Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction.
Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction.
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DOI：
10.3390/ijms18112386
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发表时间：
2017-11-10
影响因子：
5.6
通讯作者：
Chen CH
中科院分区：
文献类型：
--
作者：
Chang WH;Thai P;Xu J;Yang DC;Wu R;Chen CH
香烟烟雾已被证明会触发异常的信号通路和病理生理过程;然而，烟雾诱导的基因表达的调控机制仍有待建立。在此，我们观察到两个烟雾反应基因，HO-1和CYP 1A 1，在人支气管上皮细胞中通过不同的机制受到烟雾的强烈诱导。CYP 1A 1由芳香烃受体信号传导介导，而HO-1的诱导受氧化应激调节，并被N-乙酰半胱氨酸处理抑制。鉴于NRF 2和BACH 1在响应氧化应激和调节HO-1中的关键作用，我们研究了烟雾诱导的HO-1表达是否通过NRF 2/BACH 1轴调节。我们证明，烟雾导致显着的核转位NRF 2，但只有轻微的减少核BACH 1。NRF 2的敲低减弱了烟雾诱导的HO-1表达，而BACH 1的下调对基础和烟雾诱导的HO-1都有刺激作用，对NRF 2核转位的影响很小。染色质免疫沉淀分析表明，烟雾增强了NRF 2的启动子特异性DNA结合，但抑制了BACH 1与HO-1启动子ARE位点的结合，其中两个位于-1.0 kb和-2.6 kb的位点是新发现的。这些结果表明，NRF 2激活剂和BACH 1阻遏物的ARE位点的结合的调节是至关重要的烟雾介导的HO-1诱导。
Cigarette smoke has been shown to trigger aberrant signaling pathways and pathophysiological processes; however, the regulatory mechanisms underlying smoke-induced gene expression remain to be established. Herein, we observed that two smoke-responsive genes, HO-1 and CYP1A1, are robustly induced upon smoke by different mechanisms in human bronchial epithelia. CYP1A1 is mediated by aryl hydrocarbon receptor signaling, while induction of HO-1 is regulated by oxidative stress, and suppressed by N-acetylcysteine treatment. In light of a pivotal role of NRF2 and BACH1 in response to oxidative stress and regulation of HO-1, we examined if smoke-induced HO-1 expression is modulated through the NRF2/BACH1 axis. We demonstrated that smoke causes significant nuclear translocation of NRF2, but only a slight decrease in nuclear BACH1. Knockdown of NRF2 attenuated smoke-induced HO-1 expression while down-regulation of BACH1 had stimulatory effects on both basal and smoke-induced HO-1 with trivial influence on NRF2 nuclear translocation. Chromatin immunoprecipitation assays showed that smoke augments promoter-specific DNA binding of NRF2 but suppresses BACH1 binding to the HO-1 promoter ARE sites, two of which at −1.0 kb and −2.6 kb are newly identified. These results suggest that the regulation of NRF2 activator and BACH1 repressor binding to the ARE sites are critical for smoke-mediated HO-1 induction.
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影响因子：
3.7
作者：
Goven D;Boutten A;Leçon-Malas V;Marchal-Sommé J;Soler P;Boczkowski J;Bonay M
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通讯作者：
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