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1.
1,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3) interacts with the Vitamin D 3 receptor (VDR) to modulate proliferation and apoptosis in a variety of cell types, including breast cancer cells. In this review, we discuss three issues related to the role of the VDR in growth control: first, whether mammary glands lacking VDR exhibit abnormal growth; second, whether the VDR is essential for induction of apoptosis by 1,25(OH) 2D 3; and third, whether VDR up-regulation can sensitize cells to 1,25(OH) 2D 3. Studies from our laboratory have demonstrated that mammary glands from VDR knockout (VDR KO) mice exhibit accelerated growth and branching during puberty, pregnancy and lactation as compared to wild-type (WT) mice. In addition, involution after weaning, a process driven by epithelial cell apoptosis, proceeds at a slower rate in VDR KO mice compared to WT mice. Using cells isolated from VDR KO and WT mice, we report that both normal and transformed mammary cells derived from WT mice are growth inhibited by 1,25(OH) 2D 3, however, cells derived from VDR KO mice are completely unresponsive to 1,25(OH) 2D 3. In human breast cancer cells, we have identified a variety of agents, including steroid hormones, phytoestrogens and growth factors, that up-regulate VDR expression and enhance sensitivity to 1,25(OH) 2D 3-mediated growth inhibition. Collectively, these studies support a role for 1,25(OH) 2D 3 and the VDR in negative growth regulation of both normal mammary gland and breast cancer cells. 相似文献
2.
In a previous study, we identified the element which allows the maximum response to 1,25(OH) 2D 3 in concert with two vitamin D-responsive elements (VDREs) in the rat 25-hydroxyvitamin D 3 24-hydroxylase gene promoter, and designated it an accessory element [Ohyama, Y., Ozono, K., Uchida, M., Yoshimura, M., Shinki, T., Suda, T. and Yamamoto, O. Functional assessment of two vitamin D-responsive elements in the rat 25-hydroxyvitamin D 3 24-hydroxylase gene. J. Biol. Chem., 1996, 271, 30381-30385]. The accessory element located adjacent to the proximal VDRE is not capable of binding to the vitamin D receptor (VDR), while its nucleotide sequence resembles the consensus sequence of VDREs, direct repeat 3 (DR3). To clarify the difference between the accessory element and VDREs, the function of the accessory element was compared with that of VDREs. The mutated accessory elements with a single nucleotide substitution showed the capability of binding to the VDR in vitro. However, these mutants still did not act as a VDRE when driven by the heterologous SV40 promoter. The accessory element did not enhance the function of a cAMP-responsive element. The corresponding site of the accessory element in the human 24-hydroxylase is a DR4-type element, and this element did not function as an accessory element. These results indicate that a critical nucleotide sequence is necessary for the binding to the VDR and for mediating the vitamin D effect, and suggest the different regulation between the rat and human 24-hydroxylase gene. 相似文献
3.
We employed genetically modified mice to examine the role of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2D 3] on skeletal and calcium homeostasis. In mice expressing the null mutation for 25-hydroxyvitamin D 1 hydroxylase (1OHase −/−), or the vitamin D receptor (VDR −/−), 1,25(OH) 2D 3 and calcium were both required for optimal epiphyseal growth plate development, serum calcium and phosphorus alone were sufficient to mineralize skeletal tissue independent of 1,25(OH) 2D 3 and the VDR, and endogenous 1,25(OH) 2D 3 and the VDR were essential for baseline bone formation. In 2-week-old 1OHase −/− mice and in 2-week-old mice homozygous for the PTH null mutation(PTH −/−), PTH and 1,25(OH) 2D 3 were each found to exert independent and complementary effects on skeletal anabolism, with PTH predominantly affecting appositional trabecular bone growth and 1,25(OH) 2D 3 influencing both endochondral bone formation and appositional bone growth. Endogenous 1,25(OH) 2D 3 maintained serum calcium homeostasis predominantly by modifying intestinal and renal calcium transporters but not by producing net bone resorption. Administration of exogenous 1,25(OH) 2D 3 to double mutant PTH −/−1OHase −/− mice produced skeletal effects consistent with the actions of endogenous 1,25(OH) 2D 3. These studies reveal an important skeletal anabolic role for both endogenous and exogenous 1,25(OH) 2D 3 and point to a potential role for 1,25(OH) 2D 3 analogs in the treatment of disorders of bone loss. 相似文献
5.
