1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

Hines, Eric R.; Kolek, Olga I.; Jones, Martin; Serey, Samantha H.; Sirjani, Nafisseh B.; Kiela, Pawel R.; Jurutka, Peter W.; Haussler, Mark R.; Collins, James F.; Ghishan, Fayez K.

doi:10.1074/jbc.m404278200

Cited by 43 publications

(28 citation statements)

References 46 publications

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“…In such case, VDR sequesters the positive factor(s), which is no more available to bind to and activate the VDR-responsive region within the UGT2B15 promoter. Similar direct protein-protein interactions between VDR and other transcription factors have been reported in case of VDR negatively regulated genes, such as human parathyroid hormone or the osteoblast endopeptidase PHEX (49,50).…”

Section: Discussionmentioning

confidence: 78%

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Kaeding

Bélanger

Caron

et al. 2008

Molecular Cancer Therapeutics

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Calcitriol (1A,25-dihydroxyvitamin D 3 ), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3A-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15-and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells. [Mol Cancer Ther 2008;7(2):380 -90]

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Section: Discussionmentioning

confidence: 78%

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Kaeding

Bélanger

Caron

et al. 2008

Molecular Cancer Therapeutics

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“…In addition, expression of a dominant negative VDR inhibited 1,25(OH) 2 D 3 stimulation of FGF23 promoter activity ( Figure 5C), indicating that FGF23 is regulated directly by 1,25(OH) 2 D 3 in osteoblasts. It is interesting that 1,25(OH) 2 D 3 also is reported to suppress PHEX mRNA levels in osteoblasts and bone (30,31) and reductions in PHEX can lead to increased FGF23 expression in osteoblasts (32,33). Therefore, there seem to be both direct and indirect mechanisms for 1,25(OH) 2 D 3 to regulate FGF23 production by osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 23 Is a Counter-Regulatory Phosphaturic Hormone for Vitamin D

Liu

Tang

Zhou

et al. 2006

Journal of the American Society of Nephrology

594

485

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The regulation of the phosphaturic factor fibroblast growth factor 23 (FGF23) is not well understood. It was found that administration of 1,25-dihydroxyvitamin D 3 (1,25[OH] 2 D 3 ) to mice rapidly increased serum FGF23 concentrations from a basal level of 90.6 ؎ 8.1 to 213.8 ؎ 14.6 pg/ml at 8 h (mean ؎ SEM; P < 0.01) and resulted in a four-fold increase in FGF23 transcripts in bone, the predominate site of FGF23 expression. In the Hyp-mouse homologue of X-linked hypophosphatemic rickets, administration of 1,25(OH) 2 D 3 further increased circulating FGF23 levels. In Gcm2 null mice, low 1,25(OH) 2 D 3 levels were associated with a three-fold reduction in FGF23 levels that were increased by administration of 1,25 ( FGF23 also suppresses 1␣ hydroxylase activity in the proximal renal tubule, leading to reduced circulating levels of 1,25(OH) 2 D 3 (2,10,14,15). The significance of FGF23 regulation of 1,25(OH) 2 D 3 production is not clear, but the findings that FGF23 is produced predominantly by osteoblasts in bone and that FGF23 regulates phosphate reabsorption and 1,25(OH) 2 D 3 production by the kidney raise the possibility that FGF23 may be involved in a bone-kidney axis that controls phosphate and vitamin D homeostasis (16,17). How FGF23 is integrated with the vitamin D-parathyroid hormone (PTH) axis, which plays a central role in calcium homeostasis, skeletal development, and mineralization (18), however, is not clear. Understanding the effects of 1,25(OH) 2 D 3 on FGF23 production is important, because vitamin D therapy often is used to treat FGF23-mediated hypophosphatemic disorders, such as XLH (19).In an effort to understand more fully the regulation of FGF23 expression in osteoblasts and bone, we assessed the effect of 1,25(OH) 2 D 3 administration on circulating levels of FGF23 in wild-type Gcm2 null (20) and Hyp mice (21), as well as the effects of 1,25(OH) 2 D 3 on the FGF23 transcripts in bone. In addition, we investigated the ability of 1,25(OH) 2 D 3 to regulate endogenous FGF23 transcripts and the activity of a transfected murine FGF23 promoter luciferase reporter in osteoblasts. Our findings demonstrate the importance of bone as a target for vitamin D-mediated increments in FGF23 production and suggest that FGF23 production serves as a counterregulatory hormone to enhance renal phosphate clearance in response to vitamin D-mediated increments in gastrointestinal phosphate absorption and decrements in the phosphaturic hormone PTH. Materials and Methods 1,25(OH) 2 D 3 and PTH AdministrationBoth Hyp mice (21) and C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME). Male and female Gcm2 ϩ/Ϫ mice were mated to generate homozygous Gcm2 null mice that lacked parathyroid glands (22). All mice were maintained and used in accordance with recommendations in

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“…(7) Like FGF23, PHEX is also regulated by 1,25(OH) 2 D 3 , but its expression is repressed by the vitamin D hormone. (20,27,28) We have shown this repression of PHEX by 58% after 1,25(OH) 2 D 3 treatment of osteoblast-like cultured UMR-106 cells (Fig. 1, inset at bottom right).…”

Section: Jurutka Et Al V4mentioning

confidence: 96%

Vitamin D Receptor: Key Roles in Bone Mineral Pathophysiology, Molecular Mechanism of Action, and Novel Nutritional Ligands

Jurutka

Bartik

Whitfield

et al. 2007

Journal of Bone and Mineral Research

134

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ABSTRACT:The vitamin D hormone, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH) 2 D 3 is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH) 2 D 3 . Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH) 2 D 3 induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH) 2 D 3 synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH) 2 D 3 -mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH) 2 D 3 -FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH) 2 D 3 -PTH axis that regulates calcium. 1,25(OH) 2 D 3 also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH) 2 D 3 supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain 3/6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH) 2 D 3 -independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.

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1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter

Cited by 43 publications

References 46 publications

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Fibroblast Growth Factor 23 Is a Counter-Regulatory Phosphaturic Hormone for Vitamin D

Vitamin D Receptor: Key Roles in Bone Mineral Pathophysiology, Molecular Mechanism of Action, and Novel Nutritional Ligands

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