Thioredoxin and thioredoxin reductase influence estrogen receptor alpha-mediated gene expression in human breast cancer cells.
Thioredoxin and thioredoxin reductase influence estrogen receptor alpha-mediated gene expression in human breast cancer cells.
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DOI：
10.1677/jme-09-0053
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发表时间：
2009-12
影响因子：
3.5
通讯作者：
Nardulli AM
中科院分区：
文献类型：
--
作者：
Rao AK;Ziegler YS;McLeod IX;Yates JR;Nardulli AM
细胞中活性氧（ROS）的积累会破坏细胞内的蛋白质、脂质和DNA。为了克服ROS积累引起的氧化应激，细胞必须通过增加抗氧化酶水平来平衡自由基的产生，从而将自由基转化为危害较小的物种。我们在与dna结合的雌激素受体α (ERα)相关的复合物中发现了两种抗氧化酶，硫氧还蛋白（Trx）和Trx还原酶（TrxR）。Western分析和免疫细胞化学表明，Trx和TrxR在MCF-7人乳腺癌细胞的细胞质和细胞核中表达。更重要的是，内源性表达的ERα、Trx和TrxR相互作用，ERα和TrxR与MCF-7细胞中天然的、雌激素应答的pS2和孕激素受体基因相关。RNA干扰实验表明，Trx和TrxR对雌激素应答基因表达的影响不同，17β-雌二醇、Trx和TrxR共同改变MCF-7细胞中过氧化氢（H2O2）水平。我们的研究结果表明，Trx和TrxR是多功能蛋白，除了调节H2O2水平和转录因子活性外，还有助于ERα调节靶细胞中雌激素应答基因的表达。
Accumulation of reactive oxygen species (ROS) in cells damages resident proteins, lipids, and DNA. In order to overcome the oxidative stress that occurs with ROS accumulation, cells must balance free radical production with an increase in the level of antioxidant enzymes that convert free radicals to less harmful species. We identified two antioxidant enzymes, thioredoxin (Trx) and Trx reductase (TrxR), in a complex associated with the DNA-bound estrogen receptor α (ERα). Western analysis and immunocytochemistry were used to demonstrate that Trx and TrxR are expressed in the cytoplasm and in the nuclei of MCF-7 human breast cancer cells. More importantly, endogenously expressed ERα, Trx, and TrxR interact and ERα and TrxR associate with the native, estrogen-responsive pS2 and progesterone receptor genes in MCF-7 cells. RNA interference assays demonstrated that Trx and TrxR differentially influence estrogen-responsive gene expression and that together, 17β-estradiol, Trx, and TrxR alter hydrogen peroxide (H2O2) levels in MCF-7 cells. Our findings suggest that Trx and TrxR are multifunctional proteins that, in addition to modulating H2O2 levels and transcription factor activity, aid ERα in regulating the expression of estrogen-responsive genes in target cells.