After intravenous administration of the vitamin D 3 analog, 22-oxacalcitriol (OCT), to normal rats plasma metabolites were investigated by HPLC, GC-MS and LC-MS. Five side-chain oxidation metabolites, 24 R(OH)OCT, 24 S(OH)OCT, (25 R)-26(OH)OCT, (25 S)-26(OH)OCT and 24oxoOCT, were identified by comparison with the corresponding synthetic compounds. These side-chain oxidation metabolites were similar to those of calcitriol [1,25(OH) 2 vitamin D 3] described previously. Besides these five metabolites, two unique side-chain cleavage metabolites, 20 S(OH)-hexanor-OCT and 17,20 S(OH) 2-hexanor-OCT, were identified as main metabolites in plasma by GC-MS and LC-MS using a specific chemical reaction. Our studies suggest that OCT is extensively metabolized and circulates in blood as a number of metabolites as well as unchanged OCT. This metabolism includes both unique pathways of C 23-O 22 cleavage and 17-hydroxylation, in addition to the side-chain oxidation metabolites similar to those of 1,25-(OH) 2D 3. 相似文献
6.
Of the various risk factors contributing to osteoporosis, dietary/lifestyle factors are important. In a clinical study we reported that women with caffeine intakes >300 mg/day had higher bone loss and women with vitamin D receptor (VDR) variant, tt were at a greater risk for this deleterious effect of caffeine. However, the mechanism of how caffeine effects bone metabolism is not clear. 1,25-Dihydroxy vitamin D 3 (1,25(OH) 2D 3) plays a critical role in regulating bone metabolism. The receptor for 1,25(OH) 2D 3, VDR has been demonstrated in osteoblast cells and it belongs to the superfamily of nuclear hormone receptors. To understand the molecular mechanism of the role of caffeine in relation to bone, we tested the effect of caffeine on VDR expression and 1,25(OH) 2D 3 mediated actions in bone. We therefore examined the effect of different doses of caffeine (0.2, 0.5, 1.0 and 10 mM) on 1,25(OH) 2D 3 induced VDR protein expression in human osteoblast cells. We also tested the effect of different doses of caffeine on 1,25(OH) 2D 3 induced alkaline phosphatase (ALP) activity, a widely used marker of osteoblastic activity. Caffeine dose dependently decreased the 1,25(OH) 2D 3 induced VDR expression and at concentrations of 1 and 10 mM, VDR expression was decreased by about 50–70%, respectively. In addition, the 1,25(OH) 2D 3 induced alkaline phosphatase activity was also reduced at similar doses thus affecting the osteoblastic function. The basal ALP activity was not affected with increasing doses of caffeine. Overall, our results suggest that caffeine affects 1,25(OH) 2D 3 stimulated VDR protein expression and 1,25(OH) 2D 3 mediated actions in human osteoblast cells. 相似文献
8.
