Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase(1) gene
Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase(1) gene
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DOI：
10.1073/pnas.93.25.14960
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发表时间：
1996-12-10
影响因子：
11.1
通讯作者：
Jaiswal, AK
中科院分区：
文献类型：
--
作者：
Venugopal, R;Jaiswal, AK
人类抗氧化反应元件(HARE)的24个碱基对是NAD(P)H：苯醌氧化还原酶(1)(NQO(1))基因的高基转录及其对外源生物和抗氧化剂的诱导。HARE是一种独特的顺式元件，它包含一个完美的和一个不完美的AP1元件，它们以反向重复的形式排列，中间隔着3bp，后面跟着一个‘’GC‘’框。我们在这里报道了Jun、Fos、Fra和NRF核转录因子与兔的结合。核蛋白Jun和Fos或Jun和Fra1在人肝母细胞瘤(Hep-G2)细胞中的过表达抑制了Hare介导的氯霉素乙酰转移酶(CAT)基因表达。进一步的实验表明，这种抑制是由于c-Fos和Fra1的过度表达，而不是由于Jun蛋白。在所有可能的组合中，Jun(c-Jun、Jun-B和Jun-D)蛋白在抑制或上调Hare介导的基因表达方面或多或少是无效的。有趣的是，Nrf1和Nrf2分别在Hep-G2和猴肾(COS1)细胞中的过表达显著增加了报告载体Hare-胸苷激酶-CAT在β-萘黄酮和叔丁基对苯二酚诱导下的CAT基因表达。这些结果表明，Hare介导的NQO(1)基因的表达以及外源物质和抗氧化剂对其的诱导是由Nrf1和Nrf2介导的。然而，HARE介导的基础表达被c-Fos和Fra1的过表达抑制。
Twenty-four base pairs of the human antioxidant response element (hARE) are required for high basal transcription of the NAD(P)H:quinone oxidoreductase(1) (NQO(1)) gene and its induction in response to xenobiotics and antioxidants. hARE is a unique cis-element that contains one perfect and one imperfect AP1 element arranged as inverse repeats separated by 3 bp, followed by a ''GC'' box. We report here that Jun, Fos, Fra, and Nrf nuclear transcription factors bind to the hARE. Overexpression of cDNA derived combinations of the nuclear proteins Jun and Fos or Jun and Fra1 repressed hARE-mediated chloramphenicol acetyltransferase (CAT) gene expression in transfected human hepatoblastoma (Hep-G2) cells. Further experiments suggested that this repression was due to overexpression of c-Fos and Fra1, but not due to Jun proteins. The Jun (c-Jun, Jun-B, and Jun-D) proteins in all the possible combinations were more or less ineffective in repression or upregulation of hARE-mediated gene expression. Interestingly, overexpression of Nrf1 and Nrf2 individually in Hep-G2 and monkey kidney (COS1) cells significantly increased CAT gene expression from reporter plasmid hARE-thymidine kinase-CAT in transfected cells that were inducible by beta-naphthoflavone and tert-butyl hydroquinone. These results indicated that hARE-mediated expression of the NQO(1) gene and its induction by xenobiotics and antioxidants are mediated Nrf1 and Nrf2. The hARE-mediated basal expression, however, is repressed by overexpression of c-Fos and Fra1.