烃受体（AhR）激动剂，并且已经报道3 MC通过AhR-雌激素受体α（ER α）相互作用诱导雌激素活性。在这项研究中，我们使用3 MC和3，3 '，4，4'，5-五氯联苯（PCB）作为原型AhR配体，这两种化合物在MCF-7乳腺癌细胞中激活雌激素应答报告基因/基因产物（组织蛋白酶D）。这些AhR配体诱导的雌激素反应被抑制的抗雌激素ICI 182780和ER α的小抑制RNA的转染，但不受影响的小抑制RNA的AhR。这些结果表明，3 MC和PCB直接激活ER α，这在竞争性ER α结合测定和荧光共振能量转移实验中得到证实，其中PCB和3 MC诱导CFP-ER α/YFP-ER α相互作用。在染色质免疫沉淀试验中，PCB和3 MC增强ER α（但不是AhR）与pS2基因启动子的雌激素反应区的关联。此外，在AhR基因敲除小鼠中，3 MC增加子宫重量并诱导细胞周期蛋白D1 mRNA水平的表达。这些结果表明，PCB和3 MC直接激活ER α依赖性反式激活，并增加激活AhR和ER α的配体数量。
3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor alpha (ER alpha) interactions. In this study, we used 3MC and 3,3',4,4',5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ER alpha but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ER alpha, and this was confirmed in a competitive ER alpha binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ER alpha/YFP-ER alpha interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ER alpha (but not AhR) association with the estrogen-responsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ER alpha-dependent transactivation and extend the number of ligands that activate both AhR and ER alpha.