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Query: UNIPROT:P06889 (Mol)
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High affinity receptors (VDR) for 1,25-dihydroxycholecalciferol (calcitriol) are expressed in HL60 human leukemia cells and in low numbers in peripheral blood lymphocytes (PBL). HL60 cells, expressing some characteristics of promyelocytes, can be induced to monocytoid differentiation by calcitriol. Specific nuclear translocation of [3H]calcitriol/VDR was examined after exposure of whole cells to 10(-9) M/l calcitriol in the presence and absence of a 500-fold excess of unlabeled ligand and subsequent isolation of nuclei. Specific nuclear translocation of [3H]calcitriol/VDR was found to be time dependent reaching a maximum of approximately 2100 binding sites/nucleus after 3 h of incubation in HL60 cells, whereas a maximum of approximately 310 binding sites/nucleus was found after 3 h in PBL. Pulse exposure of HL60 to radiolabeled hormone for 3 h followed by culture in medium without serum and calcitriol lead to nuclear retention of approximately 1600 radiolabeled VDR by 8 h and approximately 1000 VDR by 24 h. Radiolabeled VDR disappeared from the nuclear compartment with a halflife of approximately 30 min if cells were cultured with identical concentrations of unlabeled hormone after the pulse (pulse/chase-experiments). No difference of VDR retention in pulse and pulse/chase-experiments was seen in PBL, where VDR halflife was approximately 30 min. No specific translocation into the nuclear compartment was seen when isolated nuclei were incubated in [3H]calcitriol. Radiolabeled hormone/receptor complexes of nuclei isolated from cells exposed for 3 h to radiolabeled hormone--in contrast to identical experiments with intact cells--did not disappear from the nuclear compartment upon incubation of nuclei with identical concentrations of the unlabeled compound. The activity of DNA relaxing enzymes (e.g. topoisomerases I and II) in nuclear extracts was measured using a PBR 322-relaxation-assay. Enhanced overall enzyme activity was found in nuclear extracts by 1 h after incubation with calcitriol (final ethanol concentration 0.0001% v/v) in HL60 and PBL. The enhanced activity disappeared after 2 h in PBL, whereas it was still enhanced by 4 h in HL60. No effect was seen in ethanol treated controls. We conclude that a specific nuclear translocation mechanism exists for calcitriol in both cell types examined, most likely due to translocation of receptor proteins after hormone binding. Translocated hormone/receptor complexes compete for a limited number of specific nuclear binding sites. Enhanced activity of topoisomerases in nuclear extracts upon translocation of VDR might reflect interaction of both within the nuclear compartment, thus initiating DNA-unwinding, a prerequisite of transcription initiation.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Kinetics of nuclear translocation and turnover of the vitamin D receptor in human HL60 leukemia cells and peripheral blood lymphocytes--coincident rise of DNA-relaxing activity in nuclear extracts. 131 93

The aim of the present study was to investigate the effect of 1,25-dihydroxycholecalciferol (1,25(OH)2-D3) on the regulation of calcium fluxes in rat thyroid FRTL-5 cells. The ATP-induced uptake of 45Ca2+ was decreased in cells pretreated with 1,25(OH)2D3 for 48 h. No effect was seen on basal uptake of 45Ca2+. At least a 24 h incubation period was required for the effect of 1,25(OH)2D3 to be expressed. Pretreatment with 1,25(OH)2D3 for 48 h did not change resting intracellular Ca2+ ([Ca2+]i) in fura-2-loaded FRTL-5 cells. However, the ATP-induced increase in [Ca2+]i was significantly enhanced in cells preincubated with 1,25(OH)2D3. The effect of 1,25(OH)2D3 was abolished in Ca(2+)-free buffer. No difference in the ionomycin-induced increase in [Ca2+]i was observed between control cells and cells pretreated with 1,25(OH)2D3. However, in Ca(2+)-free buffer the ionomycin response was decreased in cells incubated with 1,25(OH)2D3. The ATP-induced change in [Ca2+]i was decreased when ATP was added after ionomycin to cells treated with 1,25(OH)2D3. The results suggest that 1,25(OH)2D3 has a regulatory effect on Ca2+ fluxes in FRTL-5 cells, possibly by acting on Ca2+ sequestration.
Mol Cell Endocrinol 1992 Jul
PMID:Regulatory effect of 1,25-dihydroxycholecalciferol on calcium fluxes in thyroid FRTL-5 cells. 132 56

