UMLS:C0029463 - FACTA Search

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Query: UMLS:C0029463 (osteosarcoma)
16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel PTH-like peptide has recently been purified and cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. We surveyed the expression of mRNAs encoding this peptide in normal tissues by Northern analysis. One or more low abundance hybridizing transcripts was identified in poly(A)+ RNA prepared from human keratinocytes, thyroid, bone marrow, and fibroblasts, from bovine hypothalamus, pituitary, parathyroid, adrenal cortex, and adrenal medulla, and from rat brain, stomach mucosa, and fetal but not adult liver. One or more hybridizing transcripts was also identified in poly(A)+ RNA prepared from a number of established lines, including rat pituitary (GH4), rat pheochromocytoma (PC 12), human osteosarcoma (TE-85), and human medullary carcinoma (TT) cells. Northern analysis of mRNAs from abnormal human parathyroid tissue revealed an overexpression of transcripts for the PTH-like peptide which appeared to be specific for adenomatous or autonomous glands. These findings suggest that the PTH-like peptide is expressed in a number of endocrine and nonendocrine tissues, that it is developmentally expressed in at least one tissue (fetal liver), and that the regulation of its expression is abnormal in human parathyroid adenomas.
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PMID:Expression of messenger ribonucleic acids encoding a parathyroid hormone-like peptide in normal human and animal tissues with abnormal expression in human parathyroid adenomas. 321 62

A number of factors have been proposed as potential mediators of the syndrome of humoral hypercalcemia of malignancy (HHM), but to date no firm cause-and-effect relationship has been established. We attempted to establish such a relationship by determining whether the presence or absence of adenylate cyclase-stimulating activity (ACSA) in the media of cultured tumor cells predicted the occurrence of the syndrome of HHM when these cell lines were grown in nude mice in vivo. Conditioned media from 35 human renal carcinoma cell lines were surveyed for ACSA in the PTH-sensitive rat osteosarcoma 17/2.8 cell assay. 12 lines were positive (mean, 13.7-fold stimulation, range, 3.0 to 44.0), and 23 lines were negative (mean, 1.2-fold stimulation, range, 0.9 to 1.5). We were successful in establishing five of the positive and six of the negative lines in three to five nude mice per line. Mice implanted with the positive lines uniformly became hypercalcemic (mean serum calcium, 15.8 mg/dl), whereas mice implanted with the negative lines uniformly remained normocalcemic (mean serum calcium, 9.5 mg/dl), in spite of comparable mean tumor size. Acid-urea tumor extracts from each of four hypercalcemic animals contained potent in vitro ACSA (mean, 15.9-fold stimulation), while 5/5 extracts from normocalcemic animals did not (mean, 1.4-fold stimulation). Our study demonstrates that in this model system in vitro ACSA is a reliable predictive marker for HHM in vivo. Whether the protein responsible for this activity is also the mediator of the bone resorption seen in HHM remains to be demonstrated.
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PMID:In vitro adenylate cyclase-stimulating activity predicts the occurrence of humoral hypercalcemia of malignancy in nude mice. 334 41

