Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element
Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element
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DOI：
10.1016/j.bbaexp.2003.08.006
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发表时间：
2003-10-01
期刊：
影响因子：
--
通讯作者：
Johnson, JA
中科院分区：
文献类型：
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作者：
Lee, JM;Anderson, PC;Johnson, JA
抗氧化反应元件（ARE）在II相解毒酶如NAD（P）H：醌氧化还原酶1（NQO 1）的基因表达中起重要作用，NF-E2相关因子2（Nrf 2）是ARE驱动基因的转录因子。有趣的是，据报道雌激素受体（ER）通过ARE增加NQO 1基因表达。在这项研究中，我们研究了ER和Nrf 2在ARE激活中的作用，IMR-32细胞和小鼠原代星形胶质细胞。在测试的雌激素相关化合物中，只有儿茶酚类雌激素（即4-羟基雌激素）激活ARE。由于4-hydroxyestradiol诱导的ARE激活不受17 β-雌二醇或他莫昔芬的抑制，ER-α的过表达降低了4-hydroxyestradiol诱导的ARE激活，因此儿茶酚雌激素对ARE的激活不依赖于ER。而Nrf 2在4-羟基雌甾二醇诱导的ARE激活中起重要作用。4-在Nrf 2基因敲除的原代星形胶质细胞中，羟基磷灰石不激活ARE，但当Nrf 2转染到Nrf 2星形胶质细胞中时，羟基磷灰石激活ARE。此外，显性负性Nrf 2完全阻断Nrf 2 +/+星形胶质细胞中4-羟基雌二醇诱导的ARE激活，并且在IMR-32细胞中仅4-羟基雌二醇诱导Nrf 2核转位。选择性磷脂酰肌醇3-激酶（PI 3-kinase）抑制剂（LY 294002）阻断4-羟基雌二醇诱导的IMR-32细胞Nrf 2核转位和NQO 1活性诱导。综上所述，这些观察结果表明，4-羟乙烯基吡咯烷酮通过P13-激酶-Nrf 2依赖性机制激活ARE，而不涉及ER。(C)2003 Elsevier B.V保留所有权利。
The antioxidant responsive element (ARE) plays an important role in the gene expression of phase II detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), and NF-E2-related factor2 (Nrf2) is the transcription factor for the ARE-driven genes. Interestingly, estrogen receptor (ER) was reported to increase NQO1 gene expression through the ARE. In this study, we investigated the role of ER and Nrf2 in ARE activation using, IMR-32 cells and mouse primary astrocytes. Among tested estrogen-related compounds, only catechol estrogens (i.e. 4-hydroxyestradiol) activated the ARE. Since 4-hydroxyestradiol-induced ARE activation was not inhibited by either 17beta-estradiol or tamoxifen, and overexpression of ER-alpha decreased 4-hydroxyestradiol-induced ARE activation, ARE activation by catechol estrogen was independent of ER. Nrf2, however, was very important in the 4-hydroxyestradiol-induced ARE activation. 4-Hydroxyestradiol did not activate the ARE in Nrf2 knockout primary astrocytes, but did activate the ARE when Nrf2 was transfected into Nrf2 astrocytes. In addition, dominant negative Nrf2 completely blocked 4-hydroxyestradiol-induced ARE activation in Nrf2+/+ astrocytes, and only 4-hydroxyestradiol induced Nrf2 nuclear translocation in IMR-32 cells. A selective phosphatidylinositol 3-kinase (PI3-kinase) inhibitor (LY294002) blocked 4-hydroxyestradiol-induced Nrf2 nuclear translocation and NQO1 activity induction in IMR-32 cells. Taken together, these observations suggest that 4-hydroxyestradiol activates the ARE by a P13-kinase-Nrf2 dependent mechanism, not involving ER. (C) 2003 Elsevier B.V All rights reserved.