scholarly journals Stimulation of Sirt1-Regulated FoxO Protein Function by the Ligand-Bound Vitamin D Receptor

2010 ◽  
Vol 30 (20) ◽  
pp. 4890-4900 ◽  
Author(s):  
Beum-Soo An ◽  
Luz E. Tavera-Mendoza ◽  
Vassil Dimitrov ◽  
Xiaofeng Wang ◽  
Mario R. Calderon ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cell Proliferation ◽  
Phosphatase Activity ◽  
Vitamin D Receptor ◽  
Nuclear Export ◽  
Target Genes ◽  
Trichostatin A ◽  
Control Cell ◽  
Sirtuin 1 ◽  
Foxo Protein

ABSTRACT Hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signals through the nuclear vitamin D receptor (VDR). 1,25D regulates cell proliferation and differentiation and has been identified as a cancer chemopreventive agent. FoxO proteins are transcription factors that control cell proliferation and survival. They function as tumor suppressors and are associated with longevity in several organisms. Accumulating data have revealed that 1,25D and FoxO proteins regulate similarly common target genes. We show here that the ligand-bound VDR regulates the posttranslational modification and function of FoxO proteins. 1,25D treatment enhances binding of FoxO3a and FoxO4 within 4 h to promoters of FoxO target genes and blocks mitogen-induced FoxO protein nuclear export. The VDR associates directly with FoxO proteins and regulators, the sirtuin 1 (Sirt1) class III histone deacetylase (HDAC), and protein phosphatase 1. In addition, phosphatase activity and trichostatin A-resistant HDAC activity coimmunoprecipitate with the VDR. 1,25D treatment rapidly (in <4 h) induces FoxO deacetylation and dephosphorylation, consistent with activation. In contrast, ablation of VDR expression enhances FoxO3a phosphorylation, as does knockdown of Sirt1, consistent with the coupling of FoxO acetylation and phosphorylation. 1,25D regulation of common VDR/FoxO target genes is attenuated by blockade of phosphatase activity or by small interfering RNA (siRNA)-mediated knockdown of Sirt1 or FoxO protein expression. Finally, 1,25D-dependent cell cycle arrest is blocked in FoxO3a-deficient cells, indicating that FoxO proteins are key downstream mediators of the antiproliferative actions of 1,25D. These studies link 1,25D signaling through the VDR directly to Sirt1 and FoxO function and provide a molecular basis for the cancer chemopreventive actions of 1,25D.

scholarly journals The 1,25(OH)2D3-Regulated Transcription Factor MN1 Stimulates Vitamin D Receptor-Mediated Transcription and Inhibits Osteoblastic Cell Proliferation

2005 ◽  
Vol 19 (9) ◽  
pp. 2234-2244 ◽  
Author(s):  
Amelia L. M. Sutton ◽  
Xiaoxue Zhang ◽  
Tara I. Ellison ◽  
Paul N. MacDonald
Keyword(s):  
Vitamin D ◽  
Cell Proliferation ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Ion Homeostasis ◽  
Endocrine System ◽  
Osteoblastic Cells ◽  
Osteoblastic Cell ◽  
Dihydroxyvitamin D3 ◽  
And Function

Abstract The vitamin D endocrine system is essential for maintaining mineral ion homeostasis and preserving bone density. The most bioactive form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] elicits its effects by binding to the vitamin D receptor (VDR) and regulating the transcription of target genes. In osteoblasts, the bone-forming cells of the skeleton, 1,25-(OH)2D3 regulates cell proliferation, differentiation, and mineralization of the extracellular matrix. Despite these well-characterized biological functions, relatively few 1,25-(OH)2D3 target genes have been described in osteoblasts. In this study, we characterize the regulation and function of MN1, a novel 1,25-(OH)2D3-induced gene in osteoblastic cells. MN1 is a nuclear protein first identified as a gene disrupted in some meningiomas and leukemias. Our studies demonstrate that MN1 preferentially stimulates VDR-mediated transcription through its ligand-binding domain and synergizes with the steroid receptor coactivator family of coactivators. Furthermore, forced expression of MN1 in osteoblastic cells results in a profound decrease in cell proliferation by slowing S-phase entry, suggesting that MN1 is an antiproliferative factor that may mediate 1,25-(OH)2D3-dependent inhibition of cell growth. Collectively, these data indicate that MN1 is a 1,25-(OH)2D3-induced VDR coactivator that also may have critical roles in modulating osteoblast proliferation.

