scholarly journals Genomic mechanisms involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3

1996 ◽  
Vol 316 (2) ◽  
pp. 361-371 ◽  
Author(s):  
Sylvia CHRISTAKOS ◽  
Mihali RAVAL-PANDYA ◽  
Roman P. WERNYJ ◽  
Wen YANG
Keyword(s):  
Vitamin D ◽  
Transcription Factor ◽  
Target Genes ◽  
Hormone Secretion ◽  
Biologically Active ◽  
Receptor Protein ◽  
Future Research ◽  
Dihydroxyvitamin D3 ◽  
Inhibition Of Proliferation ◽  
1,25 Dihydroxyvitamin D3

The biologically active metabolite of vitamin D (cholecalciferol), i.e. 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a secosteroid hormone whose mode of action involves stereospecific interaction with an intracellular receptor protein (vitamin D receptor; VDR). 1,25(OH)2D3 is known to be a principal regulator of calcium homeostasis, and it has numerous other physiological functions including inhibition of proliferation of cancer cells, effects on hormone secretion and suppression of T-cell proliferation and cytokine production. Although the exact mechanisms involved in mediating many of the different effects of 1,25(OH)2D3 are not completely defined, genomic actions involving the VDR are clearly of major importance. Similar to other steroid receptors, the VDR is phosphorylated; however, the exact functional role of the phosphorylation of the VDR remains to be determined. The VDR has been reported to be regulated by 1,25(OH)2D3 and also by activation of protein kinases A and C, suggesting co-operativity between signal transduction pathways and 1,25(OH)2D3 action. The VDR binds to vitamin D-responsive elements (VDREs) in the 5´ flanking region of target genes. It has been suggested that VDR homodimerization can occur upon binding to certain VDREs but that the VDR/retinoid X receptor (RXR) heterodimer is the functional transactivating species. Other factors reported to be involved in VDR-mediated transcription include chicken ovalbumin upstream promoter (COUP) transcription factor, which is involved in active silencing of transcription, and transcription factor IIB, which has been suggested to play a major role following VDR/RXR heterodimerization. Newly identified vitamin D-dependent target genes include those for Ca2+/Mg2+-ATPase in the intestine and p21 in the myelomonocytic U937 cell line. Elucidation of the mechanisms involved in the multiple actions of 1,25(OH)2D3 will be an active area of future research.

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

2007 ◽  
Vol 21 (7) ◽  
pp. 1513-1525 ◽  
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.

scholarly journals A hierarchical regulatory network analysis of the vitamin D induced transcriptome reveals novel regulators and complete VDR dependency in monocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Timothy Warwick ◽  
Marcel H. Schulz ◽  
Stefan Günther ◽  
Ralf Gilsbach ◽  
Antonio Neme ◽  
...  
Keyword(s):  
Vitamin D ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Target Genes ◽  
Active Form ◽  
Transcriptional Response ◽  
Biologically Active ◽  
Open Chromatin ◽  
Monocytic Cell ◽  
Monocytic Cell Line

AbstractThe transcription factor vitamin D receptor (VDR) is the high affinity nuclear target of the biologically active form of vitamin D3 (1,25(OH)2D3). In order to identify pure genomic transcriptional effects of 1,25(OH)2D3, we used VDR cistrome, transcriptome and open chromatin data, obtained from the human monocytic cell line THP-1, for a novel hierarchical analysis applying three bioinformatics approaches. We predicted 75.6% of all early 1,25(OH)2D3-responding (2.5 or 4 h) and 57.4% of the late differentially expressed genes (24 h) to be primary VDR target genes. VDR knockout led to a complete loss of 1,25(OH)2D3–induced genome-wide gene regulation. Thus, there was no indication of any VDR-independent non-genomic actions of 1,25(OH)2D3 modulating its transcriptional response. Among the predicted primary VDR target genes, 47 were coding for transcription factors and thus may mediate secondary 1,25(OH)2D3 responses. CEBPA and ETS1 ChIP-seq data and RNA-seq following CEBPA knockdown were used to validate the predicted regulation of secondary vitamin D target genes by both transcription factors. In conclusion, a directional network containing 47 partly novel primary VDR target transcription factors describes secondary responses in a highly complex vitamin D signaling cascade. The central transcription factor VDR is indispensable for all transcriptome-wide effects of the nuclear hormone.

The impact of methylmercury on 1,25-dihydroxyvitamin D3-induced transcriptomic responses in dolphin skin cells

2010 ◽  
Vol 391 (2/3) ◽  
Author(s):  
Blake C. Ellis ◽  
Sebastiano Gattoni-Celli ◽  
Mark S. Kindy
Keyword(s):  
Vitamin D ◽  
Target Genes ◽  
Protective Role ◽  
Dihydroxyvitamin D3 ◽  
Skin Cells ◽  
1,25 Dihydroxyvitamin D3 ◽  
Atlantic Bottlenose Dolphin ◽  
Considerable Impact ◽  
The Impact

Abstract The Atlantic bottlenose dolphin has been the focus of much attention owing to the considerable impact of environmental stress on its health and the associated implications for human health. Here, we used skin cells from the dolphin to investigate the protective role of the vitamin D pathway against environmental stressors. We previously reported that dolphin skin cells respond to 1,25-dihydroxyvitamin D3 (1,25D3), the bioactive metabolite of vitamin D3, by upregulation of the vitamin D receptor (VDR) and expression of several genes. Methylmercury is a highly bioaccumulative environmental stressor of relevance to the dolphin. We currently report that in dolphin cells sublethal concentrations of methylmercury compromise the ability of 1,25D3 to upregulate VDR, to transactivate a vitamin D-sensitive promoter, and to express specific target genes. These results help elucidate the effects of vitamin D and methylmercury on innate immunity in dolphin skin and potentially in human skin as well, considering similarities in the vitamin D pathway between the two species.

scholarly journals Vitamin D metabolism and mechanisms of calcium transport.

1990 ◽  
Vol 1 (1) ◽  
pp. 30-42
Author(s):  
R Kumar
Keyword(s):  
Vitamin D ◽  
Calcium Binding ◽  
Active Form ◽  
Biologically Active ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Magnesium Atpase ◽  
Liver And Kidney ◽  
Calcium Magnesium

Vitamin D3 undergoes sequential hydroxylations in the liver and kidney to form 1,25-dihydroxyvitamin D3, the biologically active form of the vitamin. 1,25-dihydroxyvitamin D3 is metabolized by several processes in various target tissues that decrease the biological activity of the sterol. In addition, 1,25-dihydroxyvitamin D3 is excreted in the bile as polar metabolites, such as glucuronides and, possibly sulfates and neutral polar steroids. These compounds undergo an enterohepatic recirculation in both man and experimental animals. 1,25-dihydroxyvitamin D3 increases the absorption of calcium in the intestine and the reabsorption of calcium in the kidney. It induces the synthesis of several proteins, the most notable of which is calcium binding protein that is thought to play a role in the absorption of calcium. The vitamin D-dependent calcium binding proteins and the calcium-magnesium ATPase calcium pump are co-localized in several tissues that play a role in the absorption of calcium.

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