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J. Biol. Chem., Vol. 279, Issue 41, 42431-42437, October 8, 2004

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Suppression of the Human Parathyroid Hormone Promoter by Vitamin D Involves Displacement of NF-Y Binding to the Vitamin D Response Element^*

Nicholas J. Koszewski, Alexander P. Alimov, Ok-Kyong Park-Sarge¶, and Hartmut H. Malluche

From the Division of Nephrology, Bone and Mineral Metabolism and ^¶Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298

An earlier report in the literature indicated the vitamin D response element (VDRE) in the human parathyroid hormone (hPTH) promoter could be specifically bound by an unidentified transcription factor in addition to the vitamin D receptor (VDR) complex. We confirmed that OK and HeLa cell nuclear extracts formed a specific complex with the hPTH VDRE that was insensitive to competition with other VDRE sequences. However, this factor could be competed for by a consensus NF-Y DNA-binding site, and an anti-NF-Y antibody was able to supershift the bound band. Mutational analysis indicated that the NF-Y-binding site partially overlapped the 3' portion of the VDRE. Transfection studies using an hPTH promoter construct in Drosophila SL2 cells demonstrated strong synergistic transactivation by NF-Y interactions with both the VDRE site and a previously described distal NF-Y-binding site. Finally, mobility shift studies indicated that the VDR heterodimer competed with NF-Y for binding to the VDRE sequence, and NF-Y-stimulated activity of the hPTH promoter could be suppressed in a hormone-dependent manner when the VDR heterodimer complex was coexpressed in SL2 cells. In summary, these findings establish the presence of a proximal NF-Y-binding site in the hPTH promoter and highlight the potential for synergism between distal and proximal NF-Y DNA elements to strongly enhance transcription. Furthermore, findings suggest that the repressive effects of vitamin D on hPTH gene transcription may involve displacement of NF-Y binding to the proximal site by the VDR heterodimer, which subsequently attenuates synergistic transactivation.

Received for publication, July 9, 2004 , and in revised form, August 2, 2004.

^* This work was supported by National Institutes of Health Grants DK54276 (to N. J. K.), DK51530 (to H. H. M.), and HD41609 (to O.-K. P.-S.) and the University of Kentucky Medical Center Research Fund (to N. J. K.). 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.

To whom correspondence should be addressed: University of Kentucky Medical Ctr., Div. of Nephrology, Bone and Mineral Metabolism, Rm. MN562, 800 Rose St., Lexington, KY 40536-0298. Tel.: 859-323-6502 (ext. 228); Fax: 859-323-0232. E-mail: njhosz0{at}uky.edu.

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