scholarly journals Nutraceuticals Derived From Pomegranate Selectively Enhance Vitamin D Receptor Signaling to Amplify Key Vitamin D Target Genes

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Sarah Livingston ◽  
Daniel Lucas ◽  
Marya S. Sabir ◽  
Sanchita Mallick ◽  
Hespera Purdin ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Receptor Signaling

Molecular network of chromatin immunoprecipitation followed by deep sequencing-based vitamin D receptor target genes

2013 ◽  
Vol 19 (8) ◽  
pp. 1035-1045 ◽  
Author(s):  
Jun-ichi Satoh ◽  
Hiroko Tabunoki
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Deep Sequencing ◽  
Immune Cells ◽  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Molecular Network ◽  
Genome Wide

Background: Vitamin D is a liposoluble vitamin essential for calcium metabolism. The ligand-bound vitamin D receptor (VDR), heterodimerized with retinoid X receptor, interacts with vitamin D response elements (VDREs) to regulate gene expression. Vitamin D deficiency due to insufficient sunlight exposure confers an increased risk for multiple sclerosis (MS). Objective: To study a protective role of vitamin D in multiple sclerosis (MS), it is important to characterize the global molecular network of VDR target genes (VDRTGs) in immune cells. Methods: We identified genome-wide VDRTGs collectively from two distinct chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) datasets of VDR-binding sites derived from calcitriol-treated human cells of B cell and monocyte origins. We mapped short reads of next generation sequencing (NGS) data on hg19 with Bowtie, detected the peaks with Model-based Analysis of ChIP-Seq (MACS), and identified genomic locations by GenomeJack, a novel genome viewer for NGS platforms. Results: We found 2997 stringent peaks distributed on protein-coding genes, chiefly located in the promoter and the intron on VDRE DR3 sequences. However, the corresponding transcriptome data verified calcitriol-induced upregulation of only a small set of VDRTGs. The molecular network of 1541 calcitriol-responsive VDRTGs showed a significant relationship with leukocyte transendothelial migration, Fcγ receptor-mediated phagocytosis, and transcriptional regulation by VDR, suggesting a pivotal role of genome-wide VDRTGs in immune regulation. Conclusion: These results suggest the working hypothesis that persistent deficiency of vitamin D might perturb the complex network of VDRTGs in immune cells, being responsible for induction of an autoimmune response causative for MS.

scholarly journals Intron retention generates a novel isoform of the murine vitamin D receptor that acts in a dominant negative way on the vitamin D signaling pathway.

1996 ◽  
Vol 16 (7) ◽  
pp. 3393-3400 ◽  
Author(s):  
K Ebihara ◽  
Y Masuhiro ◽  
T Kitamoto ◽  
M Suzawa ◽  
Y Uematsu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Vitamin D ◽  
Ligand Binding ◽  
Signaling Pathway ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Stop Codon ◽  
Dominant Negative ◽  
Transient Expression Assay ◽  
Vitamin D Signaling

We identified and characterized a novel rat vitamin D receptor isoform (rVDR1), which retains intron 8 of the canonical VDR (rVDR0) during alternative splicing. In this isoform protein directed by the stop codon in this newly identified exon, a part of the ligand binding domain (86 amino acids) is truncated at the C-terminal end but contains 19 extra amino acids. The rVDR1 transcript was expressed at a level 1/15 to 1/20 of that of rVDR0 in the kidney and intestine in adult rats but not in embryos. The recombinant rVDR1 protein showed no ligand binding activity. Homo- and heterodimers of the recombinant rVDR0 and rVDR1 proteins bound to a consensus vitamin D response element (VDRE) but not to consensus response elements for thyroid hormone and retinoic acid. However, unlike rVDR0, rVDR1 did not form a heterodimeric complex with RXR on the VDRE. A transient expression assay showed that this isoform acted as a dominant negative receptor against rVDR0 transactivation. Interestingly, the dominant negative activities of rVDR1 differed among VDREs. Thus, the present study indicates that this new VDR isoform negatively modulates the vitamin D signaling pathway, through a particular set of target genes.

scholarly journals Relevance of Vitamin D Receptor Target Genes for Monitoring the Vitamin D Responsiveness of Primary Human Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0124339 ◽  
Author(s):  
Maja Vukić ◽  
Antonio Neme ◽  
Sabine Seuter ◽  
Noora Saksa ◽  
Vanessa D. F. de Mello ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Human Cells ◽  
Primary Human Cells

scholarly journals Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle

2020 ◽  
Vol 64 (3) ◽  
pp. 195-208 ◽  
Author(s):  
Maria K Tsoumpra ◽  
Shun Sawatsubashi ◽  
Michihiro Imamura ◽  
Seiji Fukumoto ◽  
Shin’ichi Takeda ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Musculoskeletal Diseases ◽  
Myogenic Differentiation ◽  
Biologically Active ◽  
Site Directed Mutagenesis ◽  
C2c12 Cells ◽  
Expression Vectors ◽  
Gene And Protein Expression