Parathyroid hormone (PTH)-like bioactivity, assayed as adenylate cyclase response in UMR 106-01 osteogenic sarcoma cells, was present in extracts of sheep fetal and maternal parathyroid glands and placenta. Preincubation of extracts with PTH(1-34) antiserum inhibited approximately 40% of the bioactivity in fetal parathyroid extracts, 50% in maternal parathyroid extracts, but only 10% of the bioactivity in the placental extract. Partial purification of placental extracts by chromatography yielded fractions containing PTH-like bioactivity which were similar in behaviour to that of PTH-related protein (PTHrP) from a human lung cancer cell line (BEN). An antiserum against synthetic PTHrP(1-16) partially inhibited the bioactivity of the placental extract and synthetic PTHrP(1-34), but had no effect on the bioactivity of bovine PTH(1-34) or bovine PTH(1-84). The placental PTH-like bioactivity was higher in mid- than in late gestation. Fetal parathyroid glands contained the highest PTH-like bioactivity. Thyroparathyroidectomy of one fetal twin lamb in each of 16 ewes between 110 and 125 days of gestation resulted in decreases of the plasma calcium concentration and reversal of the placental calcium gradient that existed between the ewe and the intact fetus. Perfusion of the placenta of each twin in anaesthetized ewes was carried out sequentially with autologous fetal blood in the absence of the exsanguinated fetus. The plasma calcium concentration in the blood perfusing the placenta of each twin increased, but reached a plateau at a lower concentration in the perfusing blood of thyroparathyroidectomized fetuses than in that of the intact fetuses. Addition of extracts of fetal parathyroid glands or of partially purified PTHrP resulted in further increases in plasma calcium in the autologous blood perfusing the placentae of thyroparathyroidectomized fetuses, but addition of bovine PTH(1-84) or rat PTH(1-34) had no effect. The presence of this PTH-like protein in the fetal parathyroid gland and placenta may contribute to the relative hypercalcaemia of the fetal lamb. This protein, which is similar to PTHrP associated with humoral hypercalcaemia of malignancy, stimulates the placental calcium pump responsible for maintaining a relative fetal hypercalcaemia during gestation.
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PMID:Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy. 337 58

Three bioassays are widely employed for the measurement of PTH-like adenylate cyclase-stimulating factors (ACSFs) derived from tumors associated with humoral hypercalcemia of malignancy. These include renal cortical adenylate cyclase (RAC) assays, rat osteosarcoma (ROS) adenylate cyclase assays, and fetal bone resorption (FBR) assays. A previous study has suggested that the potency of one human tumor-derived ACSF, expressed in PTH equivalents, was 30-fold higher in the ROS assay than in the RAC assay, but no study has directly compared all three bioassays using a single PTH standard and a single ACSF preparation. We compared one partially purified ACSF preparation to a single lot of bPTH 1-34 in all three bioassays. The results indicate that the relative potency of this ACSF as compared to the PTH standard varied with the assay employed, with the ROS assay yielding a specific activity estimate 47.5-fold higher than the RAC, and the FBR 6.7-fold higher than the RAC but 7.1-fold lower than the ROS. These findings support the possibility that distinct subpopulations of PTH receptors exist on different PTH target tissues. Further, they underscore the importance of bioassay choice when estimating the specific activity of tumor-derived ACSF preparations.
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PMID:The relative potency of a human tumor-derived PTH-like adenylate cyclase-stimulating preparation in three bioassays. 345 55

The tumor line CAC-8, is a serially transplantable adenocarcinoma maintained in nude mice which originated from a hypercalcemic dog. Nude mice with CAC-8 developed a syndrome of humoral hypercalcemia of malignancy. CAC-8 contained a protein factor which stimulated adenylate cyclase of bone and kidney cells in vitro. The adenylate cyclase (AC) of rat osteosarcoma cell lines, ROS 17/2.8 (ROS) and UMR-106, was stimulated by the tumor extract and potentiated by forskolin (0.1 microM). The ROS cells responded to the lowest concentration of CAC-8 extract, but UMR cells responded with a greater increase in AC activity compared to controls following exposure to CAC-8 extract. Pretreatment of ROS 17/2.8 cells with dexamethasone enhanced the response to CAC-8 extract. The opossum kidney cell line (OK) was less sensitive to the AC-stimulating activity of CAC-8 extract, but AC stimulation was increased in the presence of forskolin. Bovine (1-34) parathyroid hormone (BPTH) (10 nM) stimulated AC equally in ROS, UMR, and OK cells. Isoproterenol (1.0 microM) stimulated AC activity in ROS and UMR cells but not in OK cells. The AC-stimulating activity of CAC-8 appeared to bind to the parathyroid hormone receptor of ROS, UMR, and OK cells since addition of the parathyroid hormone receptor antagonist, [8,18norleucine, 34tyrosine]BPTH (3-34) amide, inhibited CAC-8-mediated cyclic adenosine 5'-monophosphate production and alone did not stimulate AC activity. The AC-stimulating activity of CAC-8 was acid and heat stable. Trypsin digestion reduced BPTH and CAC-8 stimulation of AC to near basal levels and treatment of CAC-8 extract with dithiothreitol reduced AC stimulation in UMR cells by approximately 50%. Extracts of the hypercalcemic tumor line (CAC-8) contained bone and kidney AC-stimulating activity which was enhanced by forskolin and dexamethasone, inhibited by [8,18Nle, 34Tyr]BPTH (3-34) amide, heat stable, trypsin sensitive, inactivated by reduction, and had a relative molecular weight of 34,000 by gel exclusion chromatography. Isolation and characterization of the factor(s) produced by CAC-8 that stimulate AC activity will be useful in further understanding the pathogenesis of humoral hypercalemia of malignancy in animal and human patients.
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PMID:Bone and kidney adenylate cyclase-stimulating activity produced by a hypercalcemic canine adenocarcinoma line (CAC-8) maintained in nude mice. 346 38