This study examines the effect of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2D 3], 24,25-dihydroxyvitamin D 3 [24,25(OH) 2D 3], two vitamin D analogues (KH 1060 and EB 1089, which are 20-epi-22-oxa and 22,24-diene-analogues, respectively), 9- cis retinoic acid and all- trans retinoic acid on proliferation of SH-SY5Y human neuroblastoma cells, after treatment for 7 days. Cell number did not change when the cells were incubated with 1, 10 or 100 nM 1,25(OH) 2D 3 or its derivatives, but significantly decreased in the presence of the two retinoids (0.001–10 μM final concentration). A synergistic inhibition was observed, when SH-SY5Y cells were treated combining 0.1 μM 9- cis retinoic acid and 10 nM 1,25(OH) 2D 3 or 10 nM KH 1060, and 1 μM 9- cis retinoic acid and 10 nM 1,25(OH) 2D 3 or 10 nM EB 1089. Acetylcholinesterase activity showed a significant increase, in comparison with controls, after treatment of the cells for 7 days with 0.1 or 1 μM 9- cis retinoic acid, alone or combined with 10 nM 1,25(OH) 2D 3 or 10 nM KH 1060 or 10 nM EB 1089. This increase was synergistic, combining 1 μM 9- cis retinoic acid and 10 nM 1,25(OH) 2D 3 or EB 1089. The levels of the c- myc encoded protein remarkably decreased after treatment of SH-SY5Y cells for 1, 3, 7 days with 0.1 and 1 μM 9- cis retinoic acid, alone or combined with 10 nM 1,25(OH) 2D 3 or 10 nM KH 1060 or 10 nM EB 1089. In particular, the association of 1 μM 9- cis retinoic acid and 10 nM 1,25(OH) 2D 3 or 10 nM EB 1089 resulted in a synergistic c- myc inhibition, in comparison with that obtained in the presence of the retinoid alone. These findings may have therapeutic implications in human neuroblastoma. 相似文献
9.
The biologically active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3), regulates osteoblast proliferation and differentiation. Production of 1,25(OH) 2D 3 is catalysed by the enzyme 25-hydroxyvitamin D 3-1-hydroxylase (CYP27B1). Though highly expressed in the kidney, the CYP27B1 gene is also expressed in non-renal tissues including bone. It is hypothesised that local production of 1,25(OH) 2D 3 by osteoblasts plays an autocrine or paracrine role. The aim of this study was to investigate what factors regulate expression of the CYP27B1 gene in osteoblast cells. ROS 17/2.8 osteoblast cells were transiently transfected with plasmid constructs containing the 5′-flanking sequence of the human CYP27B1 gene fused to a luciferase reporter gene. Cells were treated with either parathyroid hormone (PTH), 1,25(OH) 2D 3, transforming growth factor-beta (TGF-β) or insulin-like growth factor-1 (IGF-1) and luciferase activity was measured 24 h later. The results showed that 1,25(OH) 2D 3 did not alter expression of the reporter construct, however treatment with PTH, IGF-1 and TGF-β decreased expression by 18, 53 and 58% respectively. The repressive action of TGF-β was isolated to the region between −531 and −305 bp. These data suggest that expression of the 5′-flanking region for the CYP27B1 gene in osteoblast cells may be regulated differently to that previously described in kidney cells. 相似文献
10.
Adequate supply of vitamin D 3 is not sufficient for the prevention of post-menopausal osteoporosis, because of a tightly regulated critical step in formation of the most active vitamin D metabolite 1,25-dihydroxyvitamin D 3. Direct application of 1,25(OH) 2D 3, however, was effective in reducing fracture rate and increasing bone mineral density as has been shown in large clinical studies. Extracts from Solanum glaucophyllum and Trisetum flavescens plants containing 1,25(OH)2D3-glycosides were characterized by their vitamin D-activity in a quail eggshell bioassay and applied in an osteoporosis model in ovariectomized rats. An extract from the grass T. flavescens and a purified extract from S. glaucophyllum were characterized by the absence of alkaloids and the analytically determined content of 1,25(OH)2D3. In the ovariectomized rat model after 6 months duration, the bone metabolism relevant markers serum calcium, 1,25(OH)2D3, urinary crosslinks and calcium were measured. At termination tibial mineral content was determined and as imaging procedure micro-computerized tomography was applied. The bisphosphonate alendronate was used as a positive standard. While alendronate reduced bone resorption, as seen in a reduced urinary crosslink excretion, both vitamin D metabolite-containing extracts were able to improve bone mineral density by an enhanced calcium turnover. 相似文献
12.