The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1–50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases.

scholarly journals Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Elżbieta Gocek ◽  
Hanna Baurska ◽  
Aleksandra Marchwicka ◽  
Ewa Marcinkowska
Keyword(s):  
Signal Transduction ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Protein Trafficking ◽  
Target Genes ◽  
Biological Activities ◽  
Protein Stabilization ◽  
Cell Surface Receptor ◽  
Intracellular Signal Transduction ◽  
Intracellular Signal

1α,25-Dihydroxyvitamin D3 (1,25(OH)2D) exerts its biological activities through vitamin D receptor (VDR), which is a member of the superfamily of steroid receptors, that act as ligand-dependent transcription factors. Ligated VDR in complex with retinoid X receptor (RXR) binds to regulatory regions of 1,25(OH)2D-target genes. 1,25(OH)2D is able to induce differentiation of leukemic blasts towards macrophage-like cells. Many different acute myeloid leukemia (AML) cell lines respond to 1,25(OH)2D by increasing CD14 cell surface receptor, some additionally upregulate CD11b and CD11c integrins. In untreated AML cells VDR protein is present in cytosol at a very low level, even though its mRNA is continuously expressed. Ligation of VDR causes protein stabilization and translocation to the cell nuclei, where it regulates transcription of target genes. Several important groups of genes are regulated by 1,25(OH)2D in HL60 cells. These genes include differentiation-related genes involved in macrophage function, as well as a gene regulating degradation of 1,25(OH)2D, namely CYP24A1. We summarize here the data which demonstrate that though some cellular responses to 1,25(OH)2D in AML cells are transcription-dependent, there are many others which depend on intracellular signal transduction, protein trafficking and stabilization. The final effect of 1,25(OH)2D action in leukemic cells requires all these acting together.

Temporal changes in tissue 1α,25-dihydroxyvitamin D3, vitamin D receptor target genes, and calcium and PTH levels after 1,25(OH)2D3 treatment in mice

2013 ◽  
Vol 304 (9) ◽  
pp. E977-E989 ◽  
Author(s):  
Edwin C. Y. Chow ◽  
Holly P. Quach ◽  
Reinhold Vieth ◽  
K. Sandy Pang
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Calcium Ion ◽  
Target Genes ◽  
Feedback Regulation ◽  
Plasma Calcium ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Temporal Correlations ◽  
Temporal Profiles

The vitamin D receptor (VDR) maintains a balance of plasma calcium and 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], its natural active ligand, by directly regulating the calcium ion channel (TRPV6) and degradation enzyme (CYP24A1), and indirectly regulating the parathyroid hormone (PTH) for feedback regulation of the synthetic enzyme CYP27B1. Studies that examined the intricate relationships between plasma and tissue 1,25(OH)2D3 levels and changes in VDR target genes and plasma calcium and PTH are virtually nonexistent. In this study, we investigated temporal correlations between tissue 1,25(OH)2D3 concentrations and VDR target genes in ileum and kidney and plasma calcium and PTH concentrations in response to 1,25(OH)2D3 treatment in mice (2.5 μg/kg ip, singly or q2d × 4). After a single ip dose, plasma 1,25(OH)2D3 peaked at ∼0.5 h and then decayed biexponentially, falling below basal levels after 24 h and then returning to baseline after 8 days. Upon repetitive ip dosing, plasma, ileal, renal, and bone 1,25(OH)2D3 concentrations rose and decayed in unison. Temporal profiles showed increased expressions of ileal Cyp24a1 and renal Cyp24a1, Mdr1/P-gp, and VDR but decreased renal Cyp27b1 mRNA after a time delay in VDR activation. Increased plasma calcium and attenuated PTH levels and increased ileal and renal Trpv6 expression paralleled the changes in tissue 1,25(OH)2D3 concentrations. Gene changes in the kidney were more sustained than those in intestine, but the magnitudes of change for Cyp24a1 and Trpv6 were lower than those in intestine. The data revealed that 1,25(OH)2D3 equilibrates with tissues rapidly, and VDR target genes respond quickly to exogenously administered 1,25(OH)2D3.

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