Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-gamma-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-gamma and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-gamma action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-gamma/Stat1-induced transcription. This novel 1,25D-IFN-gamma cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.
Mol Cell Biol 2002 Apr
PMID:Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. 1190 70

Jansen's metaphyseal chondrodysplasia (JMC) is an autosomal dominant disorder characterized by short-limbed dwarfism, delayed ossification, and hypercalcemia. Activating mutations in the PTH/PTHrP receptor have been identified as the molecular cause of this disorder. Although these mutations have been shown to increase cAMP accumulation, little is known about possible target genes of the downstream signaling pathways that may contribute to the pathogenesis of the disease. Here we demonstrate that JMC mutations of the PTH/PTHrP receptor induce activation of the cyclin D1 and cyclin A promoters in primary mouse chondrocytes and rat chondrosarcoma cells. Induction of cyclin D1 expression is required for stimulation of E2F-dependent transcription by mutant receptors. Activation of the cyclin D1 and cyclin A promoters requires a functional cAMP response element in both genes. Inhibition of protein kinase A or the transcription factor cAMP response element binding protein blocks the stimulation of both promoters by mutant receptors, whereas inhibition of activating transcription factor 2, c-Fos, or c-Jun has only minor effects. In summary, our data suggest that stimulation of cell cycle gene expression and cell cycle progression by mutant PTH/PTHrP receptors contribute to the pathogenesis of JMC.
Mol Endocrinol 2002 Sep
PMID:The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia. 1219 52

Plasma concentrations of the main vitamin D(3) metabolites (i.e., 25(OH)D(3), 1,25(OH)(2)D(3), and 24,25(OH)(2)D(3)) were measured in 14 weeks old large- and small-breed dogs (adult body weight 60 kg vs. 6 kg), raised under the same conditions. Levels of 25(OH)D(3) (approx. 22 microg/l) and 1,25(OH)(2)D(3) (approx. 40 ng/l) were similar in both groups, whereas plasma 24,25(OH)(2)D(3) concentrations were lower in large-breed dogs (7 microg/l vs. 70 microg/l, large- vs. small-breed dogs, respectively). The lower plasma 24,25(OH)(2)D(3) concentrations could be explained by the higher plasma GH and IGF-I concentrations in the large- vs. small-breed dogs, and these hormones are known to suppress 24-hydroxylation. Plasma 24,25(OH)(2)D(3) concentrations increased during Ca supplementation in small-breed but not in large-breed dogs (100 microg/l vs. 7 microg/l, respectively). Hypophosphatemia induced by a high dietary Ca content was only seen together with increased plasma 1,25(OH)(2)D(3) concentrations in euparathyroid dogs and not in hypoparathyroid dogs. Hyperparathyroidism due to Ca deficiency was accompanied by increased plasma 1,25(OH)(2)D(3) concentrations and decreased plasma 24,25(OH)(2)D(3) concentrations in both large- and small-breed dogs, together with generalized osteoporosis. Large-breed pups fed on a standard diet supplemented with Ca and P had decreased plasma concentrations of both 25(OH)D(3) and 1,25(OH)(2)D(3), which may indicate an increased clearance of these metabolites; the low plasma concentrations of the di-hydroxylated vitamin D metabolites were considered responsible for the disturbance in cartilage maturation (i.e., osteochondrosis) in these dogs. Even lower concentrations of all vitamin D(3) metabolites were seen in young dogs raised on a vitamin D(3)-deficient diet, and led to disturbed osteoid and cartilage mineralization (i.e., rickets). These studies indicate that there is a hierarchy of factors regulating vitamin D(3) metabolism in dogs, i.e., GH and IGF-I suppress 24-hydroxylase more than hypercalcemia or hypophosphatemia does; 1,25(OH)(2)D(3) and 24,25(OH)(2)D(3) are only reciprocally related in hyperparathyroidism; excessive Ca and P intake increases the turnover of vitamin D(3) metabolites; and the synergism between parathyroid hormone and 1,25(OH)D(3) seems to play a role in skeletal mineralization. The low plasma 24,25(OH)(2)D(3) concentrations in large-breed dogs raised on standard dog food may play a role in the etiology of disturbances in endochondral ossification during the rapid growth phase.
Mol Cell Endocrinol 2002 Nov 29
PMID:Vitamin D3 metabolism in dogs. 1243 92

