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This version published online on November 9, 2006
Molecular Endocrinology, doi:10.1210/me.2006-0231
Molecular Endocrinology Vol. 0, No. 2006 200602311-
doi:10.1210/me.2006-0231
Copyright © 2006 by the Endocrine Society.
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Submitted on May 26, 2006
Accepted on November 1, 2006

1{alpha},25(OH)2D3 -induced transrepression by vitamin D receptor through E-box-type elements in the human parathyroid hormone gene promoter

Mi-sun Kim, Ryoji Fujiki, Akiko Murayama, Hirochika Kitagawa, Kazuyoshi Yamaoka, Yoko Yamamoto, Masatomo Mihara, Ken-ichi Takeyama, and Shigeaki Kato*

Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan; Teijin Institute for Biomedical Research, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino, Tokyo, 191-8512, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan

* To whom correspondence should be addressed. E-mail: uskato{at}mail.ecc.u-tokyo.ac.jp.

Although transactivation by the liganded vitamin D receptor (VDR) is well described at the molecular level, the precise molecular mechanism of negative regulation by the liganded VDR remains to be elucidated. We have previously reported a novel class of nVDRE (1{alpha}nVDRE) in the human 25(OH)D31{alpha}-hydroxylase [1{alpha}(OH)ase] gene by 1{alpha},25(OH)2D3-bound VDR. This element was composed of two E-box-type motifs that bound to VDIR for transactivation, which was attenuated by liganded VDR. Here, we explore the possible functions of VDIR and E-box motifs in the human PTH (hPTH) and PTH-related peptide (hPTHrP) gene promoters. Functional mapping of the hPTH and hPTHrP promoters identified E-box-type elements acting as negative vitamin D response elements in both the hPTH promoter (hPTHnVDRE; -87bp to -60bp) and in the hPTHrP promoter (hPTHrPnVDRE; -850 to -600 bps; -463 to -104 bps) in a mouse renal tubule cell line. The hPTHnVDRE alone was enough to direct ligand-induced transrepression mediated through VDR/RXR and VDIR. Direct DNA binding of hPTHnVDRE to VDIR, but not VDR/RXR, was observed and ligand-induced transrepression was coupled with recruitment of VDR and histone deacetylase 2 (HDAC2) to the hPTH promoter. These results suggest that negative regulation of the hPTH gene by liganded VDR is mediated by VDIR directly binding to the E-box-type nVDRE at the promoter, together with recruitment of an HDAC co-repressor for ligand-induced transrepression.
Key words: Vitamin D • Vitamin D receptor • transrepression • 1{alpha}(OH)ase • PTH • E-box

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR
Coregulators:   HDAC2
Ligands:   Calcitriol



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