Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, CA 95616, USA.
Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan.
Int J Mol Sci. 2017 Nov 10;18(11):2386. doi: 10.3390/ijms18112386.
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, and , are robustly induced upon smoke by different mechanisms in human bronchial epithelia. is mediated by aryl hydrocarbon receptor signaling, while induction of is regulated by oxidative stress, and suppressed by -acetylcysteine treatment. In light of a pivotal role of NRF2 and BACH1 in response to oxidative stress and regulation of , we examined if smoke-induced 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 expression while down-regulation of BACH1 had stimulatory effects on both basal and smoke-induced 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 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 induction.
香烟烟雾已被证实会引发异常信号通路和病理生理过程；然而，烟雾引起基因表达的调控机制仍有待确定。在此，我们观察到，在人类支气管上皮细胞中，两种对烟雾有反应的基因 和 ，通过不同的机制在烟雾作用下被强烈诱导。 是由芳香烃受体信号介导的，而 的诱导则受氧化应激调控，并被 -乙酰半胱氨酸处理抑制。鉴于 NRF2 和 BACH1 在应对氧化应激和 调控中的关键作用，我们研究了烟雾诱导 的表达是否通过 NRF2/BACH1 轴进行调节。我们证明，烟雾会导致 NRF2 大量核转位，但核 BACH1 仅略有减少。NRF2 的敲低会减弱烟雾诱导的 表达，而 BACH1 的下调对基础和烟雾诱导的 均有刺激作用，对 NRF2 的核转位影响甚微。染色质免疫沉淀试验表明，烟雾会增强 NRF2 对启动子特异性 DNA 结合，但抑制 BACH1 结合到 启动子 ARE 位点，其中两个位于-1.0 kb 和-2.6 kb 的位点是新鉴定的。这些结果表明，NRF2 激活剂和 BACH1 抑制剂结合到 ARE 位点的调控对于烟雾介导的 诱导至关重要。