Peptides corresponding to the amino-terminal region of the parathyroid hormone-related protein (PTHrP) of humoral hypercalcemia of malignancy were synthesized. A 34-amino acid peptide, PTHrP(1-34), was two to four times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of adenosine 3',5'-monophosphate (cAMP) and plasminogen activator activity in osteogenic sarcoma cells and adenylate cyclase activity in chick kidney membranes. Like parathyroid hormone itself, in which the activity resides in the first 34 residues, PTHrP peptides of less than 30 residues from the amino terminus showed substantially reduced activity. PTHrP(1-34) had only 6% of the potency of bovine PTH(1-34) in promoting bone resorption in vitro. PTHrP(1-34) strongly promoted the excretion of cAMP and phosphorus and reduced the excretion of calcium in the isolated, perfused rat kidney consistent with the symptoms seen in malignant hypercalcemia.
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PMID:Parathyroid hormone-related protein of malignancy: active synthetic fragments. 368 95

Parathyroid hormone (PTH) regulates calcium and phosphate metabolism through a G-protein-coupled receptor which is shared with PTH-related protein (PTHrP). Therefore, structure-activity studies of PTH and PTHrP with their common receptor provide an unusual opportunity to examine the structural elements in the two hormones and their common receptor which are involved in the expression of biological activity. Our approach to studying the nature of the bimolecular interface between hormone and receptor is to use a series of specially designed photoreactive benzophenone- (BP-) containing PTH analogs in "photoaffinity scanning" of the PTH/PTHrP receptor. In this report we describe a series of BP-containing agonists and antagonists which have been synthesized by solid-phase methodology and characterized physiocochemically and biologically. Each of the 12 analogs contains a single BP moiety at a different defined position. Examples of BP-containing agonists prepared and studied in human osteogenic sarcoma Saos-2/B-10 cells are [Nle8,18,Lys13(epsilon-pBZ2),L-2-Nal23,Tyr34]bPTH(1-34 )NH2(K13)(Kb = 13 nM; Km = 2.7 nM) and [Nle8,18,L-Bpa23,Tyr34[bPTH(1-34)NH2(L-Bpa23) (Kb = 42 nM; Km = 8.5 nM). Another BP-containing analog, [Nle8,18,D-2-Nal12,Lys13(epsilon-pBZ2),L-2-Nal23 ,Tyr34]bPTH(7-34)NH2, was a potent antagonist (Kb = 95 nM; Ki = 72 nM). The amino acids substituted by residues carrying the BP moiety span the biologically active domain of the hormone (Phe7, Gly12, Lys13, Trp23, and Lys26). Analysis of photo-cross-linked conjugates of PTH/PTHrP receptor with BP-containing PTH analogs should help to identify the "contact points" between ligand and receptor.
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PMID:Probing the bimolecular interactions of parathyroid hormone with the human parathyroid hormone/parathyroid hormone-related protein receptor. 1. Design, synthesis and characterization of photoreactive benzophenone-containing analogs of parathyroid hormone. 765 10