A rat thyroid cell line (FRTL-5) was used to study the effect of cholecalciferols on cAMP production. The active cholecalciferol metabolite, calcitriol, caused a reduction in basal and thyrotropin (TSH)-stimulated cAMP production. The inhibitory effects were demonstrated after 1 and 2 days, respectively. The maximum effect on both basal and TSH-stimulated cAMP production was observed after 3-4 days of treatment. The effect was detectable at 10(-10) and maximal at 10(-8) mol/l. Calcitriol was about 300 times more potent than calcidiol in attenuating cAMP production, whereas (24R)-hydroxycalcidiol in concentrations up to 3 x 10(-8) mol/l had no effect. After removal of added calcitriol the cAMP response to TSH returned to normal within 8 days. Calcitriol (10(-8) mol/l) also inhibited cell growth. Our results show that calcitriol at physiological concentrations inhibits both basal and TSH-stimulated cAMP production in rat thyroid cells. This indicates that calcitriol may modulate the effect of TSH on thyroid function and growth.
Mol Cell Endocrinol 1991 Apr
PMID:Cholecalciferol metabolites attenuate cAMP production in rat thyroid cells (FRTL-5). 166 3

One of the hallmarks of the granulomatous response to infection is the formation of multinucleated giant cells (MGC.) In an effort to study MGC, we examined the fusion-promoting effects of a variety of stimulating factors on human peripheral blood monocytes cultured on plastic surfaces in serum-supplemented media. MGC formation was minimally to moderately enhanced by interferon-gamma (IFN-gamma), interleukin (IL)-3, granulocyte/macrophage colony-stimulating factor (GM-CSF), 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), retinoic acid (RA), and IL-6. IL-4 (which has been reported to promote MGC formation from murine macrophages) had an inhibitory effect. IFN-gamma was not required for MGC formation but it significantly increased the fusion-promoting activity of GM-CSF, 1,25-(OH)2D3, RA, and IL-6, IL-3, a hematopoietic growth factor, has been recently shown to induce osteoclast formation from murine bone marrow mononuclear cells. The most striking effect was seen with the combination of IL-3 and IFN-gamma. Fusion index is defined as a percentage of nuclei found within MGC, and an index of 67% at 1 wk was found. The formation of some very large cells with 50 to 100 nuclei was noted. Both Langhans' and foreign-body type cells were seen. Transmission electron micrographs clearly demonstrate the absence of plasma membrane between nuclei. Induction of MGC from peripheral human blood monocytes by IL-3 and IFN-gamma provides an in vitro system for the study of the formation and function of these cells.
Am J Respir Cell Mol Biol 1992 Jan
PMID:Induction of multinucleated giant cell formation from in vitro culture of human monocytes with interleukin-3 and interferon-gamma: comparison with other stimulating factors. 172 95

We have looked at the effects of calcitriol (1 alpha,25-dihydroxyvitamin D3) on the expression of the members of the fos and jun families of protooncogenes in an osteoblastic cell line and in primary cultures of osteoblasts. Calcitriol treatment of starved, confluent cultures of MC3T3-E1 cells induced a rapid and transient stimulation of the expression of c-fos, fos-B, c-jun, and jun-B with varying kinetics. The expression of fra-1 and jun-D was not affected by calcitriol in those cells. The selective stimulation of fos and jun family members by calcitriol was also observed in primary cultures of osteoblasts isolated from newborn mouse calvaria, suggesting that this modulation is a physiological response of the bone cells and not an artefact of the established cell line. The calcitriol effect was specific and dose-dependent. The expression of the c-Fos protein correlated with the expression of the mRNA in calcitriol-treated cells. The calcitriol-induced stimulation of c-fos expression was modulated, at least in part, at the level of the initiation and elongation of transcription, whereas its effects on c-jun and jun-B expression was controlled at the posttranscriptional level by a mechanism that does not implicate stabilization of their respective mRNAs. The differential stimulation of the expression of certain members of the fos and jun families by calcitriol support a role for these oncoproteins in bone cell physiology.
Mol Endocrinol 1991 Dec
PMID:Differential stimulation of fos and jun family members by calcitriol in osteoblastic cells. 179 29

