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J. Biol. Chem., Vol. 282, Issue 9, 6875-6886, March 2, 2007

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JunB and JunD Regulate Human Heme Oxygenase-1 Gene Expression in Renal Epithelial Cells^*

Thomas D. Hock, Karen Liby^¶, Marcienne M. Wright, Sean McConnell¹, Marina Schorpp-Kistner^||, Thomas M. Ryan, and Anupam Agarwal²

From the Department of Medicine, Nephrology Research and Training Center, and the Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, ^¶Dartmouth Medical School, Hanover, New Hampshire 03755, and ^||Division for Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany

Heme oxygenase-1 is a highly inducible gene, the product of which catalyzes breakdown of the prooxidant heme. The purpose of this study was to investigate the regulation of the human heme oxygenase-1 gene in renal epithelial cells. DNase I hyper-sensitivity studies identified three distal sites (HS-2, -3, and -4) corresponding to approximately -4.0, -7.2, and -9.2 kb, respectively, of the heme oxygenase-1 promoter in addition to one proximal region, HS-1, which we have shown previously to be an E box. In vivo dimethyl sulfate footprinting of the HS-2 region revealed six individual protected guanines. Two mutations within HS-2 combined with a third mutation of the proximal E box abolished hemin- and cadmium-driven heme oxygenase-1 promoter activation, suggesting that these three sites synergized for maximal heme oxygenase-1 induction. Jun proteins bound to the antioxidant response element in the HS-2 region in vitro and associated with the heme oxygenase-1 promoter in vivo. JunB and JunD contribute opposing effects; JunB activated whereas JunD repressed heme oxygenase-1 expression in human renal epithelial cells, results that were corroborated in junB^-/- and junD^-/- cells. We propose that heme oxygenase-1 induction is controlled by a dynamic interplay of regulatory proteins, and we provide new insights into the molecular control of the human heme oxygenase-1 gene.

Received for publication, September 1, 2006 , and in revised form, November 24, 2006.

^* This work was supported in part by National Institutes of Health Grants DK059600, HL068157, and DK067472 (to A. A.). 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.

¹ Recipient of support from the Carmichael Fund.

² To whom correspondence should be addressed: Division of Nephrology, Zeigler Research Bldg., Rm. 614, University of Alabama at Birmingham, 703 19th St. South, Birmingham, AL 35294. Tel.: 205-996-6670; Fax: 205-996-6650; E-mail: agarwal{at}uab.edu.

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