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1,25(OH)₂D₃-Induced Transrepression by Vitamin D Receptor through E-Box-Type Elements in the Human Parathyroid Hormone Gene Promoter

Institute of Molecular and Cellular Biosciences (M.-s.K., R.F., A.M., H.K., Y.Y., M.M., K.-i.T., S.K.), University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; Teijin Institute for Biomedical Research (K.Y.), Teijin Pharma Limited, Hino, Tokyo 191-8512, Japan; Graduate School of Life and Environmental Sciences (A.M.), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; and Exploratory Research for Advanced Technology (K.Y., S.K.), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Address all correspondence and requests for reprints to: Shigeaki Kato, The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. 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 negative vitamin D response element (nVDRE) called 1nVDRE in the human 25(OH)D₃1-hydroxylase [1(OH)ase] gene by 1,25(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 (h) PTH and hPTHrP gene promoters. Functional mapping of the hPTH and hPTHrP promoters identified E-box-type elements acting as nVDREs in both the hPTH promoter (hPTHnVDRE; –87 to –60 bp) and in the hPTHrP promoter (hPTHrPnVDRE; –850 to –600 bp; –463 to –104 bp) in a mouse renal tubule cell line. The hPTHnVDRE alone was enough to direct ligand-induced transrepression mediated through VDR/retinoid X receptor and VDIR. Direct DNA binding of hPTHnVDRE to VDIR, but not VDR/retinoid X receptor, 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 corepressor for ligand-induced transrepression.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Coregulators:   HDAC2

Ligands:   Calcitriol

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