Ligand-triggered stabilization of vitamin D Receptor/Retinoid X receptor heterodimer conformations on DR4-type response elements

Abstract Pituitary transcription factor-1 (Pit-1) plays a key role in cell differentiation during organogenesis of the anterior pituitary, and as a transcriptional activator for the pituitary GH and prolactin genes. However, Pit-1 is also expressed in nonpituitary cell types and tissues. In breast tumors, Pit-1 mRNA and protein levels are increased with respect to normal breast, and in MCF-7 human breast adenocarcinoma cells, Pit-1 increases GH secretion and cell proliferation. We report here that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] administration to MCF-7 cells induces a significant decrease in Pit-1 mRNA and protein levels. By deletion analyses, we mapped a region (located between −147 and −171 bp from the transcription start site of the Pit-1 gene) that is sufficient for the repressive response to 1,25-(OH)2D3. Gel mobility shift and chromatin immunoprecipitation assays confirmed the direct interaction between the vitamin D receptor (VDR) as homodimer (without the retinoid X receptor), and the Pit-1 promoter, supporting the view that Pit-1 is a direct transcriptional target of VDR. Our data also indicate that recruitment of histone deacetylase 1 is involved in this repressive effect. This ligand-dependent Pit-1 gene inhibition by VDR in the absence of the retinoid X receptor seems to indicate a new mechanism of transcriptional repression by 1,25-(OH)2D3.

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Vitamin D Receptor and Retinoid X Receptor Subcellular Trafficking

Vitamin D ◽

10.1016/b978-012252687-9/50025-5 ◽

2005 ◽

pp. 363-379

Author(s):

JULIA BARSONY

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Retinoid X Receptor ◽

Subcellular Trafficking

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

Molecular Endocrinology ◽

10.1210/me.2006-0231 ◽

2007 ◽

Vol 21 (2) ◽

pp. 334-342 ◽

Cited By ~ 82

Author(s):

Mi-sun Kim ◽

Ryoji Fujiki ◽

Akiko Murayama ◽

Hirochika Kitagawa ◽

Kazuyoshi Yamaoka ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Gene Promoter ◽

Negative Regulation ◽

Retinoid X Receptor ◽

Gene Promoters ◽

Histone Deacetylase 2 ◽

E Box ◽

Renal Tubule Cell ◽

Precise Molecular Mechanism

Abstract 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 1αnVDRE in the human 25(OH)D31α-hydroxylase [1α(OH)ase] gene by 1α,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.

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