Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tumor production of parathyroid hormone-related protein (PTHRP) is responsible for most cases of hypercalcemia of malignancy. The transplantable rat Leydig tumor H-500 is known to cause hypercalcemia in rats by the release of abundant PTHRP and to closely reproduce the human syndrome. We have demonstrated recently that Ras oncogene can stimulate PTHRP gene expression in Fr3T3 fibroblasts in vitro and cause hypercalcemia in vivo. Using rat Leydig tumor H-500 cells, we have investigated the role of effector pathways downstream of Ras in serum-induced PTHRP expression. The Ras inhibitors B-1086 and Lovastatin decreased PTHRP mRNA expression. i.p. administration of B-1086 (50-100 mg/kg/day) into H-500 tumor-bearing male Fischer rats resulted in a dose-dependent reduction in tumor volume, serum calcium, plasma PTHRP, and tumoral PTHRP mRNA expression. Transient transfection of dominant-negative Ras (Ras N17) and Raf (Raf C4B) reduced, whereas activated Raf-1 (Raf BXB) increased, basal expression of PTHRP in H-500 cells. A similar decrease in PTHRP production was seen with a mitogen-activated protein kinase kinase (MEK) inhibitor (PD 098059), implicating the involvement of Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway. In addition, stimulation with UV light, which can activate c-Jun NH2-terminal kinase (JNK), or expression of an activated form of Rac (Rac V12) was sufficient to increase PTHRP mRNA. Moreover, a dominant-negative Rac (Rac N17) blocked serum-induced PTHRP gene expression. Collectively, these results demonstrate that PTHRP is induced via both Raf-ERK and Rac-JNK mediated pathways, effects which can be blocked by chemical inhibitors and dominant-negative mutants of these pathways in vitro and in vivo. Availability of selective inhibitors of Ras signaling molecules may therefore add to our existing armamentarium to control hypercalcemia of malignancy.
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PMID:Role of mitogen-activated protein kinases in the induction of parathyroid hormone-related peptide. 1074 50

Tumor cells frequently have pronounced effects on the skeleton including bone destruction, bone pain, hypercalcemia, and depletion of bone marrow cells. Despite the serious sequelae associated with skeletal metastasis, the mechanisms by which tumor cells alter bone homeostasis remain largely unknown. In this study, we tested the hypothesis that the disruption of bone homeostasis by tumor cells is due in part to the ability of tumor cells to upregulate osteopontin (OPN) mRNA in osteoblasts. Conditioned media were collected from tumor cells that elicit either osteolytic (MCF-7, PC-3) or osteoblastic responses (LNCaP) in animal models and their effects on OPN gene expression were compared using an osteoblast precursor cell line, MC3T3-E1 cells. Secretory products from osteolytic but not osteoblastic tumor cell lines were demonstrated to upregulate OPN in osteoblasts while inhibiting osteoblast proliferation and differentiation. Signal transduction studies revealed that regulation of OPN was dependent on both protein kinase C (PKC) and the mitogen-activated protein (MAP) kinase cascade. These results suggest that the upregulation of OPN may play a key role in the development of osteolytic lesions. Furthermore, these results suggest that drugs that prevent activation of the MAP kinase pathway may be efficacious in the treatment of osteolytic metastases.
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PMID:Secretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cells. 1086 58

