Non-classical mechanisms of transcriptional regulation by the vitamin D receptor: Insights into calcium homeostasis, immune system regulation and cancer chemoprevention

AbstractThe bioactive vitamin D3, 1α,25(OH)2D3, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D3 leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)2D3 synthesis, but are poorly efficient. In this study, we identify WBP4 as a new VDR interactant, and demonstrate that it controls VDR subcellular localization. Moreover, we show that the vitamin D analogue ZK168281 enhances the interaction between VDR and WBP4 in the cytosol, and normalizes the expression of VDR target genes and serum calcium levels in 1α,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1α,25(OH)2D3-induced VDR signaling in fibroblasts of a patient with impaired vitamin D degradation, this VDR antagonist represents a promising therapeutic option for 1α,25(OH)2D3-induced hypercalcemia.

Download Full-text

Transcriptional regulation of J32-integrin expression by 1,25-dihydroxyvitamin D3 is dependent on vitamin D receptor expression

Bone ◽

10.1016/8756-3282(95)97398-y ◽

1995 ◽

Vol 17 (3) ◽

pp. 330

Author(s):

E. Hughson ◽

L. Faulkner ◽

D.R. Katz ◽

J.L.H. O'Riordan ◽

M. Hewison

Keyword(s):

Vitamin D ◽

Transcriptional Regulation ◽

Vitamin D Receptor ◽

Receptor Expression ◽

Integrin Expression ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3

Download Full-text

Cellular Expression Levels of the Vitamin D Receptor Are Critical to Its Transcriptional Regulation by the Pituitary Transcription Factor Pit-1

Molecular Endocrinology ◽

10.1210/me.2006-0554 ◽

2007 ◽

Vol 21 (7) ◽

pp. 1513-1525 ◽

Cited By ~ 8

Author(s):

Samuel Seoane ◽

Isabel Ben ◽

Viviana Centeno ◽

Roman Perez-Fernandez

Keyword(s):

Vitamin D ◽

Transcription Factor ◽

Transcriptional Regulation ◽

Vitamin D Receptor ◽

Binding Protein ◽

Target Cells ◽

Dihydroxyvitamin D3 ◽

Expression Levels ◽

1,25 Dihydroxyvitamin D3 ◽

Mcf 7

Abstract The biological role of 1,25-dihydroxyvitamin D3 has generally been related to calcium homeostasis, but this hormone also has fundamental effects on processes of cellular proliferation and differentiation. The genomic actions of 1,25-dihydroxyvitamin D3 are mediated by the vitamin D receptor (VDR) present in target cells. However, VDR transcriptional regulation is not well understood, probably attributable to the complexity of the VDR gene and its promoter. In the present study, it is demonstrated that administration of the pituitary transcription factor Pit-1 (originally found in the pituitary gland but also present in other nonpituitary cell types and tissues) to the MCF-7 (human breast adenocarcinoma) cell line induces a significant increase in VDR mRNA and protein levels. Conversely, Pit-1-targeted small interference RNA markedly reduced expression of VDR in MCF-7 cells. Reporter gene assays demonstrated that the effect of Pit-1 is mediated by its binding to a region located between −254 and −246 bp from the VDR transcription start site. Selective mutations of this site completely abolished VDR transcription. Chromatin immunoprecipitation analysis showed that binding of Pit-1 to the VDR promoter leads additionally to recruitment of cAMP response element-binding protein binding protein, acetylated histone H4, and RNA polymerase II. Surprisingly, Pit-1 binding also recruits VDR protein to the VDR promoter. Using several cell lines with different levels of VDR expression, it was demonstrated that up-regulation of VDR transcription by Pit-1 is dependent on the presence of VDR protein, suggesting that transcriptional expression of VDR in a given cell type is dependent on, among other factors, its own expression levels.

Download Full-text

Vitamin D Receptor Agonists, Cancer and the Immune System: An Intricate Relationship

Current Topics in Medicinal Chemistry ◽

10.2174/156802606777864890 ◽

2006 ◽

Vol 6 (12) ◽

pp. 1297-1301 ◽

Cited By ~ 20

Author(s):

Luciano Adorini ◽

Kenn Daniel ◽

Giuseppe Penna

Keyword(s):

Vitamin D ◽

Immune System ◽

Vitamin D Receptor ◽

Receptor Agonists

Download Full-text

Ageing and vitamin D deficiency: effects on calcium homeostasis and considerations for vitamin D supplementation

British Journal Of Nutrition ◽

10.1017/s0007114509338842 ◽

2009 ◽

Vol 101 (11) ◽

pp. 1597-1606 ◽

Cited By ~ 30

Author(s):

Christian Oudshoorn ◽

Tischa J. M. van der Cammen ◽

Marion E. T. McMurdo ◽

Johannes P. T. M. van Leeuwen ◽

Edgar M. Colin

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Calcium Homeostasis ◽

Human Body ◽

Steroid Hormone ◽

Endocrine System ◽

Vitamin D Supplementation ◽

Multiple Systems ◽

Almost All ◽

Ca Homeostasis

Vitamin D is a fat-soluble, seco-steroid hormone. In man, the vitamin D receptor is expressed in almost all tissues, enabling effects in multiple systems of the human body. These effects can be endocrine, paracrine and autocrine. The present review summarises the effects of ageing on the vitamin D endocrine system and on Ca homeostasis. Furthermore, consequences for vitamin D supplementation are discussed.

Download Full-text