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)

Hypercalcemia is one of well-recognized paraneoplastic syndromes and occurs occasionally in patients with oral cancers. Because bone is the richest source of calcium in the body, it has been proposed that humoral bone resorbing factors which are released by tumors are responsible for the pathogenesis of hypercalcemia. In the present study, partial purification and identification of bone resorbing humoral factors were carried out employing VX2 squamous cell carcinoma which has been known to induce hypercalcemia in rabbits. In addition, extra- and intra-cellular mechanisms which are operating to confer autonomous growth on VX2 cancer cells were also studied. VX2 carcinoma induced marked hypercalcemia not only in rabbits but also in nude mice in parallel with tumor enlargement. Administration of indomethacin (INDO), a prostaglandin (PG) synthesis inhibitor, before onset of the hypercalcemia prevented an elevation of serum calcium levels and growth of the tumor. INDO, however, failed to decrease serum calcium levels and tumor growth when administered after development of the hypercalcemia and tumor enlargement. These results indicate that not only PGs but other humoral factors are involved in the pathogenesis of the hypercalcemia seen in VX2 cancer-bearing animals. VX2 cancer cells in culture retained their cancerous phenotypic properties, synthesized PGE2, PGF2 alpha and 6-keto PGF1 alpha and secreted highly levels of PGE2, a powerful bone resorber, into the culture medium in a time- and cell density-dependent manner. The culture supernatants also contained a trypsin- and heat-sensitive bone risorbing factor (BRF) with a molecular weight of approximately 20kD. BRF was presumed to be similar to parathyroid hormone related protein (PTHrP) from its biological and biochemical behaviors. Both PGE2 and PTHrP promoted VX2 cell growth, thus suggesting that these two substances are autocrine growth factors for VX2 cells. Calcium stimulated VX2 cell growth and secretion of PGE2 and BRF (PTHrP) in a concentration-dependent fashion. Stimulation of VX2 cell proliferation by PGE2 and PTHrP was closely correlated with a transient elevation of intracellular free calcium ion ([Ca2+]i). [Ca2+]i elevated transiently in response to PGE2 and PTHrP was shown to be supplied by influx of extracellular free calcium ion ([Ca2+]e) through calcium channel present in plasma membrane. Involvement of protein kinase C in autocrine growth stimulation of VX2 cells by PGE2 and PTHrP was unclear. These results demonstrate that PGE2 and PTHrP secreted by VX2 cancer cells not only induce hypercalcemia but promote VX2 cell growth as autocrine growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Mechanism of hypercalcemia associated with malignancy: interactions between induction of hypercalcemia and autonomous growth in VX2 cancer cells]. 263 47

Parathyroid hormone-related protein (PTHrP) was discovered as a hypercalcemia-inducing product of malignant cells and has since been demonstrated to be a product of many tissues. Although it is robustly expressed in fetal lung, PTHrP expression has not been assigned to alveolar epithelial cells in adult lung. We have shown that PTHrP is expressed in the adult rat lung and by cultured rat alveolar type II epithelial cells with sensitive and specific immunoassays and immunohistochemical techniques. Immunoassay of cell extracts demonstrated that freshly isolated type II cells contained PTHrP (136 pg/10(7) cells), whereas freshly isolated alveolar macrophages and cultured macrophages did not express PTHrP. Cultured type II cells secreted PTHrP into medium, 202 +/- 11 fg PTHrP/micrograms cell protein in 24 h. Basal secretion remained stable up to 7 days in culture. Treatment with phorbol myristate acetate or 1-oleoyl-2-acetyl-sn-glycerol produced a dose-related, 2- to 4-fold increase in PTHrP secretion. However, forskolin, ionomycin, ATP, phenylephrine, capsaicin, and bradykinin had no effect. Thus, PTHrP secretion appeared to be regulated by a protein kinase C-dependent pathway. PTHrP could also be demonstrated in pulmonary lavage fluid. Although the function of PTHrP in the adult lung is unknown, it could involve control of cell growth and differentiation or control of surfactant lipid secretion. Further studies are necessary to elucidate the function of PTHrP in the lung.
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PMID:Alveolar epithelial cells express and secrete parathyroid hormone-related protein. 794 99

Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.
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PMID:Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression. 796 63

