Convergence of vitamin D and retinoic acid signalling at a common hormone response element

Department of Medicine, McGill University, 3655 Drummond St, Montreal, Quebec, Canada H3G 1Y6.
EMBO Reports (Impact Factor: 9.06). 03/2006; 7(2):180-5. DOI: 10.1038/sj.embor.7400594
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Although 1,25-dihydroxyvitamin D3 (1,25D3) and retinoic acid (RA) have distinct developmental and physiological roles, both regulate the cell cycle. We provide molecular and genomic evidence that their cognate nuclear receptors regulate common genes through everted repeat TGA(C/T)TPyN8PuG(G/T)TCA (ER8) response elements. ER8 motifs were found in the promoters of several target genes of 1,25D3 and/or RA. Notably, an element was characterized in the cyclin-dependent kinase (CDK) inhibitor p19ink4d gene, and 1,25D3- or RA-induced p19INK4D) expression. P19ink4d knockdown together with depletion of p27kip1, another CDK inhibitor regulated by 1,25D3 and RA, rendered cells resistant to ligand-induced growth arrest. Remarkably, p19INK4D-deficient cells showed increased autophagic cell death, which was markedly enhanced by 1,25D3, but not RA, and attenuated by loss of p27KIP1. These results show a limited crosstalk between 1,25D3 and RA signalling by means of overlapping nuclear receptor DNA binding specificities, and uncover a role for p19INK4D in control of cell survival.

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Available from: Benjamin Lallemant, Oct 06, 2015
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    • "Titration out of common co-activators, but not of RXR, may be the mechanism by which ligand-bound VDR represses retinoic acid receptor (RAR) transactivation in GH4C1 pituitary cells (Jiménez-Lara and Aranda, 1999). The relation between 1α,25(OH)2D3 and retinoic acid is however complex, as cooperative effects on target genes and cellular outcome (proliferation inhibition and differentiation) have been described in other systems (Tavera-Mendoza et al., 2006; Anand et al., 2008; Ng et al., 2010). As for estrogen receptor (ER), D. Feldman's group has shown that 1α,25(OH)2D3 exerts a multilevel protective effect against breast cancer that includes the inhibition of estrogen synthesis through the direct and indirect repression of aromatase (CYP19) and the downregulation of ER-α expression through two VDREs in its promoter region (Krishnan et al., 2010; Swami et al., 2013). "
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    ABSTRACT: Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)2D3 may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)2D3 resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.
    Frontiers in Physiology 02/2014; 5:60. DOI:10.3389/fphys.2014.00060 · 3.53 Impact Factor
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    • "VDRE elements are composed of tandem motifs having the consensus PuG(G/T)TCA, which are often arranged as direct repeats separated by 3 nucleotides (DR3-Type) [1] [3]. However, other types of VDREs, such as direct repeats with 4 spacing nucleotides (DR4-Type) or everted repeats with a spacer of 6–9 nucleotides (ER6-9) have been described [3] [6] [7]. This process is normally indicated as the " VDR genomic pathway " , in order to discern it from the " non genomic pathway " that is based on a putative 1,25(OH)2D3 surface receptor, followed by the activation of several intracellular transduction signaling cascades [3,8–10]. "
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    ABSTRACT: Orosomucoid 1 (ORM1), also named Alpha 1 acid glycoprotein A (AGP-A), is an abundant plasma protein characterized by anti-inflammatory and immune-modulating properties. The present study was designed to identify a possible correlation between ORM1 and Vitamin D3 (1,25(OH)2D3), a hormone exerting a widespread effect on cell proliferation, differentiation and regulation of the immune system. In particular, the data described here indicated that ORM1 is a 1,25(OH)2D3 primary response gene, characterized by the presence of a VDRE element inside the 1kb sequence of its proximal promoter region. This finding was demonstrated with gene expression studies, Chromatin Immunoprecipitation and luciferase transactivation experiments and confirmed by VDR full length and dominant negative over-expression. In addition, several experiments carried out in human normal monocytes demonstrated that the 1,25(OH)2D3 - VDR - ORM1 pathway plays a functional role inside the macrophage de-activation process and that ORM1 may be considered as a signaling molecule involved in the maintenance of tissue homeostasis and remodeling.
    Experimental Cell Research 08/2013; 319(20). DOI:10.1016/j.yexcr.2013.08.017 · 3.25 Impact Factor
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    • "VDR forms a heterodimer with retinoid X receptor (RXR), another member of the nuclear receptor superfamily, and binds preferentially to VDREs that are formed as direct repeat of two hexameric core binding motifs with 3 nucleotides spacing, so-called DR3-type VDREs (9). However, also other types of VDREs, such as direct repeats with 4 intervening nucleotides (DR4) (10) or everted repeats (ERs) with a spacer of 6–9 nucleotides (ER6-9) (11,12) have been reported. Single gene analyses suggest that VDR target genes often contain multiple functional VDREs (13–16). "
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    ABSTRACT: A global understanding of the actions of the nuclear hormone 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) and its vitamin D receptor (VDR) requires a genome-wide analysis of VDR binding sites. In THP-1 human monocytic leukemia cells we identified by ChIP-seq 2340 VDR binding locations, of which 1171 and 520 occurred uniquely with and without 1α,25(OH)(2)D(3) treatment, respectively, while 649 were common. De novo identified direct repeat spaced by 3 nucleotides (DR3)-type response elements (REs) were strongly associated with the ligand-responsiveness of VDR occupation. Only 20% of the VDR peaks diminishing most after ligand treatment have a DR3-type RE, in contrast to 90% for the most growing peaks. Ligand treatment revealed 638 1α,25(OH)(2)D(3) target genes enriched in gene ontology categories associated with immunity and signaling. From the 408 upregulated genes, 72% showed VDR binding within 400 kb of their transcription start sites (TSSs), while this applied only for 43% of the 230 downregulated genes. The VDR loci showed considerable variation in gene regulatory scenarios ranging from a single VDR location near the target gene TSS to very complex clusters of multiple VDR locations and target genes. In conclusion, ligand binding shifts the locations of VDR occupation to DR3-type REs that surround its target genes and occur in a large variety of regulatory constellations.
    Nucleic Acids Research 08/2011; 39(21):9181-93. DOI:10.1093/nar/gkr654 · 9.11 Impact Factor
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