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Nucleic Acids Research Advance Access originally published online on October 16, 2007
Nucleic Acids Research 2007 35(21):7074-7086; doi:10.1093/nar/gkm638
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Nucleic Acids Research, 2007, Vol. 35, No. 21 7074-7086
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1

John F. Reichard*, Gregory T. Motz and Alvaro Puga

Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA

* To whom correspondence should be addressed. Tel: +1 513 558 0712; Fax: +1 513 558 0925; Email: john.reichard{at}childrens.harvard.edu

Received May 21, 2007. Revised July 12, 2007. Accepted August 1, 2007.

Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.


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J. F. Reichard, M. A. Sartor, and A. Puga
BACH1 Is a Specific Repressor of HMOX1 That Is Inactivated by Arsenite
J. Biol. Chem., August 15, 2008; 283(33): 22363 - 22370.
[Abstract] [Full Text] [PDF]


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