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Int. J. Mol. Sci. 2017, 18(11), 2386; doi:10.3390/ijms18112386

Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction

1
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
2
Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
3
Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA 95616, USA
4
Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA
*
Author to whom correspondence should be addressed.
Received: 5 October 2017 / Revised: 31 October 2017 / Accepted: 8 November 2017 / Published: 10 November 2017
(This article belongs to the Special Issue Inhaled Pollutants Modulate Respiratory and Systemic Diseases)
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Abstract

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. View Full-Text
Keywords: smoke; HO-1; NRF2; gene regulation; airway epithelium smoke; HO-1; NRF2; gene regulation; airway epithelium
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MDPI and ACS Style

Chang, W.-H.; Thai, P.; Xu, J.; Yang, D.C.; Wu, R.; Chen, C.-H. Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction. Int. J. Mol. Sci. 2017, 18, 2386.

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