The extracellular Ca(2+)-sensing receptor (CaR) responds to polycations, including Ca(2+) and neomycin. This receptor is a physiological regulator of systemic Ca(2+) metabolism and may also mediate the toxic effects of hypercalcemia. A number of divalent cations, including Pb(2+), Co(2+), Cd(2+), and Fe(2+), are toxic to the kidney, brain, and other tissues where the CaR is expressed. To determine which divalent cations can activate the CaR, we expressed the human CaR in HEK-293 cells and measured activation of phospholipase A(2) (PLA(2)) and the mitogen-activated protein kinase p42ERK in response to potential agonists for the receptor. HEK-293 cells expressing the nonfunctional mutant CaR R796W served as controls. Extracellular Ca(2+), Ba(2+), Cd(2+), Co(2+), Fe(2+), Gd(3+), Ni(2+), Pb(2+), and neomycin activated the CaR, but Hg(2+) and Fe(3+) did not. We analyzed the kinetics of activation of p42ERK and PLA(2) by the CaR in response to Ca(2+), Co(2+), and Pb(2+). The EC(50) values ranged from approximately 0.1 mM for Pb(2+) to approximately 4.0 mM for Ca(2+). The Hill coefficients were >3, indicating multiple cooperative ligand binding sites or subunits. Submaximal concentrations of Ca(2+) and Pb(2+) were additive for activation of the CaR. The EC(50) for Ca(2+) or Pb(2+) was reduced four- to fivefold by the presence of the other ion. These divalent cations also activated PLA(2) via the CaR in Madin-Darby canine kidney cells that stably express the CaR. We conclude that many divalent cations activate the CaR and that their effects are additive. The facts that the CaR is a promiscuous polycation sensor and that the effects of these ions are additive to activate it suggest that the CaR may contribute to the toxicity of some heavy metals such as Pb(2+), Cd(2+), Co(2+), and Fe(2+) for the kidney and other tissues where it is expressed.
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PMID:Extracellular Ca(2+)-sensing receptor is a promiscuous divalent cation sensor that responds to lead. 1109 27

Vitamin D, parathyroid hormone (PTH), and parathyroid hormone-related peptide (PTHrP) are major regulators of calcium metabolism and vitamin D can also reduce the growth of normal cells and tumor cells. PTHrP and PTH act via a common membrane receptor (PTHR). The mouse PTHR is regulated by a kidney-selective upstream promoter P(1) and ubiquitous downstream promoter P(2). In vitro and in vivo 1,25(OH)(2)D can inhibit PTHR expression in bone but not cartilage by downregulating transcription via P(2). Gene transcription of PTHrP per se can also be downregulated by 1,25(OH)(2)D and by low calcemic vitamin D analogs. This inhibitory effect may reduce the hypercalcemia caused by overproduction of PTHrP by tumor cells. In a malignant keratinoctye cell line, phosphorylation of the retinoid X receptor alpha occurs through the activated Ras-MAP kinase pathway and results in attenuated trans-activation by the vitamin D receptor, its heterodimeric partner. This decreases the growth-inhibitory efficacy of 1,25(OH)(2)D. Studies of the capacity of vitamin D to alter PTHrP production and action and of its anti-proliferative effects can, therefore, shed important light on basic mechanisms controlling these events, and may also have major implications for clinical medicine and therapeutics.
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PMID:Studies of the effects of 1,25-dihydroxyvitamin D on skeletal and calcium homeostasis and on inhibition of tumor cell growth. 1138 62

Antibodies to cell surface receptors can cause endocrine dysfunction by mimicking or blocking the actions of their respective hormones. We sought patients with autoantibodies to the extracellular calcium (Ca(2+)(o))-sensing receptor (CaR), which sets the normal level of blood calcium, that mimic the genetic disorder, familial hypocalciuric hypercalcemia, caused by heterozygous inactivating mutations of the CaR. Four individuals from two kindreds were identified with PTH-dependent hypercalcemia, who had other autoimmune manifestations: one with sprue and antigliadin and antiendomyseal antibodies and three with antithyroid antibodies. Three of the patients also had relative or absolute hypocalciuria. The patients' sera contained antibodies that reacted with the cell surface of bovine parathyroid cells in a manner similar to an authentic polyclonal anti-CaR antibody, stained bands on Western analysis of sizes similar to those labeled by the anti-CaR antiserum, and reacted with several synthetic peptides derived from sequences within the CaR's extracellular amino terminus. The patients' sera also stimulated PTH release from dispersed human parathyroid cells compared with the effect of sera from normocalcemic control subjects. This stimulation could be blocked by preabsorbing serum with membranes from CaR-transfected, but not nontransfected, human embryonic kidney (HEK293) cells. Finally, in two of the patients, antibodies affinity-purified using a synthetic peptide from within the CaR's extracellular domain inhibited high Ca(2+)(o)-stimulated, CaR-mediated accumulation of inositol phosphates and activation of mitogen-activated protein kinase in CaR-transfected HEK293 cells. DNA sequencing revealed no mutations within the index patients' CaR genes in the two families. Therefore, a biochemical phenotype of PTH-dependent hypercalcemia resembling that caused by heterozygous inactivating mutations of the CaR in familial hypocalciuric hypercalcemia can be observed in patients with antibodies to the CaR's extracellular domain that stimulate PTH release, probably by inhibiting activation of the CaR by Ca(2+)(o). Autoimmune hypocalciuric hypercalcemic is an acquired disorder of Ca(2+)(o) sensing that should be differentiated from that caused by inactivating mutations of the CaR.
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PMID:A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. 1251 31

