A novel role of the NRF2 transcription factor in the regulation of arsenite-mediated keratin 16 gene expression in human keratinocytes.
A novel role of the NRF2 transcription factor in the regulation of arsenite-mediated keratin 16 gene expression in human keratinocytes.
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DOI：
10.1289/ehp.10696
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发表时间：
2008-07
影响因子：
10.4
通讯作者：
Yoshida, Takahiko
中科院分区：
文献类型：
--
作者：
Endo, Hitoshi;Sugioka, Yoshihiko;Nakagi, Yoshihiko;Saijo, Yasuaki;Yoshida, Takahiko
关键词：
无机亚砷酸钠（iAs）是一种普遍存在的环境污染物，与皮肤角化过度和癌症的风险增加有关。我们研究了在人角质形成细胞系HaCaT中由iAs调节角蛋白16（K16）基因的分子机制。我们进行了逆转录酶聚合酶链反应，荧光素酶测定，蛋白质印迹和电泳迁移率变动分析，以确定由iAs的K16基因的转录调控。我们使用基因过表达的方法来阐明核因子红细胞衍生2相关因子2（NRF 2）参与K16诱导。iAs诱导K16的mRNA和蛋白表达。我们还发现，K16的表达是由iAs通过激活蛋白-1样位点和其基因启动子区的抗氧化反应元件（ARE）转录诱导的。用iAs处理还增强了NRF 2转录因子（ARE结合蛋白）的产生和易位，使其进入细胞核而不改变其mRNA表达。此外，iAs延长了NRF 2蛋白的半衰期。当在HaCaT细胞中过表达时，NRF 2不仅直接参与解毒基因硫氧还蛋白的上调，还直接参与K16基因的表达。我们的数据清楚地表明，K16基因是NRF 2的一个新靶点。此外，我们的研究结果还表明，NRF 2在细胞中具有相反的作用-激活解毒途径和促进皮肤病的发展。
Inorganic sodium arsenite (iAs) is a ubiquitous environmental contaminant and is associated with an increased risk of skin hyperkeratosis and cancer. We investigated the molecular mechanisms underlying the regulation of the keratin 16 (K16) gene by iAs in the human keratinocyte cell line HaCaT. We performed reverse transcriptase polymerase chain reaction, luciferase assays, Western blots, and electrophoretic mobility shift assays to determine the transcriptional regulation of the K16 gene by iAs. We used gene overexpression approaches to elucidate the nuclear factor erythroid-derived 2 related factor 2 (NRF2) involved in the K16 induction. iAs induced the mRNA and protein expression of K16. We also found that the expression of K16 was transcriptionally induced by iAs through activator protein-1–like sites and an antioxidant response element (ARE) in its gene promoter region. Treatment with iAs also enhanced the production and translocation of the NRF2 transcription factor, an ARE-binding protein, into the nucleus without modification of its mRNA expression. In addition, iAs elongated the half-life of the NRF2 protein. When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. Our data clearly indicate that the K16 gene is a novel target of NRF2. Furthermore, our findings also suggest that NRF2 has opposing roles in the cell—in the activation of detoxification pathways and in promoting the development of skin disorders.
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影响因子：
4.8
作者：
Chen, XL;Varner, SE;Kunsch, C
通讯作者：
Kunsch, C
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
DOI：
10.1073/pnas.90.14.6786
发表时间：
1993-07-15
影响因子：
11.1
作者：
JIANG, CK;MAGNALDO, T;BLUMENBERG, M
通讯作者：
BLUMENBERG, M
影响因子：
30.8
作者：
Wakabayashi, N;Itoh, K;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
10.4
作者：
Çöl, M;Çöl, C;Öztürk, S
通讯作者：
Öztürk, S