1Alpha,25(OH)2D3-induced transrepression by vitamin D receptor through E-box-type elements in the human parathyroid hormone gene promoter.
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 1alphanVDRE in the human 25(OH)D31alpha-hydroxylase [1alpha(OH)ase] gene by 1alpha,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.
Kim
Mi-sun
MS
The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
Fujiki
Ryoji
R
Murayama
Akiko
A
Kitagawa
Hirochika
H
Yamaoka
Kazuyoshi
K
Yamamoto
Yoko
Y
Mihara
Masatomo
M
Takeyama
Ken-ichi
K
Kato
Shigeaki
S
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D024721:E-Box Elements; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D010281:Parathyroid Hormone / Q000235:genetics / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D030181:Vitamin D Response Element
C470125:PTH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D002117:Calcitriol