Bisphosphonates have been used for the treatment of hypercalcemia associated with malignancies and osteoporosis. It was previously reported that the mevalonate pathway is involved in nitrogen-containing bisphosphonate-induced apoptosis in osteoclasts and myeloma cells. The aim of this study was to determine the effects of two bisphosphonates, incadronate, and newly developed bisphosphonate YM529 on human myeloma cells, U266, RPMI-8226, and HS-Sultan. Both incadronate and YM529 induced S-phase cell cycle arrest and apoptosis in these myeloma cells. Treatment of the myeloma cells with cell-permeable substrates for mevalonate pathways, geranylgeraniol, and farnesol prevented bisphosphonate-mediated growth suppression. Checkpoint kinases, Chk1/2, and MAPK became phosphorylated after stimulation with bisphosphonates in the myeloma cells. Bisphosphonate-induced apoptosis was partially prevented by the pretreatment with MAPK inhibitor. These results demonstrate that incadronate and YM529 suppress the proliferation of myeloma cells through mevalonate pathway and MAPK pathway.
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PMID:Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway. 1274 32

Cultured primary human keratinocytes were the first non-cancer-derived cell type reported to produce the humoral hypercalcemia factor, parathyroid hormone-related protein (PTHrP). Emerging evidence suggests that only a subset of keratinocytes produce high levels of PTHrP in vivo. We found that the PTHrP mRNA content of intact human skin was minimal, whereas transcripts were easily detectable in primary keratinocytes derived from those skin samples. We hypothesized that conditions associated with growth in culture activated PTHrP gene expression in primary keratinocytes. In culture, keratinocytes produce a number of epidermal growth factor (EGF)-like ligands (transforming growth factor-alpha, heparin binding-EGF and amphiregulin) and their receptor, ErbB1. Treatment of keratinocytes with a specific erbB1 inhibitor (PD153035) reduced PTHrP mRNA levels by >80% in rapidly growing keratinocytes. Treatment of keratinocytes with reagents that neutralize amphiregulin reduced PTHrP mRNA levels by approximately 60%. Blockade of erbB1 signaling reduces transcription from the endogenous PTHrP P3-TATA promoter. The Ets transcription factor-binding site, 40 bases upstream of the P3 promoter, is required for baseline expression of PTHrP reporter gene constructs in keratinocytes; in addition, cotransfection of Ets-1 and Ets-2 expression vectors activate the reporter gene constructs. Finally, disruption of both ras and raf signaling reduce reporter gene expression by 80%, suggesting that ErbB1 signaling is mediated by the classic ras/MAP kinase pathway. These findings suggest that acquisition of EGF-like ligand expression has the potential to substantially activate PTHrP gene expression in the epidermis.
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PMID:Regulation of parathyroid hormone-related protein gene expression by epidermal growth factor-family ligands in primary human keratinocytes. 1507 78

MAPK (mitogen-activated protein kinase) pathways constitute major regulators of cellular transcriptional programmes. We analysed the ERK1,2 (extracellular-signal-regulated kinase 1,2) transcriptome in a non-transformed MEC (mammary epithelial cell) line, MCF-12A, utilizing rAd MEK1EE, a recombinant adenovirus encoding constitutively active MEK1 (MAPK/ERK kinase 1). rAd MEK1EE infection induced morphological changes and DNA synthesis which were inhibited by the MEK1,2 inhibitor PD184352. Hierarchical clustering of data derived from seven time points over 24 h identified 430 and 305 co-ordinately up-regulated and down-regulated genes respectively. c-Myc binding sites were identified in the promoters of most of these up-regulated genes. A total of 46 candidate effectors of the Raf/MEK/ERK1,2 pathway in MECs were identified by comparing our dataset with previously reported Raf-1-regulated genes. These analyses led to the identification of a suite of growth factors co-ordinately induced by MEK1EE, including multiple ErbB ligands, vascular endothelial growth factor and PHRP (parathyroid hormone-related protein). PHRP is the primary mediator of humoral hypercalcaemia of malignancy, and has been implicated in metastasis to bone. We demonstrate that PHRP is secreted by MEK1EE-expressing cells. This secretion is inhibited by PD184352, but not by ErbB inhibitors. Our results suggest that, in addition to anti-proliferative properties, MEK1,2 inhibitors may be anti-angiogenic and possess therapeutic utility in the treatment of PHRP-positive tumours.
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PMID:Analysis of the ERK1,2 transcriptome in mammary epithelial cells. 1510 7

