Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes.
Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes.
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DOI：
10.1042/bj20061611
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发表时间：
2007-06
期刊：
影响因子：
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通讯作者：
Jianyong Zhang;Tomonori Hosoya;Atsushi Maruyama;K. Nishikawa;J. Maher;T. Ohta;H. Motohashi;A. Fukamizu;S. Shibahara;K. Itoh;Masayuki Yamamoto
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文献类型：
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作者：
Jianyong Zhang;Tomonori Hosoya;Atsushi Maruyama;K. Nishikawa;J. Maher;T. Ohta;H. Motohashi;A. Fukamizu;S. Shibahara;K. Itoh;Masayuki Yamamoto
转录因子Nrf2包含两个转录激活结构域，Neh4(Nrf2 ECH同源4)和Neh5，它们协调调节细胞保护基因的反式激活。在本研究中，我们旨在阐明Neh5结构域在Nrf2介导的基因调控中的作用。在人肾上皮细胞中，Neh5结构域的完整缺失降低了内源性Nrf2靶基因的表达，如HO-1(血红素加氧酶1)、NQO1[NAD(P)H：苯醌氧化还原酶1]和GCLM(谷氨酸半胱氨酸连接酶调制亚单位)。此外，Neh5的缺失显著抑制了CBP[CREB(cAMP反应元件结合蛋白)结合蛋白]和BRG1(Brahma相关基因1)与Nrf2的结合，削弱了它们对HO-1启动子活性的协同增强。Neh5结构域的突变分析显示了一个与β-肌动蛋白和ARP1(肌动蛋白相关蛋白1)有显著同源性的基序。该基序的突变选择性地降低了HO-1的表达，但不影响NQO1和GCLM的表达。综上所述，这些结果表明，Neh5结构域具有调控Nrf2靶基因转录的能力，但其在转录中的作用因基因而异。
The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) contains two transcription activation domains, Neh4 (Nrf2 ECH homology 4) and Neh5, which co-ordinately regulate transactivation of cytoprotective genes. In the present study we aimed to clarify the role of the Neh5 domain in Nrf2-mediated gene regulation. Deletion of the complete Neh5 domain reduces expression of endogenous Nrf2 target genes, such as HO-1 (haem oxygenase 1), NQO1 [NAD(P)H:quinone oxidoreductase 1] and GCLM (glutamate cysteine ligase modulatory subunit), in human kidney epithelial cells. Furthermore, the deletion of Neh5 markedly repressed CBP [CREB (cAMP-response-element-binding protein)-binding protein] and BRG1 (Brahma-related gene 1) from associating with Nrf2, diminishing their co-operative enhancement of HO-1 promoter activity. Mutational analysis of the Neh5 domain revealed a motif that shares significant homology with beta-actin and ARP1 (actin-related protein 1). Mutagenesis of this motif selectively decreased HO-1, but not NQO1 and GCLM, expression. Taken together, these results indicate that the Neh5 domain has the ability to regulate Nrf2 target gene transcription, yet the role of the Neh5 domain in transcription varies from gene to gene.