Journal of Molecular Biology
Volume 304, Issue 5, 15 December 2000, Pages 793-801
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Regular Article
Agonist-triggered Modulation of the Activated and Silent State of the Vitamin D3 Receptor by Interaction with Co-repressors and Co-activators,☆☆

https://doi.org/10.1006/jmbi.2000.4267Get rights and content

Abstract

The nuclear receptor for the hormone 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), VDR, regulates gene expression via a ternary complex with the retinoid X receptor (RXR) and a 1α,25(OH)2D3 response element (VDRE). This complex mediates transcriptional repression through interaction with co-repressor proteins, such as NCoR, and transactivation through agonist-triggered contacts with co-activator proteins, such as SRC-1. This study demonstrates that the interaction of the VDR with NCoR results in a preferential stabilization of the VDR in a non-agonistic conformation (silent state), whereas within a complex with SRC-1 VDR is in its agonistic conformation (activated state). Helix 12 of the ligand-binding domain of the VDR was found to be a critical sensor for the differential stabilization of the activated and silent state of the receptor. VDR agonists that showed similar sensitivity in inducing VDR-RXR-VDRE complex formation were found to mediate a different dose-dependent release of NCoR from these complexes, which correlates with their ability to stabilize the silent state of the VDR in the presence of NCoR. Interestingly, up to 50 % of all VDR-NCoR complexes were found to be stable even in the presence of saturating agonist concentrations. This was confirmed by a quenching effect of overexpressed NCoR on agonist-induced gene activity mediated by VDR-RXR heterodimers. Taken together, co-activator and co-repressor proteins antagonize each other in stabilizing the activated and silent state of the receptor and modulate in this way the sensitivity and potency of the transcriptional activation by the ligand-responsive transcription factor VDR.

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      This epigenetic event decreases the concentration of available 1,25(OH)2D3 within the tumor tissue. The second level of interaction of vitamin D endocrinology with the epigenome comprises direct protein-protein interaction of VDR with chromatin components, such as members of the Mediator complex (Rachez et al., 1999) or co-activators of the NCOA family (Herdick and Carlberg, 2000), which have HAT activity leading to local chromatin opening. In turn, the interaction of VDR with co-repressor proteins, such as NCOR1 (Polly et al., 2000), mediates the contact with HDACs that close chromatin at the respective genomic loci.

    • Vitamin D Signaling Modulators in Cancer Therapy

      2016, Vitamins and Hormones
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      In some cases, multiple copies of the VDREs are positioned not only in the proximal promoter but dispersed up to several thousand kilobases of 5′ of the transcription start site in vitamin D responsive genes (Vaisanen, Dunlop, Sinkkonen, Frank, & Carlberg, 2005). Transcription activation through 1,25D3 and VDR is enhanced by nuclear receptor coactivator proteins such as steroid receptor coactivators, vitamin D receptor interacting protein complexes (Barletta, Freedman, & Christakos, 2002; Herdick & Carlberg, 2000; MacDonald, Baudino, Tokumaru, Dowd, & Zhang, 2001; Zhang et al., 2003). In addition, 1,25D3 may act independent of VDR/DNA binding through nongenomic pathways (Norman et al., 1992).

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    Abbreviations used: 1α,25(OH)2D3, 1α,25-dihydroxyvitamin D3; AF-2, (trans) activation function-2; ANF, atrial natriuretic factor; c1LPD, agonistic conformation; c3LPD, non-agonistic conformation; DR3, direct repeat spaced by three nucleotides; EC50, half maximal activation; FBS, fetal bovine serum; GST, glutathione S-transferase; IPTG, isopropyl-β-d-thio-galactopyranoside; LPD, limited protease digestion; LBD, ligand binding domain; NCoR, nuclear receptor co-repressor; RXR, retinoid X receptor; SRC-1, steroid receptor co-activator-1; VDR, 1α,25(OH)2D3 receptor; VDRE, 1α,25(OH)2D3 response element; DMSO, dimethylsulfoxide

    ☆☆

    Edited by J. Karn

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    E-mail address of the corresponding author: [email protected]

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