Familial benign hypocalciuric hypercalcemia (FBHH), in which calcium homeostasis is disordered, can be distinguished from mild primary hyperparathyroidism by the finding of a heterozygous loss-of-function mutation in the calcium-sensing receptor (CaSR). Here, we report a Polish kindred with FBHH, the proband of which had undergone an unsuccessful parathyroidectomy. Direct sequence analysis of exon 4 of her CASR gene identified a heterozygous R227Q mutation in the extracellular domain of the receptor. This mutation segregated with other affected family members. A de novo heterozygous R227L mutation had previously been identified in a case of neonatal hyperparathyroidism. We performed a functional analysis by transiently transfecting wild-type and mutant (R227Q, R227L) CaSRs in human embryonic kidney (HEK293) cells. Both mutant receptors were expressed at a similar level to that of the wild-type, demonstrated a 160-kDa molecular species consistent with having undergone full maturation, and were visualized on the cell surface. Although both mutants were impaired in their MAPK responses to increasing extracellular calcium concentrations relative to wild type, this was more marked for R227L (EC(50) = 9.7 mM) than R227Q (EC(50) = 7.9 mM) relative to wild type (EC(50) = 3.7 mM). When cotransfected with wild-type CaSR to mimic the heterozygous state, the curves for both R227Q and R227L were right shifted intermediate to the curves for wild type and the respective mutant. This differential responsiveness may account, in part, for the markedly different clinical presentation of the R227Q mutation, classic FBHH, vs. the neonatal hyperparathyroidism of the R227L mutation.
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PMID:Functional characterization of calcium-sensing receptor codon 227 mutations presenting as either familial (benign) hypocalciuric hypercalcemia or neonatal hyperparathyroidism. 1557 18

Vitamin D derivatives have demonstrated anti-cancer activity, but their clinical use is precluded by hypercalcemia. Previously, we found that carnosic acid potentiates differentiation of human leukemia cells induced by low concentrations of 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)). In this study, we investigated if this effect is a general property of antioxidants, and whether there is a common mechanism whereby antioxidants potentiate monocytic differentiation. We found that all antioxidants tested enhanced differentiation-related cell cycle arrest induced by a low (1 nM) concentration of 1,25D(3). Addition of antioxidants to 1,25D(3) activated the JNK pathway as indicated by increased phosphorylation of c-jun and ATF-2, although each compound alone had a minimal effect. Antioxidants also enhanced the 1,25D(3)-induced AP-1 DNA binding and transactivation ability. Expression of Egr-1 and c-fos was increased by combinations of antioxidants and 1,25D(3), in parallel with the activation of the JNK pathway. The potentiation of differentiation by antioxidants was inhibited by JNK inhibitor SP600125 and a dominant negative JNK 1/2 construct, and Egr-1 and c-fos expression was proportionally decreased, suggesting that JNK pathway regulates these transcription factors. While potentiating the prodifferentiation effect of 1,25D(3), antioxidants did not promote the elevation of basal levels of intracellular calcium by 1,25D(3). The results indicate that JNK-AP1 pathway has an important role in the potentiation of 1,25D(3)-induced differentiation by antioxidants, and regulates expression of Egr-1 and c-fos. Combinations of antioxidants with 1,25D(3) should be further evaluated for use in cancer chemoprevention and therapy.
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PMID:Cooperation between antioxidants and 1,25-dihydroxyvitamin D3 in induction of leukemia HL60 cell differentiation through the JNK/AP-1/Egr-1 pathway. 1579 27


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