Parathyroid hormone-related protein (PTHrP), a tumor product responsible for malignancy-associated hypercalcemia, is also produced in many normal tissues, including vascular smooth muscle cells (SMC). As PTHrP exhibits vasodilatory properties, we postulated that other vasoactive agents may control PTHrP gene expression in SMC. Addition of angiotensin II to serum-deprived SMC resulted in a marked induction of PTHrP mRNA by 2 h, with a peak (6-10-fold) at 4-6 h. Angiotensin II effects on PTHrP gene expression were inhibited by saralasin, an angiotensin II receptor antagonist, and blocked by actinomycin D and cycloheximide, suggesting a requirement for gene transcription and protein synthesis. Nuclear run-off assays revealed a 3-fold increase in PTHrP gene transcription 1 h after angiotensin II treatment. Angiotensin II also prolonged PTHrP mRNA half-life by 2-3-fold. Angiotensin-induced PTHrP mRNA is partially dependent on cyclooxygenase products and protein kinase C activation. Other vasoconstrictor substances, including serotonin and bradykinin, also stimulated PTHrP expression, whereas the vasodilator atrial natriuretic peptide did not. Addition of recombinant PTHrP-(1-141) significantly inhibited angiotensin II-induced SMC DNA synthesis. PTHrP expression is increased by angiotensin II through transcriptional and post-transcriptional mechanisms. In addition, PTHrP modulates the effect of angiotensin II on SMC proliferation. This suggests that PTHrP acts locally in SMC, possibly to oppose the vasoactive and/or growth-promoting effects of vasoconstrictor agents such as angiotensin II.
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PMID:Angiotensin II regulates parathyroid hormone-related protein expression in cultured rat aortic smooth muscle cells through transcriptional and post-transcriptional mechanisms. 842 Sep 73

The discovery of PTHrP was the result of research on the mechanisms by which some cancers cause hypercalcemia (humoral hypercalcemia of malignancy) without necessarily metastasizing to bone. PTHrP is also present in various normal adult and fetal tissues. Its concentration is normally very low (picomolar) in blood, but it is more abundant in milk (nanomolar concentration). PTHrP seems able to exert autocrine/paracrine as well as endocrine effects on bone metabolism. A major role for PTHrP in regulation of fetal bone metabolism has been demonstrated in mice. Homologous recombination has been used in these rodents to remove the major coding exon from one copy of the mouse PTHrP gene in embryonic stem cells. Subsequently generated chimeric mice transmit the mutant PTHrP allele through the germline. Homozygous mutants died immediately after birth and had a multitude of skeletal abnormalities. So PTHrP seems necessary to embryonic development of the skeleton. PTHrP (1-34), like PTH (1-34) fragments, might be responsible for both bone resorption and formation. Although the effects of the carboxyl-terminal fragments are still controversial, PTHrP (107-111) fragment seems able to inhibit osteoclast activity. PTHrP (1-34), whose 8 of the first 13 amino-acids are identical with those in PTH (1-34), acts through the same receptor as PTH on osteoblasts and renal cells membrane. The PTHrP/PTH receptor sequence is now well established. PTHrP-receptor coupling is mediated by cyclic AMP and/or inositols-phosphate. The consequent activation of protein kinase A and intracellular calcium or protein kinase C, respectively, locally induces growth factors or cytokines secretion, responsible for the observed effects. The role of PTHrP appears important during pregnancy and lactation, when it stimulates fetal bone growth by increasing calcium transport from the dam to its fetus and maternal bone resorption allowing calcium supply for milk production, respectively. Such a role would be particularly important in domestic ruminants, which are often simultaneously pregnant and lactating. The role of PTHrP during aging (especially in post-menopausal women in which bone loss may induce osteoporosis) remains unknown and might be of peculiar interest since PTHrP (1-34) and (107-111) are able to restore bone loss induced by ovariectomy in rats.
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PMID:[Parathyroid hormone related peptide (PTHrP) and bone metabolism]. 857 73

Ascites sarcoma 180 (S180A) is a transplantable tumor that induces hypercalcemia in tumor-bearing mice and stimulates bone resorption in cultured neonatal mouse calvaria without parathyroid hormone (PTH)-like activity. The serum-free conditioned media of S180A cell cultures (S180A-CM) stimulated [3H]thymidine incorporation (178.3% of the control) and inhibited alkaline phosphatase activity (39.0% of the control) in the osteoblastic osteosarcoma cell line UMR 106-01, contrary to PTH. To investigate signal transduction by S180A-CM, we determined the levels of intracellular free calcium ([Ca2+]i), inositol 1,4,5-triphosphate (IP3), 1,2-diacylglycerol (DAG), phosphatidylcholine (PC) and protein kinase (PK) C activity in UMR 106-01 cells. PTH and PTH-related protein (PTHrP), both potent bone-resorbing factors (BRFs), caused an increase in [Ca2+]i and stimulated IP3 production, whereas S180A-CM had little or no effect on these parameters. On the other hand, S180A-CM stimulated DAG production, accompanied by PC breakdown, and the translocation of PKC activity from the cytosol to the membrane fraction. Sphingosine, a specific PKC inhibitor, inhibited bone-resorbing activity (BRA) in S180A-CM more effectively than PTH or PTHrP-stimulated resorption. H-7, an inhibitor of both cAMP-dependent PKA and PKC, completely inhibited BRA in S180A-CM. These results suggest that BRFs of S180A-CM stimulate osteoblastic cell proliferation and bone resorption via two signal transduction pathways, which are different from those of PTH: 1) activation of PKC by DAG resulting from PC hydrolysis and 2) activation of PKA subsequent to prostaglandin E2 production by bone.
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PMID:Humoral factors of ascites sarcoma 180 stimulate osteoblastic UMR 106-01 cell proliferation and bone resorption via signal transduction pathways, which are clearly different from those of parathyroid hormone. 891 16

