Human catechol-O-methyltransferase down-regulation by estradiol
Human catechol-O-methyltransferase down-regulation by estradiol
复制标题
DOI：
10.1016/s0028-3908(03)00286-7
复制
发表时间：
2003-12-01
影响因子：
4.7
通讯作者：
Ho, SL
中科院分区：
文献类型：
--
作者：
Jiang, H;Xie, T;Ho, SL
儿茶酚-O-甲基转移酶（COMT）是多巴胺和左旋多巴代谢的关键酶。以前我们报道，生理浓度的17 β-雌二醇（E2）下调稳定状态的1.3 kb COMT mRNA水平在MCF-7细胞。在这项研究中，我们研究了在胶质细胞系（U138 MG）中是否发生了类似的减少，以及COMT蛋白和活性水平是否与MCF-7细胞中COMT mRNA水平的减少一致。此外，我们还探讨了E2的作用机制。E2对U138 MG细胞中COMT mRNA水平没有影响，但显著降低了MCF-7细胞中COMT蛋白和活性（相对于非E2处理的细胞，在10（-7）M E2时活性降低53%，在10（-8）M E2时活性降低45%，在10（-9）M E2时活性降低28%）。一种特异性雌激素受体拮抗剂（ICI 182780）阻断了这些雌激素效应。用E2（10（-9）M）预处理MCF-7细胞48 h后，用电泳迁移率变动分析（EMSA）测定，细胞核提取物中的雌激素受体与整个启动子近端和远端区域结合。我们建议，E2通过下调其基因和蛋白质表达介导的ER与基因启动子区的响应元件的相互作用，降低COMT活性。我们的研究结果可以解释女性COMT活性低于男性的原因，部分原因是E2治疗对绝经后帕金森病患者的有益作用。(C)2003 Elsevier Ltd.保留所有权利。
Catechol-O-methyltransferase (COMT) is a crucial enzyme in dopamine and levodopa metabolism. Previously we reported that physiological concentrations of 17beta-estradiol (E2) down-regulated steady-state 1.3-kb COMT mRNA levels in MCF-7 cells. In this study, we investigated whether similar reductions occurred in a glial cell line (U138MG) and whether COMT protein and activity levels paralleled the reduction in COMT mRNA levels in MCF-7 cells. In addition, we explored the mechanism of E2 action. E2 had no effect on COMT mRNA levels in U138MG cells, but significantly reduced COMT protein and activity in MCF-7 cells (activity by 53% at 10(-7) M of E2, by 45% at 10(-8) M, and by 28% at 10(-9) M relative to non-E2-treated cells). A specific estrogen receptor antagonist (ICI 182780) blocked these estrogenic effects. Estrogen receptor in nuclear extracts of MCF-7 cells, which were pretreated with E2 (10(-9) M) for 48 h, bound to the whole proximal and distal promoter regions, as determined by electrophoretic mobility shift analysis (EMSA). We propose that E2 decreased COMT activity through down-regulation of its gene and protein expression mediated via ER interaction with response elements in the promoter region of the gene. Our findings may explain the lower of COMT activity in women compared to that in men, and, in part, the beneficial effects of E2 therapy in post-menopausal Parkinson's disease patients. (C) 2003 Elsevier Ltd. All rights reserved.