1,25-Dihydroxyvitamin D 3, [1,25(OH) 2D 3], the biologically most active metabolite of vitamin D 3, is involved in the regulation of calcium homeostasis and bone metabolism. Recently, receptors for 1,25(OH) 2D 3 have also been shown in cells and tissues not directly related to calcium homeostasis. Experimental data obtained with leukemic and cancer cell lines, both in vitro and in vivo, showed the effects of 1,25(OH) 2D 3 on cell differentiation and proliferation. However, high doses of the sterol have to be used to observe these effects. Additional studies are needed to establish whether 1,25(OH) 2D 3 or suitable analogues have a therapeutic potential in malignant diseases without unacceptable toxicity like the development of hypercalcemia. 相似文献
18.
Vitamin D is produced by exposure of 7-dehydrocholesterol in the skin to UV irradiation (UVR) and further converted in the skin to the biologically active metabolite, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) and other compounds. UVR also results in DNA damage producing cyclobutane pyrimidine dimers (CPD). We previously reported that 1,25(OH) 2D 3 at picomolar concentrations, protects human skin cells from UVR-induced apoptosis, and decreases CPD in surviving cells. 1,25(OH) 2D 3 has been shown to generate biological responses via two pathways—the classical steroid receptor/genomic pathway or a rapid, non-genomic pathway mediated by a putative membrane receptor. Whether the rapid response pathway is physiologically relevant is unclear. A cis-locked, rapid-acting agonist 1,25(OH) 2lumisterol 3 (JN), entirely mimicked the actions of 1,25(OH) 2D 3 to reduce fibroblast and keratinocyte loss and CPD damage after UVR. The effects of 1,25(OH) 2D 3 were abolished by a rapid-acting antagonist, but not by a genomic antagonist. Skh:hr1 mice exposed to three times the minimal erythemal dose of solar-simulated UVR and treated topically with 1,25(OH) 2D 3 or JN immediately after UVR showed reduction in UVR-induced UVR-induced sunburn cells ( p < 0.01 and <0.05, respectively), CPD ( p < 0.01 for both) and immunosuppression ( p < 0.001 for both) compared with vehicle-treated mice. These results show for the first time an in vivo biological response mediated by a rapid-acting analog of the vitamin D system. The data support the hypothesis that 1,25(OH) 2D 3 exerts its photoprotective effects via the rapid pathway and raise the possibility that other D compounds produced in skin may contribute to the photoprotective effects. 相似文献
19.
The affinity of purified human vitamin D-binding protein from serum (DBP) for 25-hydroxyvitamin D 3 (25-OHD 3) and 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2D 3] was measured in the presence of free fatty acids (FFA), cholesterol, prostaglandins and several drugs. Mono- and polyunsaturated fatty acids markedly decreased the affinity of both 25-OHD 3 and 1,25-(OH) 2D 3 for DBP, whereas saturated fatty acids (stearic and arachidic acid), cholesterol, cholesterol esters, retinol, retinoic acid and prostaglandins (A 1 and E 1) did not affect the apparent affinity. Several chemicals known to decrease the binding of thyroxine to its plasma-binding protein did not affect the affinity of DBP. The apparent affinity of DBP for both 25-OHD3 and 1,25-(OH)2D3 decreased 2.4- to 4.6-fold in the presence of 36 μM of linoleic or arachidonic acid, respectively. Only a molar ratio of FFA:DBP higher than 10,000 was able to decrease the binding of 25-OHD3 to DBP by 20%. Much smaller ratio's of FFA:DBP (25 for arachidonic and 45 for oleic acid), however, decreased the binding of 1,25-(OH)2D3 to DBP. These latter ratio's are well within the physiological range. The addition of human albumin in a physiological albumin:DBP molar ratio did not impair the inhibitory effect of linoleic acid on the binding of [3H]25-OHD3 to DBP. The binding and bioavailability of vitamin D metabolites thus might be altered by mono- and polyunsaturated but not by saturated fatty acids. 相似文献
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