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

Vitamin D, a steroid hormone and exerts its biological effects through its active metabolite 1alpha, 25 dihydroxyvitamin D3 [1,25(OH)2D3]. Like steroid hormones, 1,25(OH)2D3 is efficacious at very low concentrations and serves as a ligand for vitamin D receptors (VDR), associating with VDR very high affinity. Despite its potent property as a differentiating agent, its use in the clinical practice is hampered by the induction of hypercalcemia at a concentration required to suppress cancer cell proliferation. Therefore nearly 400 structural analogs of vitamin D3 have been synthesized and evaluated for their efficacy and toxicity. Among these analogs, relatively less toxic but highly efficacious analogs, EB1089, RO24-5531, 1alpha-hydroxyvitamin D5 and a few others have been evaluated in a preclinical toxicity and in Phase I clinical trials for dose tolerance in advanced cancer patients. Clinical trials using vitamin D analogs for prevention or therapy of cancer patients are still in their infancy. Vitamin D mediates its action by two independent pathways. Genomic pathway involves nuclear VDR and induces biological effects by interactions with hormone response elements and modulation of differential gene expressions. Evidence also suggests that vitamin D analogs also interact with steroid hormone(s) inducible genes. The non-genomic pathway is characterized by rapid actions of vitamin D. It involves interactions with membrane-VDR interactions and its interactions with protein kinase C and by altering intracellular calcium channels. Thus, the development of nontoxic analogs of vitamin D analogs and understanding of their molecular mechanism(s) of action are of significant importance in the prevention and treatment of cancer by vitamin D.
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PMID:Vitamin D and cancer. 1201 55

Since Calcitonin (CT) inhibits osteoclastic bone resorption, it has been widely used to treat metabolic bone disorders, such as Paget's disease of bone, malignancy-associated hypercalcemia, and osteoporosis. It is recognized, however, that continuous treatment with CT causes a loss of its inhibitory effects on bone resorption. We and other investigators have studied the mechanism and the results indicated that desensitization to CT was closely associated with the down regulation of the CT receptor (CTR). This down regulation was due not only to internalization of the receptor but also to reduced cell surface receptor concentration through inhibition of de novo CTR synthesis. An essential signal for osteoclast differentiation from its precursor cells, which was termed as ODF, was also found identical to tumor necrosis factor (TNF) related activation induced cytokine (TRANCE) and receptor activator of nuclear factor-kappa B ligand (RANKL). Using soluble RANKL and macrophage colony stimulating factor, we recently studied the mechanisms of the biological responses to CT in cells of human osteoclast lineage. The signaling pathway responsible for CTR down regulation in human osteoclasts is different from that observed in mouse osteoclasts: the activation of protein kinase A pathway is primarily responsible for CTR regulation in mouse osteoclasts, while the activation of protein kinase C was predominant in humans. Treatment with CT reduced concentration of cellular surface CTR and CTR mRNA expression also in human osteoclasts. The reduced specific binding, CTR mRNA levels and CT-sensitive adenylate cyclase responsiveness returned to the control levels by 96h after removal of CT. These results may suggest that intermittent administration of CT would be effective for the treatment of osteoporosis, resulting in reduced desensitization in CT target cells.
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PMID:[Appropriate clinical usage of calcitonin escape phenomenon and intermittent v.s. daily administration of calcitonin]. 1577 28

Calcium sensing receptor (CaSR) mutations implicated in familial hypocalciuric hypercalcemia, pancreatitis and idiopathic epilepsy syndrome map to an extended arginine-rich region in the proximal carboxyl terminus. Arginine-rich motifs mediate endoplasmic reticulum retention and/or retrieval of multisubunit proteins so we asked whether these mutations, R886P, R896H or R898Q, altered CaSR targeting to the plasma membrane. Targeting was enhanced by all three mutations, and Ca(2+)-stimulated ERK1/2 phosphorylation was increased for R896H and R898Q. To define the role of the extended arginine-rich region in CaSR trafficking, we independently determined the contributions of R890/R891 and/or R896/K897/R898 motifs by mutation to alanine. Disruption of the motif(s) significantly increased surface expression and function relative to wt CaSR. The arginine-rich region is flanked by phosphorylation sites at S892 (protein kinase C) and S899 (protein kinase A). The phosphorylation state of S899 regulated recognition of the arginine-rich region; S899D showed increased surface localization. CaSR assembles in the endoplasmic reticulum as a covalent disulfide-linked dimer and we determined whether retention requires the presence of arginine-rich regions in both subunits. A single arginine-rich region within the dimer was sufficient to confer intracellular retention comparable to wt CaSR. We have identified an extended arginine-rich region in the proximal carboxyl terminus of CaSR (residues R890 - R898) which fosters intracellular retention of CaSR and is regulated by phosphorylation. Mutation(s) identified in chronic pancreatitis and idiopathic epilepsy syndrome therefore increase plasma membrane targeting of CaSR, likely contributing to the altered Ca(2+) signaling characteristic of these diseases.
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PMID:Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. 2079 21


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