Genetic evidence that small Maf proteins are essential for the activation of antioxidant response element-dependent genes
Genetic evidence that small Maf proteins are essential for the activation of antioxidant response element-dependent genes
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DOI：
10.1128/mcb.25.18.8044-8051.2005
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Katsuoka, F;Motohashi, H;Yamamoto, M
虽然小的Maf蛋白被认为是Nrf2介导的抗氧化反应元件(ARE)依赖基因的激活所必需的，但它们所需的程度仍未得到充分的证明。为了解决这个问题，我们产生了具有MafK的mafG：：Maff双突变小鼠作为单一可用的小Maf。经丁基羟基苯甲醚处理的双突变小鼠的NAD(P)H：苯醌氧化还原酶1(NQO1)基因的诱导显著受损，而其他ARE依赖基因的影响较小。同样，在Keap1缺失的背景中，许多Are依赖的基因以Nrf2依赖的方式被结构性激活，只有包括NQO1在内的Are依赖基因的子集对MafG和Maff的同时缺陷敏感。对单个和双个小MAF突变细胞的检测表明，MafK也有助于诱导ARE依赖的基因。为了获得决定性的证据，我们建立了mafG：：mafK：：maff三个突变的成纤维细胞，这些细胞完全缺乏小MAT，并被证明对氧化应激高度敏感。我们发现，在三个突变的细胞中，对马来酸二乙酯的诱导在更大范围的ARE依赖基因中被取消。这些数据清楚地表明，小MAF在很大一部分ARE依赖基因的诱导表达中发挥关键作用。
While small Maf proteins have been suggested to be essential for the Nrf2-mediated activation of antioxidant response element (ARE)-dependent genes, the extent of their requirement remains to be fully documented. To address this issue, we generated mafG::mafF double-mutant mice possessing MafK as the single available small Maf. Induction of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene was significantly impaired in double-mutant mice treated with butylated hydroxyanisole, while other ARE-dependent genes were less affected. Similarly, in a keap1-null background, where many of the ARE-dependent genes are constitutively activated in an Nrf2-dependent manner, only a subset of ARE-dependent genes, including NQO1, were sensitive to a simultaneous deficiency in MafG and MafF. Examination of single and double small maf mutant cells revealed that MafK also contributes to the induction of ARE-dependent genes. To obtain decisive evidence, we established mafG::mafK::mafF triple-mutant fibroblasts that completely lack small Mats and turned out to be highly susceptible to oxidative stress. We found that induction in response to diethyl maleate was abolished in a wider range of ARE-dependent genes in the triple-mutant cells. These data explicitly demonstrate that small Mafs play critical roles in the inducible expression of a significant portion of ARE-dependent genes.