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J. Biol. Chem., Vol. 279, Issue 45, 46406-46414, November 5, 2004

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1,25-Dihydroxyvitamin D₃ Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter^*

Eric R. Hines, Olga I. Kolek¶, Marci D. Jones¶, Samantha H. Serey, Nafisseh B. Sirjani, Pawel R. Kiela, Peter W. Jurutka||, Mark R. Haussler||, James F. Collins, and Fayez K. Ghishan**

From the Departments of Pediatrics, ^¶Orthopedic Surgery, and ^||Biochemistry and Molecular Biophysics, College of Medicine, Steele Memorial Children's Research Center, University of Arizona, Tucson, Arizona 85724

The PHEX gene encodes an endopeptidase expressed in osteoblasts that inactivates an uncharacterized peptide hormone, phosphatonin, which suppresses bone mineralization as well as renal phosphate reabsorption and vitamin D bioactivation. We demonstrate that 1-25-dihydroxyvitamin D (1,25(OH)₂D₃), the, active renal vitamin D metabolite, decreases PHEX mRNA in the rat osteoblastic cell line, UMR-106, as well as in mouse calvaria. Promoter/reporter construct analysis of the murine PHEX gene in transfected UMR-106 cells localized the repressive effect of 1,25(OH)₂D₃ to the –133 to –74 bp region, and gel mobility shift experiments revealed that 1,25(OH)₂D₃ treatment of the cells diminished the binding of a nuclear protein(s) to a stretch of 17 adenines from bp –116 to –100 in the proximal PHEX promoter. Either overexpression of a dominant-negative vitamin D receptor (VDR) or deletion of this sequence of 17 A-T base pairs abolished the repressive effect of 1,25(OH)₂D₃ by attenuating basal promoter activity, indicating that this region mediates the 1,25(OH)₂D₃ response and is involved in basal transcription. South-western blot analysis and DNA affinity purification show that an unidentified 110 kDa nuclear protein binds to the poly(A) element. Because 1,25(OH)₂D₃-liganded VDR neither binds to the polyadenine region of the PHEX promoter nor directly influences the association of the 110 kDa transfactor, we conclude that 1,25(OH)₂D₃ indirectly decreases PHEX expression via VDR-mediated repression (or modification) of this novel transactivator. Thus, we have identified a cis-element required for PHEX gene transcription that participates in negative feedback control of PHEX expression and thereby modulates the actions of phosphatonin.

Received for publication, April 16, 2004 , and in revised form, August 11, 2004.

^* This work was supported by National Institutes of Health Grants R01-DK-33209 (to F. K. G.) and R01-DK-33351 (to M. R. H.) and an Orthopedic Research and Education Foundation Grant (to M. D. J). 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.

These two authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Pediatrics, Director, Steele Memorial Children's Research Center, University of Arizona Health Sciences Center, 1501 N. Campbell Ave., Tucson, AZ 85724. Tel.: 520-626-5170; Fax: 520-626-4141; E-mail: fghishan{at}peds.arizona.edu.

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