The vitamin D receptor functions as a transcription regulator in the absence of 1,25-dihydroxyvitamin D3

Abstract

The vitamin D receptor (VDR) is a critical mediator of the biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). As a nuclear receptor, ligand activation of the VDR leads to the protein’s binding to specific sites on the genome that results in the modulation of target gene expression. The VDR is also known to play a role in the hair cycle, an action that appears to be 1,25(OH)2D3-independent. Indeed, in the absence of VDR as in hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) both skin defects and alopecia emerge. Recently, we generated a mouse model of HVDRR without alopecia wherein a mutant human VDR lacking 1,25(OH)2D3-binding activity was expressed in the absence of endogenous mouse VDR. While 1,25(OH)2D3 failed to induce gene expression in these mice, resulting in an extensive skeletal phenotype, the receptor was capable of restoring normal hair cycling. We also noted a level of secondary hyperparathyroidism that was much higher than that seen in the VDR null mouse and was associated with an exaggerated bone phenotype as well. This suggested that the VDR might play a role in parathyroid hormone (PTH) regulation independent of 1,25(OH)2D3. To evaluate this hypothesis further, we contrasted PTH levels in the HVDRR mouse model with those seen in Cyp27b1 null mice where the VDR was present but the hormone was absent. The data revealed that PTH was indeed higher in Cyp27b1 null mice compared to VDR null mice. To evaluate the mechanism of action underlying such a hypothesis, we measured the expression levels of a number of VDR target genes in the duodena of wildtype mice and in transgenic mice expressing either a normal or a hormone-binding deficient mutant VDRs. We also compared expression levels of these genes between VDR null mice and Cyp27b1 null mice. In a subset of cases, the expression of VDR target genes was lower in mice containing the VDR as opposed to mice that did not. We suggest that the VDR may function as a selective suppressor/de-repressor of gene expression in the absence of 1,25(OH)2D3.

BsmI (rs1544410) and FokI (rs2228570) vitamin D receptor polymorphisms, smoking, and body mass index as risk factors of cutaneous malignant melanoma in northeast Italy

“…We also observed that ≥20 years of ever in life smoking combined with certain genetic traits, specifically, with bb, Bb+bb (b allele carriers), Ff, and Ff+ff (f allele carriers) are associated with significant crude ORs ranging from 4 to 9 for MetM cases vs healthy controls. Thus, smoke effects in melanoma can be modulated by VDR activity and by the pleiotropic vitamin D endocrine system 11 - 13 , 44 . Further studies are necessary to substantiate this significant and complex issue 10 , 11 , 44 .…”

“…Thus, smoke effects in melanoma can be modulated by VDR activity and by the pleiotropic vitamin D endocrine system 11 - 13 , 44 . Further studies are necessary to substantiate this significant and complex issue 10 , 11 , 44 .…”

Vitamin D receptor polymorphisms in immune thrombocytopenic purpura

“…VDR is central to this pathway and is a critical mediator of the biological actions of 1,25-dihydroxy vitamin D, the active form of the hormone. 24 Another important issue is that mean 25(OH)D was <20 ng/mL and similar in both groups. The vast majority of the participants lived in the same geographic area and the blood samples were taken in the same season.…”

“…This is because the vitamin D hormone pathway modulates immune function and is important in autoimmune diseases. VDR is central to this pathway and is a critical mediator of the biological actions of 1,25‐dihydroxy vitamin D, the active form of the hormone …”

The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights

“…The mechanisms of VDR action relative to coregulatory factors requires further exploration, including how coregulatory factors are recruited and how their properties are exploited to modulate transcriptional output. Some evidence has emerged that the VDR may function in a ligand-independent manner (i.e., hair follicle cycling) (39,95,(111)(112)(113); however, since VDR/DNA binding is largely ligand dependent both in vitro and in vivo, only a small subset of genes are likely to represent direct targets of this activity (49). It is also unclear how the numerous epigenetic modifications that have been identified across the genome and that are influenced by transcription factors such as the VDR influence genetic output (114).…”