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J. Biol. Chem., Vol. 279, Issue 45, 46779-46786, November 5, 2004

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Development and Refinement of Pregnane X Receptor (PXR) DNA Binding Site Model Using Information Theory

INSIGHTS INTO PXR-MEDIATED GENE REGULATION^*

Carrie A. Vyhlidal, Peter K. Rogan¶, and J. Steven Leeder||

From the Section of Developmental Pharmacology and Experimental Therapeutics, Division of Pediatric Clinical Pharmacology and Medical Toxicology and ^¶Laboratory of Human Molecular Genetics, Children's Mercy Hospital and Clinics, Kansas City, Missouri 64108

The pregnane X receptor (PXR) acts as a receptor to induce gene expression in response to structurally diverse xenobiotics through binding as a heterodimer with the 9-cis retinoic acid receptor (RXR) to enhancers in target gene promoters. We identified and estimated the affinities of novel PXR/RXR binding sites in regulated genes and additional genomic targets of PXR with an information theory-based model of the PXR/RXR binding site. Our initial PXR/RXR model, the result of the alignment of 15 previously characterized binding sites, was used to scan the promoters of known PXR target genes. Sites from these genes, with information contents of >8 bits bound by PXR/RXR in vitro, were used to revise the information weight matrix; this procedure was repeated by screening for progressively weaker binding sites. After three iterations of refinement, the model was based on 48 validated PXR/RXR binding sites and has an average information content (R_sequence) of 14.43 ± 3.21 bits. A scan of the human genome predicted novel PXR/RXR binding sites in the promoters of UGT1A3 (19.78 bits at –8040 and 16.37 bits at –6930) and UGT1A6 (12.74 bits at –9216), both of which were identified previously as targets for PXR. These sites were subsequently demonstrated to specifically bind PXR/RXR in competition electrophoretic mobility shift assays. A strong PXR site was also predicted upstream of the CASP10 gene (18.69 bits at –7872) and was validated by binding studies and reporter assays as a PXR responsive element. This suggests that the PXR-mediated response extends beyond genes involved in drug biotransformation and transport.

Received for publication, July 26, 2004 , and in revised form, August 13, 2004.

^* This work was funded by Grant R01 ES10855-04 from the National Institutes of Health. 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 Supplementary Tables 1 and 2.

These authors contributed equally to this study.

^|| To whom correspondence should be addressed: Section of Developmental Pharmacology and Experimental Therapeutics, Div. of Pediatric Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospital and Clinics, 2401 Gillham Rd., Kansas City, MO 64108. Tel.: 816-234-3059; Fax: 816-855-1958; E-mail: sleeder{at}cmh.edu.

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