Parathyroid hormone-related protein (PTHrP) is produced by many tumors not associated with humoral hypercalcemia, including breast cancers. In this study, we used three human immortalized mammary epithelial cell lines that differ in tumorigenicity and PTHrP expression. Using RT-PCR we investigated 5' and 3' alternative splicing of PTHrP transcripts and promoter usage in the lines. Increased levels of P3-derived transcripts and the 1-139 mRNA isoform were observed in the most tumorigenic cell line. Transient transfection experiments identified elements close to P3 promoter that appeared to account for a portion of differential PTHrP expression among the three cell lines. Using site-directed mutagenesis, a previously described Ets-1/Sp1 binding site upstream of P3 was determined to be crucial for full activity of this promoter. RT-PCR and western blot evaluation of Ets family member expression found that Ese-1 was present in all three lines, but that appreciable levels of Ets-1 protein were present exclusively in the most tumorigenic line. Cotransfection of Ets-1 expression vectors activated PTHrP reporter constructs in the most tumorigenic line but not in the other cell lines. These findings suggest a potential mechanism by which PTHrP transcription may be regulated as a consequence of events that promote tumorigenic behavior in breast epithelial cells.
Mol Cell Endocrinol 2003 Jun 30
PMID:Ets-1 activates parathyroid hormone-related protein gene expression in tumorigenic breast epithelial cells. 1285 Feb 90

The active metabolite of vitamin D, 1alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3]--a seco-steroid hormone is a pivotal regulator of cellular proliferation and differentiation those are independent of its classical function of calcium homeostasis and bone mineralization. The existence of the nuclear vitamin D receptor (VDR) has been found in numerous tissues in different organs, which are the so-called 'non-classical' targets of this seco-steroid hormone. Vitamin D has been documented as a potent antiproliferative agent in different tissues and cells. Epidemiological studies reveal a negative correlation between physiological level of vitamin and cancer risk. Studies using animal models clearly demonstrate protective role of vitamin D in different cancer types by the reduction in tumor progression and by monitoring biochemical parameters. Experiments with cultured human and animal cancer cell lines show similar antiproliferative role of vitamin D manifested by up or down regulations of crucial genes leading to inhibition of cellular growth. Hypercalcemia hinders broad-spectrum therapeutic uses of vitamin D in cancer chemotherapy. Application of vitamin D analogs having similar chemical structures or other compounds having vitamin D like actions but lacking calcemic adverse effects are getting significant attention towards rational therapeutics to treat cancer. The current review focuses on the application of vitamin D and its analogs in different forms of cancer and on the molecular mechanism involved in vitamin D mediated inhibition in cellular proliferation, cell cycle, induction of apoptosis and tumor suppression, which may eventually evolve as a meaningful cancer therapy.
Mol Cell Biochem 2003 Nov
PMID:Antiproliferative role of vitamin D and its analogs--a brief overview. 1461 76

1,25-Dihydroxyvitamin D (calcitriol), the most active metabolite of vitamin D, has significant antineoplastic activity in preclinical models. Several mechanisms of activity have been proposed. These include inhibition of proliferation associated with cell cycle arrest and, in some models, differentiation, reduction in invasiveness and angiogenesis, and induction of apoptosis. Proposed mechanisms differ between tumor models and experimental conditions, and no unifying hypothesis about the mechanism of antineoplastic activity has emerged. Synergistic and/or additive effects with cytotoxic chemotherapy, radiation, and other cancer drugs have been reported. Significantly supraphysiological concentrations of calcitriol are required for antineoplastic effects. Such concentrations are not achievable in patients when calcitriol is dosed daily due to predictable hypercalcemia and hypercalcuria; however, phase I trials have demonstrated that intermittent dosing allows substantial dose escalation and has produced potentially therapeutic peak calcitriol concentrations. Recently, a phase II study reported encouraging levels of activity for the combination of high-dose calcitriol and docetaxel administered on a weekly schedule in patients with androgen-independent prostate cancer. This regimen is now under study in a placebo-controlled randomized trial in androgen-independent prostate cancer and in phase II studies in several other tumor types. Further work is needed to elucidate the molecular mechanisms of antineoplastic activity and optimal clinical applications of calcitriol in cancer.
Mol Cancer Ther 2004 Mar
PMID:Calcitriol in cancer treatment: from the lab to the clinic. 1502 58

