+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Dynamic and ligand-selective interactions of vitamin D receptor with retinoid X receptor and cofactors in living cells

Dynamic and ligand-selective interactions of vitamin D receptor with retinoid X receptor and cofactors in living cells

Molecular Pharmacology 80(6): 1147-1155

The vitamin D receptor (VDR) mediates vitamin D signaling in numerous physiological and pharmacological processes, including bone and calcium metabolism, cellular growth and differentiation, immunity, and cardiovascular function. Although transcriptional regulation by VDR has been investigated intensively, an understanding of ligand-selective dynamic VDR conformations remains elusive. Here, we examined ligand-dependent dynamic interactions of VDR with retinoid X receptor (RXR), steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in cells using fluorescence resonance energy transfer (FRET) and chromatin immunoprecipitation (ChIP) assays. We compared the effects of 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], lithocholic acid (LCA), and (25R)-25-adamantyl-1α,25-dihydroxy-2-methylene-22,23-didehydro-19,26,27-trinor-20-epivitamin D(3) (ADTT), a partial agonist/antagonist vitamin D derivative. In the absence of ligand, VDR homodimers were preferred to RXR heterodimers and were associated with SMRT. 1,25(OH)(2)D(3) induced heterodimerization with RXR, dissociation of SMRT, and association of SRC-1. LCA and ADTT induced those effects to a lesser extent at concentrations that did not induce expression of the VDR target gene CYP24A1 in human embryonic kidney (HEK) 293 cells. Unlike in HEK293 cells, ADTT increased CYP24A1 expression in HCT116 cells and increased the association of VDR and SMRT on the CYP24A1 promoter. The results indicate that ligand-selective conformation may lead to unique cofactor complex formation in a cell context-dependent manner. The combination of FRET and ChIP assays is a powerful tool useful in understanding ligand-selective dynamic VDR conformations and the development of selective VDR modulators.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 036263111

Download citation: RISBibTeXText

PMID: 21917910

DOI: 10.1124/mol.111.074138

Related references

Retinoid X receptor ligand binding domains Use of mass spectrometry to study ligand/receptor interactions. Abstracts of Papers American Chemical Society 208(1-2): BIOL 37, 1994

Antagonistic effects of transforming growth factor-beta on vitamin D3 enhancement of osteocalcin and osteopontin transcription: reduced interactions of vitamin D receptor/retinoid X receptor complexes with vitamin E response elements. Endocrinology 137(5): 2001-2011, 1996

Natural vitamin D3 response elements formed by inverted palindromes: polarity-directed ligand sensitivity of vitamin D3 receptor-retinoid X receptor heterodimer-mediated transactivation. Molecular and Cellular Biology 15(3): 1154-1161, 1995

Synergistic activation of retinoic acid -responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor alpha -, RAR-beta-, or RAR-gamma-selective ligand in combination with a retinoid X receptor-specific ligand. Molecular & Cellular Biology 15(12): 6481-6487, 1995

New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells. Journal of Medicinal Chemistry 50(4): 782-793, 2007

Retinoid X receptor in retinoic acid receptor-retinoid X receptor heterodimers selectively confers an RXR ligand response to target genes in epidermis. Journal of Investigative Dermatology 106(4): 819, 1996

Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. Biochemistry 56(32): 4201-4209, 2017

Interactions of the vitamin D receptor with the retinoid X receptor and a vitamin D response element monitored by fluorescence anisotropy. Biophysical Journal 70(2 Part 2): A116, 1996

The retinoid X receptor ligand restores defective signalling by the vitamin D receptor. EMBO Reports 7(10): 1030-1034, 2006

Ligand occupancy is not required for vitamin D receptor and retinoid receptor-mediated transcriptional activation. Molecular Endocrinology 9(2): 232-242, 1995

Hairless modulates ligand-dependent activation of the vitamin D receptor-retinoid X receptor heterodimer. Biological and Pharmaceutical Bulletin 35(4): 582-587, 2012

Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers. Molecular and Cellular Biology 14(5): 3329-3338, 1994

Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements. Journal of Molecular Biology 296(3): 743-756, 2000

9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5. Nutrition Reviews 76(12): 929-941, 2018

Inhibition of vitamin D receptor-retinoid X receptor-vitamin D response element complex formation by nuclear extracts of vitamin D-resistant New World primate cells. Endocrinology 137(2): 786-789, 1996