1,25-Dihydroxyvitamin D3 has been shown to induce rapid changes in calcium fluxes in skeletal muscle and other target tissues independently of gene activation. The possibility that the hormone would produce similar effects in heart where 1,25-dihydroxyvitamin D3 receptors and activities have been shown, was studied. A significant increase of 45Ca uptake by left ventricular slices from vitamin D-deficient chicks was observed upon incubation for 1-10 min with physiological doses of 1,25-dihydroxyvitamin D3. This stimulation was dose-dependent and specific for the hormone when compared with vitamin D3, 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 and could not be associated to changes in lipid synthesis as assessed by measurements of [3H]glycerol incorporation into cardiac tissue lipids. The Ca channel blockers nifedipine (30 microM) and verapamil (10 microM) abolished the increase in Ca uptake produced by 1,25-dihydroxyvitamin D3. The rapid effects of the hormone on heart Ca influx were accompanied by a stimulation of the phosphorylation of two microsomal proteins of 43 kDa and 55 kDa. These results further support a direct action of 1,25-dihydroxyvitamin D3 in the regulation of cardiac muscle Ca metabolism which may involve activation of Ca channels.
Mol Cell Endocrinol 1991 May
PMID:Rapid stimulation of calcium uptake and protein phosphorylation in isolated cardiac muscle by 1,25-dihydroxyvitamin D3. 181 4

Neural and systemic somatotrophic effects of the ultraviolet component of sunlight through the skin-vitamin D endocrine system are considered as alternate or additional to the neuroendocrine effects of the visual component of light through the retino-diencephalic input. The extensive distribution of soltriol nuclear receptor cells, revealed by autoradiography with tritium-labeled 1,25 dihydroxycholecalciferol (vitamin D, soltriol) and related effects, indicate an involvement of vitamin D-soltriol in the actinic induction of seasonal biorhythms. This is considered to be independent of the traditionally assigned effects of vitamin D on systemic calcium regulation. Skin-soltriol mediated seasonal, and to a degree daily, genomic activation involves many target regions in the brain. These include neurons in the central nucleus of the amygdala, in the linked part of the bed nucleus of the stria terminalis, in periventricular hypothalamic neurons, dorsal raphe nucleus, reticular thalamic nucleus and autonomic, endocrine as well as sensory and motor components of the brainstem and spinal cord. Additional to the eye-regulated "suprachiasmatic clock", existence of a soltriol-vitamin D regulated neural "timing circuit(s)" is proposed. Both, activational and organizational effects of soltriol on mature and developing brain regions, respectively are likely to play a role in the regulation of neuronal functions that include the modulation and entrainment of biorhythms. Soltriol's central effects correlate with peripheral effects on elements in skin, bone, teeth, kidney, intestine, heart and blood vessels, endocrine organs, and tissues of the immune and reproductive system.
J Steroid Biochem Mol Biol 1991 Aug
PMID:The steroid hormone of sunlight soltriol (vitamin D) as a seasonal regulator of biological activities and photoperiodic rhythms. 188 89

Micromolar concentrations of aluminum sulfate consistently stimulated [3H]thymidine incorporation into DNA and increased cellular alkaline phosphatase activity (an osteoblastic differentiation marker) in osteoblast-line cells of chicken and human. The stimulations were highly reproducible, and were biphasic and dose-dependent with the maximal stimulatory dose varied from experiment to experiment. The mitogenic doses of aluminum ion also stimulated collagen synthesis in cultured human osteosarcoma TE-85 cells, suggesting that aluminum ion might stimulate bone formation in vitro. The effects of mitogenic doses of aluminum ion on basal osteocalcin secretion by normal human osteoblasts could not be determined since there was little, if any, basal secretion of osteocalcin by these cells. 1,25 Dihydroxyvitamin D3 significantly stimulated the secretion of osteocalcin and the specific activity of cellular alkaline phosphatase in the human osteoblasts. Although mitogenic concentrations of aluminum ion potentiated the 1,25 dihydroxyvitamin D3-dependent stimulation of osteocalcin secretion, they significantly inhibited the hormone-mediated activation of cellular alkaline phosphatase activity. Mitogenic concentrations of aluminum ion did not stimulate cAMP production in human osteosarcoma TE 85 cells, indicating that the mechanism of aluminum ion does not involve cAMP. The mitogenic activity of aluminum ion is different from that of fluoride because (a) unlike fluoride, its mitogenic activity was unaffected by culture medium changes; (b) unlike fluoride, its mitogenic activity was nonspecific for bone cells; and (c) aluminum ion interacted with fluoride on the stimulation of the proliferation of osteoblastic-line cells, and did not share the same rate-limiting step(s) as that of fluoride. PTH interacted with and potentiated the bone cell mitogenic activity of aluminum ion, and thereby is consistent with the possibility that the in vivo osteogenic actions of aluminum ion might depend on PTH. In summary, low concentrations of aluminum ion could act directly on osteoblasts to stimulate their proliferation and differentiation by a mechanism that is different from fluoride.
Mol Cell Biochem 1991 Jul 10
PMID:Aluminum stimulates the proliferation and differentiation of osteoblasts in vitro by a mechanism that is different from fluoride. 192 12

