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J. Biol. Chem., Vol. 281, Issue 34, 24423-24430, August 25, 2006

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Pescadillo Interacts with the Cadmium Response Element of the Human Heme Oxygenase-1 Promoter in Renal Epithelial Cells^*

Eric M. Sikorski, Takuma Uo, Richard S. Morrison, and Anupam Agarwal¹

From the Division of Nephrology, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the Department of Neurological Surgery, University of Washington, Seattle, Washington 98195

Renal tubular cells elicit adaptive responses following exposure to nephrotoxins, such as cadmium. One response is the up-regulation of the 32-kDa redox-sensitive protein, heme oxygenase-1. Exposure of renal proximal tubular epithelial cells to 10 µM cadmium demonstrated induction (20-fold) of heme oxygenase-1 mRNA and protein. Using a 4.5-kb human heme oxygenase-1 promoter construct, the importance of a previously identified cadmium response element (TGCTAGAT) in HeLa cells was verified in renal epithelial cells. Specific protein-DNA interaction with this sequence was demonstrated using nuclear extracts from cadmium-treated cells. Yeast one-hybrid screen of a human kidney cDNA library resulted in the identification of pescadillo, a unique nucleolar, developmental protein, as an interacting protein with the cadmium response element and was confirmed by chromatin immunoprecipitation in vivo and gel shift assays with purified glutathione S-transferase-pescadillo protein in vitro. The specificity of the DNA-protein interaction was verified by the absence of a binding complex when the core sequence of the cadmium response element was mutated or deleted. In addition, B23/nucleophosmin, another nucleolar protein, did not interact with the cadmium response sequence. Overexpression of pescadillo resulted in increased activity of the 4.5-kb human heme oxygenase-1 promoter construct but failed to activate this construct when the cadmium response sequence was mutated. The findings demonstrate the important and previously unrecognized role of pescadillo as a DNA-binding protein interacting specifically with the cadmium response element of the human heme oxygenase-1 gene.

Received for publication, March 10, 2006 , and in revised form, May 30, 2006.

^* This work was supported by National Institutes of Health (NIH) Grants DK59600 and HL068157 (to A. A.), a National Kidney Foundation postdoctoral fellowship (to E. M. S.), and NIH Grants NS42123 and NS35533 (to R. S. M.). 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 To whom correspondence should be addressed: Division of Nephrology, University of Alabama at Birmingham, 703 South 19th St., Zeigler Research Bldg., Rm. 614, Birmingham, AL 35294-0007; Tel.: 205-996-6670; Fax: 205-996-6650; E-mail: agarwal{at}uab.edu.

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