Preventing oxidative stress: a new role for XBP1.
Preventing oxidative stress: a new role for XBP1.
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DOI：
10.1038/cdd.2009.14
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发表时间：
2009-06
影响因子：
12.4
通讯作者：
Shinomura, Y.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Adachi, M.;Zhao, S.;Hareyama, M.;Koong, A. C.;Luo, Dan;Rando, T. A.;Imai, K.;Shinomura, Y.
抗氧化剂分子减少氧化应激，保护细胞免受活性氧（ROS）介导的细胞损伤，并可能发展为癌症。我们研究了X-box结合蛋白（XBP 1），一个主要的内质网应激相关的转录因子，细胞抗氧化应激的贡献。暴露于过氧化氢（H2 O2）或强活性氧诱导剂孤雌生殖后，线粒体膜电位（MMP）的损失和随后的细胞死亡发生更广泛的XBP 1缺陷细胞比野生型小鼠胚胎成纤维细胞，而其他两种抗癌药物诱导死亡类似的两种细胞。在XBP 1缺陷细胞中，H2 O2暴露诱导更广泛的ROS产生和延长p38磷酸化，和几种抗氧化分子，包括过氧化氢酶的表达较低。敲低XBP 1降低过氧化氢酶的表达，增强ROS的产生和MMP的损失后H2 O2暴露，但外源性过氧化氢酶供应拯救他们。过表达的XBP 1恢复过氧化氢酶的表达在XBP 1缺陷的细胞和减少ROS产生后H2 O2暴露。过氧化氢酶启动子区域的突变分析表明，CCAAT盒，NF-γ结合位点，对于XBP 1介导的增强作用具有关键作用。总之，这些结果表明，对氧化应激的保护作用的XBP 1，和过氧化氢酶表达的正调控可能至少在一定程度上解释了这一功能。
Antioxidant molecules reduce oxidative stress and protect cells from reactive oxygen species (ROS)-mediated cellular damage and probably the development of cancer. We have investigated the contribution of X-box-binding protein (XBP1), a major endoplasmic reticulum stress-linked transcriptional factor, to cellular resistance to oxidative stress. After exposure to hydrogen peroxide (H2O2) or a strong ROS inducer parthenolide, loss of mitochondrial membrane potential (MMP) and subsequent cell death occurred more extensively in XBP1-deficient cells than wild-type mouse embryonic fibroblast cells, whereas two other anticancer agents induced death similarly in both cells. In XBP1-deficient cells, H2O2 exposure induced more extensive ROS generation and prolonged p38 phosphorylation, and expression of several antioxidant molecules including catalase was lower. Knockdown of XBP1 decreased catalase expression, enhanced ROS generation and MMP loss after H2O2 exposure, but extrinsic catalase supply rescued them. Overexpression of XBP1 recovered catalase expression in XBP1-deficient cells and diminished ROS generation after H2O2 exposure. Mutation analysis of the catalase promoter region suggests a pivotal role of CCAAT boxes, NF-Y-binding sites, for the XBP1-mediated enhancing effect. Taken together, these results indicate a protective role of XBP1 against oxidative stress, and its positive regulation of catalase expression may at least in part account for this function.
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