Protection against chromium (VI)-induced oxidative stress and apoptosis by Nrf2. Recruiting Nrf2 into the nucleus and disrupting the nuclear Nrf2/Keap1 association
Protection against chromium (VI)-induced oxidative stress and apoptosis by Nrf2. Recruiting Nrf2 into the nucleus and disrupting the nuclear Nrf2/Keap1 association
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DOI：
10.1093/toxsci/kfm081
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发表时间：
2007-07-01
影响因子：
3.8
通讯作者：
Ma, Qiang
中科院分区：
文献类型：
--
作者：
He, Xiaoqing;Lin, Gary X.;Ma, Qiang
铬（Cr）（VI）是一种主要的环境有毒金属和人类致癌物。目前，介导细胞对Cr（VI）反应的分子事件尚不清楚。我们发现，Cr（VI）强力诱导小鼠Hepa 1c 1c 7细胞凋亡和活性氧（ROS）的产生，并呈浓度依赖性。缺乏Nrf 2的小鼠胚胎成纤维细胞表现出升高的ROS产生和凋亡，这是显着的Cr（VI）进一步增加，这表明Nrf 2对Cr（VI）毒性的保护作用。Nrf 2的保护作用与细胞保护基因Ho-1和Nqo 1的诱导相关。Cr（VI）对基因的诱导涉及抑制Nrf 2的泛素化和Nrf 2向细胞核中的积累。在细胞核中，处理铬（VI），但不是酚类抗氧化剂叔丁基氢醌，从Nrf 2/Keap 1协会和招聘Nrf 2的抗氧化反应元件（ARE）位于Ho-1和Nqo 1的增强子。Cr（VI）激活Nrf 2伴随着核转位和Keap 1的去泛素化，这意味着Keap 1在Nrf 2信号转导中的再循环。因此，针对Cr（VI）毒性的保护涉及转录信号传导环，其包括通过有毒金属激活Nrf 2、ARE驱动的基因的转录和ROS产生的减少。
Chromium (Cr) (VI) is a major environmental toxic metal and a human carcinogen. The molecular events mediating cellular responses to Cr(VI) are not clear at present. We show that Cr(VI) potently induced apoptosis and production of reactive oxygen species (ROS) in mouse hepa1c1c7 cells in a concentration-dependent manner. Mouse embryonic fibroblast cells lacking Nrf2 exhibited elevated ROS production and apoptosis, which were markedly further increased by Cr(VI), suggesting a protective role of Nrf2 against Cr(VI) toxicity. Protection by Nrf2 correlated with induction of cytoprotective genes Ho-1 and Nqo1. Induction of the genes by Cr(VI) involved inhibition of ubiquitination of Nrf2 and accumulation of Nrf2 into the nucleus. In the nucleus, treatment with Cr(VI), but not phenolic antioxidant tert-butylhydroquinone, librates Nrf2 from the Nrf2/Keap1 association and recruits Nrf2 to the antioxidant response elements (ARE) located in the enhancers of Ho-1 and Nqo1. Activation of Nrf2 by Cr(VI) was accompanied by the nuclear translocation and deubiquitination of Keap1 implicating recycling of Keap1 in Nrf2 signaling. Thus, protection against Cr(VI) toxicity involves a transcriptional signaling loop that includes activation of Nrf2 by the toxic metal, transcription of ARE-driven genes, and reduction of ROS production.