The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.
J Steroid Biochem Mol Biol 2004 May
PMID:Characterization of five 19-nor-analogs of 1alpha,25(OH)2-Vitamin D3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties. 1522 54

gamma-Interferon [gamma-IFN] induction of macrophage 1alpha-hydroxylase mRNA and activity causes severe hypercalcemia in granulomatous disorders. These studies demonstrate transcriptional regulation. gamma-IFN induces the activity of the murine 1alpha-hydroxylase [-1651; +22] promoter in the murine macrophage cell line Raw 264.7 only after a 24h exposure. This slow kinetics is incompatible with classical gamma-IFN-mediated transactivation. In fact, gamma-IFN response mapped to the minimal [-85; +11] promoter, which lacks GAS or ISRE sites but contains a putative C/EBPbeta site. C/EBPbeta is a gamma-IFN inducible gene and a novel mediator of gamma-IFN-regulated transcription. As expected for a C/EBPbeta-driven transcription, ectopic C/EBPbeta expression was sufficient to increase 1alpha-hydroxylase activity, enhance minimal promoter activity and potentiate the induction of this promoter by gamma-IFN. Importantly, the dominant negative C/EBPbeta isoform antagonized C/EBPbeta-transcriptional activity. gamma-IFN induction of C/EBPbeta expression is not sufficient for gamma-IFN induction of minimal promoter activity. There is also a cell-specific induction of C/EBPbeta-transcriptional activity by gamma-IFN. In Raw cells, specific inhibition of gamma-IFN induction of endogenous-C/EBPbeta phosphorylation by MEKK1 markedly reduced basal promoter activity and the response to gamma-IFN. We conclude that gamma-IFN-induction of C/EBPbeta expression and activation by phosphorylation contributes to gamma-IFN-transcriptional control of 1alpha-hydroxylase expression in murine macrophages.
J Steroid Biochem Mol Biol 2004 May
PMID:1alpha-Hydroxylase transactivation by gamma-interferon in murine macrophages requires enhanced C/EBPbeta expression and activation. 1522 60

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2) D(3)) is a potent regulator of cell growth and differentiation, with recent evidence showing inhibition of tumor invasion, angiogenesis and tumor cell death. The growth-inhibitory properties of 1,25-(OH)(2) D(3) could be harnessed in the treatment of patients with cancer if the development of systemic hypercalcemia is avoided. Hepatocellular cancer (HCC) presents a setting where the tumor is accessible for treatment through the hepatic artery and also where the tumor is highly lipiodol avid. On this basis, we hypothesised that, 1,25-(OH)(2) D(3) dissolved in lipiodol and administered through the hepatic artery may prove to be a rational approach to the use of the drug in the treatment of HCCs. In brief, 6 years of work with 1,25-(OH)(2) D(3) at cellular, animal and clinical level has provided us with plenty of support for this hypothesis. Sensitivity of HCCs in cell culture to 1,25-(OH)(2) D(3), growth retardation of human HCC xenografts in nude mice, uptake and retention of 1,25-(OH)(2) D(3)-lipiodol by liver tumors in cell culture and animals, escalation of the 1,25-(OH)(2) D(3) dose by 100x without the development of hypercalcemia in both liver tumor bearing rats and in patients with HCC are some of the evidence that will be discussed in this paper.
J Steroid Biochem Mol Biol 2004 May
PMID:1,25-Dihydroxyvitamin D3 in lipiodol for the treatment of hepatocellular carcinoma: cellular, animal and clinical studies. 1522 30

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.
J Steroid Biochem Mol Biol 2004 May
PMID:Anti-tumor activity of calcitriol: pre-clinical and clinical studies. 1522 31


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