NF-κB and AP-1 are key signaling pathways in the modulation of NAD(P)H:quinone oxidoreductase 1 gene by mercury, lead, and copper
NF-κB and AP-1 are key signaling pathways in the modulation of NAD(P)H:quinone oxidoreductase 1 gene by mercury, lead, and copper
复制标题
DOI：
10.1002/jbt.20238
复制
发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
El-Kadi, Ayman O. S.
中科院分区：
文献类型：
--
作者：
Korashy, Hesham M.;El-Kadi, Ayman O. S.
我们先前已经证明，Hg2+、Pb2+和Cu2+通过氧化应激依赖的机制显著调节HEPA 1c1c7细胞中NAD(P)：Quone氧化还原酶1(NQO1)的表达。在本研究中，我们研究了氧化还原敏感转录因子、核因子-kappaB和AP-1信号通路在重金属调控NQO1中的作用。我们的结果表明，用L-丁硫氨酸-(S，R)-亚磺胺去除细胞内GSH，在基因和活性水平上进一步增强了重金属介导的NQO_1的诱导作用。核因子-kappaB激活剂PMA可显著消除金属对NQO1mRNA和活性的影响。同时，NF-kappa B抑制剂PDTC进一步增强了Pb2+和Hg2+介导的NQO1mRNA和活性水平的诱导。SP600125抑制AP-1上游信号通路如JNK，显著抑制重金属诱导的NQO1mRNA和活性水平。相反，U0126对ERK的抑制进一步增强了重金属对NQO1mRNA的影响，而仅增强了Hg2+对NQO1活性的诱导作用。此外，p38MAPK抑制剂SB203580在mRNA水平上进一步增强了Pb2+和Cu2+介导的作用，但不改变活性水平。这些结果清楚地表明，核因子-kappaB的激活对重金属对NQO1的表达具有负性调节作用，而AP-1信号通路对重金属介导的效应有不同的调节作用。(C)2008年威利期刊公司。
We have previously shown that Hg2+, Pb2+, and Cu2+, significantly modulate the expression of NAD(P):quinone oxidoreductase 1. (Nqo1) in Hepa 1c1c7 cells through oxidative stress-dependent mechanisms. In the current study, we examined the role of redox-sensitive transcription factors, NF-kappa B and AP-1 signaling pathways in the modulation of Nqo1 by heavy metals. Our results show that the depletion of cellular GSH using L-buthionine-(S,R)-sulfoximine further potentiated the heavy metal-mediated induction of Nqo1 at the mRNA and activity levels. The NF-kappa B activator, PMA, significantly abolished the metal-mediated effects on Nqo1 mRNA and activity. In parallel, the NF-kappa B inhibitor, PDTC, further potentiated the Pb2+- and Hg2+-mediated induction of Nqo1 mRNA and activity levels, respectively. Inhibition of AP-1 upstream signaling pathway such as JNK by SP600125 significantly suppressed heavy metal-mediated induction of Nqo1 mRNA and activity levels. In contrast, inhibition of ERK by U0126 further potentiated heavy metal-mediated effects on Nqo1 mRNA, while only potentiated Hg2+-mediated induction of Nqo1 activity. Furthermore, p38 MAPK inhibitor, SB203580 further potentiated Pb2+- and Cu2+- mediated effects at the mRNA levels, whereas did not alter the activity levels. These results clearly demonstrate that activation of NF-kappa B negatively regulates the expression of Nqo1 by heavy metals, whereas AP-1 signaling pathways differentially modulates the heavy metal-mediated effects. (C) 2008 Wiley Periodicals, Inc.