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J. Biol. Chem., Vol. 283, Issue 33, 22363-22370, August 15, 2008

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BACH1 Is a Specific Repressor of HMOX1 That Is Inactivated by Arsenite^*

John F. Reichard¹, Maureen A. Sartor, and Alvaro Puga

From the Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, Ohio 45267 and the Department of Pediatrics, Division of Newborn Medicine, Children's Hospital Boston, Boston, Massachusetts 02115

Intracellular heme is a redox active molecule that can be detrimental to cells at high concentrations or under oxidizing conditions. To prevent accumulation, the inducible enzyme heme oxygenase-1 (HMOX1) catalyzes degradation of heme. In the absence of elevated intracellular heme or oxidative stress, the basic region leucine zipper transcriptional regulator BACH1 binds HMOX1 antioxidant response elements and represses transcription. Conversely, increased intracellular heme or sulfhydryl oxidation inactivate BACH1, permitting transcriptional induction of HMOX1. Here, we investigate the effect of BACH1 inactivation on the induction of HMOX1 and as a mechanism for broader gene induction. We show that BACH1 is inactivated at low micromolar arsenite concentrations and that BACH1 inactivation is necessary and sufficient for transcriptional induction of HMOX1. Because BACH1 is thought to interact with antioxidant response element motifs, we further examined the role of BACH1 as a regulator of inducible antioxidant gene expression by assessing the global profile of gene expression following BACH1 knockdown using small interfering RNA. The loss of BACH1 function in human keratinocytes results almost exclusively in HMOX1 induction, suggesting that BACH1 may function as a rheostat regulating levels of intracellular free heme.

Received for publication, March 5, 2008 , and in revised form, June 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 ES10807 and P30 ES06096. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ Supported in part by NIEHS, National Institutes of Health Grant T32 ES07250 and an Environmental Carcinogenesis and Mutagenesis Training Grant. To whom correspondence should be addressed. Tel.: 617-919-4535; Fax: 617-730-0260; E-mail: john.reichard{at}childrens.harvard.edu.

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