The chronic administration of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) to 9-day-old suckling rats induced no change on day 13 in the calcitonin (CT) mRNA steady-state level of thyroid glands measured by Northern hybridization. Thyroidal CT contents were decreased in relation to increased plasma calcium levels in animals treated with 0.1 or 1 microgram 1,25-(OH)2D3/kg. Using a lower dose (0.01 microgram/kg), neither plasma calcium, nor thyroidal CT contents were changed. No correlation was found between CT mRNA levels and thyroidal CT contents as well as for plasma CT levels and thyroidal CT contents since hormone in blood remained unchanged after treatment by the active vitamin D3 metabolite. Intraperitoneal calcium administration in fasted 13-day-old rats was associated with a 5-fold increase in plasma CT 30 min after injection, but CT mRNA levels were unchanged within 240 min. By contrast, stomach gavage with calcium in fasted 13-day-old rats induced a sustained increase in plasma CT (X2), and a 4-fold increase in the steady-state level of CT mRNA. Calcium per se is a potent stimulator of CT release in suckling rats, but did not change the amount of CT mRNA. However, gastrointestinal factors may be implied directly or indirectly in the increased CT mRNA level after calcium gavage. In conclusion, 1,25-(OH)2D3 which is known to affect CT gene expression in adult rats is ineffective in 13-day-old suckling rats. This observation may be related to developmental changes in the amount of 1,25-(OH)2D3 receptors of C cells.
Mol Cell Endocrinol 1991 Aug
PMID:Effects of 1,25-dihydroxycholecalciferol and calcium on calcitonin mRNA levels in suckling rats. 193 45

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) receptor concentration, cell proliferation, and the steady-state level of c-myc mRNA were examined in the C3H/10T1/2 mouse embryo fibroblasts, before and after exposing the cells to 1,25-(OH)2D3. The non-transformed, logarithmically growing C3H/10T1/2 Cl 8 cells contained a high concentration of 1,25-(OH)2D3 receptor (164 fmol/mg of protein). An up-regulation of the 1,25-(OH)2D3 receptor and a potent inhibition of cell growth were observed by exposing the cells to 10 nM 1,25-(OH)2D3. The concentration of 1,25-(OH)2D3 receptor in the two chemically transformed, tumorigenic cell lines. C3H/10T1/2 Cl 16 and C3H/10T1/2 TPA 482, was 218 and 63 fmol/mg of protein, respectively. In the two transformed cell lines, 10 nM 1,25-(OH)2D3 had only negligible effect on cell growth. In the Cl 16 cells, an up-regulation of the 1,25-(OH)2D3 receptor was demonstrated, but only a weak up-regulation was found in the TPA 482 cells by the 1,25-(OH)2D3 treatment. No major changes were found in c-myc mRNA levels by the 1,25-(OH)2D3 treatment. Despite inhibition of cell growth, the steady-state level of c-myc mRNA was slightly induced (35%, mean) in the Cl 8 cells compared to control cells. In the transformed cells, no consistent change of the c-myc level was found. In contrast to earlier reports, we did not find any correlation between the 1,25-(OH)2D3 receptor and c-myc level, nor did we find any decrease of c-myc mRNA by 1,25-(OH)2D3 treatment in the C3H/10T1/2 fibroblasts.
Mol Cell Endocrinol 1990 Dec 21
PMID:Effect of 1,25-(OH)2-vitamin D3 on growth, homologous receptor and c-myc regulation in C3H/10T1/2 cells. 196 47


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