BRCA1 induces antioxidant gene expression and resistance to oxidative stress
BRCA1 induces antioxidant gene expression and resistance to oxidative stress
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DOI：
10.1158/0008-5472.can-04-1119
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Rosen, EM
中科院分区：
文献类型：
--
作者：
Bae, I;Fan, S;Rosen, EM
乳腺癌易感基因1（BRCA 1）是一种肿瘤抑制基因，其突变会增加患乳腺癌、卵巢癌和前列腺癌的风险。为了研究BRCA 1基因的功能，我们进行了DNA微阵列和验证性逆转录PCR分析，以确定BRCA 1调控的基因表达变化。我们发现BRCA 1上调了参与细胞保护性抗氧化反应的多个基因的表达，包括谷胱甘肽S-转移酶、氧化还原酶和其他抗氧化基因。与这些发现一致，BRCA 1过表达赋予抗性，而BRCA 1缺乏赋予对几种不同氧化剂（过氧化氢和百草枯）的敏感性。此外，在氧化应激（由于过氧化氢）的情况下，BRCA 1将细胞的氧化还原平衡转移到还原型谷胱甘肽与氧化型谷胱甘肽的更高比例。最后，BRCA 1刺激抗氧化反应元件驱动的转录活性，并增强抗氧化反应转录因子核因子红细胞衍生2样2 [也称为NRF 2（NFE 2L 2）]的活性。BRCA 1刺激抗氧化反应元件依赖性转录和保护细胞免受氧化应激的能力通过抑制核因子红细胞衍生2样2而减弱。这些发现表明BRCA 1的新功能，即，保护细胞免受氧化应激。这一功能与BRCA 1作为保护基因组完整性的看守基因的假定作用一致。
Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.