The regulation of vitamin D receptor (VDR) abundance in MC3T3-E1 mouse osteoblasts and UMR 106-01 rat osteosarcoma cells by rat PTH 1-34, human PTH-related protein 1-34, and agents that activate specific signal transduction pathways was studied. Treatment of these cells with forskolin (FSK) caused up-regulation of VDR, whereas treatment with phorbol esters suppressed VDR levels. PTH or PTH-related protein treatment induced a 2- to 3-fold increase in VDR, which was equivalent to that elicited by FSK in UMR 106-01 cells but less than the FSK-induced increase (approximately 8-fold) in MC3T3-E1 cells. PTH treatment of MC3T3-E1 cells resulted in an approximately 3-fold increase in VDR levels with maximum stimulation occurring at 10(-9) M PTH after 4 h of treatment. In UMR 4-7 cells, a subclone of UMR 106-01 cells that express cAMP resistance due to regulated expression of a mutant form of the type 1 regulatory subunit of the cAMP-dependent protein kinase A (PKA), the up-regulation of VDR abundance due to FSK and PTH treatment was mostly prevented. Pretreatment of MC3T3-E1 cells with staurosporine, an inhibitor of PKC, resulted in an approximately 3-fold increase in basal VDR levels but did not enhance the PTH-mediated up-regulation of VDR. Collectively, these data suggest that the increase in VDR abundance observed in these target cells is mainly due to the activation of the PKA signal transduction pathway. Treatment of UMR 106-01 cells with PTH for 4 h before exposure of the cells to 1,25-dihydroxyvitamin D3 resulted in a 2-fold increase in the induction of 25-hydroxyvitamin D3-24 hydroxylase messenger RNA. Thus, exposure of target cells to PTH augments their response to 1,25-dihydroxyvitamin D3 due to up-regulation of VDR abundance.
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PMID:Regulation of 1,25-dihydroxyvitamin D3 receptors by parathyroid hormone in osteoblastic cells: role of second messenger pathways. 783 3

Calcium and phosphorus metabolism is mainly regulated by PTH through its actions on kidney and bone. PTHrP, which is associated with the hypercalcemia of malignancy syndrome, binds to and activates the same receptor that PTH does. cDNA clones of PTH/PTHrP receptors from rat osteosarcoma (ROS 17/2.8) and opossum kidney (OK) cells are highly homologous and are members of a novel G protein-linked receptor family that includes calcitonin, glucagon, GLP-1, GHRH, VIP, and secretin receptors. Analysis of the protein sequence predicts a receptor with 7 transmembrane domains, a 155 amino acids (aa) extracellular (EC) N-terminal, and 130aa intracellular C-terminal domaina. The extracellular domain has 6 conserved cysteines and 4 potential glycosylation sites. When transfected in COS cells, both receptors are able to bind PTH and PTHrP active fragments with equal affinity. Likewise, agonists activate both adenylate cyclase and phospholipase C efficiently. The N-terminal EC domain and the first EC loop seem to determine the receptor binding capacity with the agonists. Activation of adenylate cyclase and phospholipase C might involve multiple sites between the 3rd helix and the C-terminal tail. Partial characterization of the rat PTH/PTHrP receptor gene demonstrates the existence of at least 15 exons. The first six transmembrane domains are encoded by separated exons. The PTH/PTHrP receptor mRNA is expressed mainly in kidney and bone, and also is widely expressed in many tissues, but not all. A major 2.3-2.5 kb transcript is observed in all these tissues. Nevertheless, 2 larger transcripts are observed in kidney and liver, and multiple smaller mRNA species are observed in kidney, skin, and testis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Mode of action of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) in target organs]. 785 77

The biologic activities of human parathyroid hormone-related protein [hPTHrP(1-34] and bovine PTH [bPTH(1-34)] are remarkably similar despite marked sequence divergence in their primary binding domain, residues 25-34. Chicken PTHrP (cPTHrP) is identical to hPTHrP through residue 21. However, in the 25-34 region, cPTHrP displays three fewer basic residues than hPTHrP and contains five residues not present in any other member of the PTH/PTHrP family. To assess the biologic consequences of these structural differences, we compared the activities of synthetic [36Tyr]cPTHrP(1-36)NH2 and hPTHrP(1-34)NH2 with those of bPTH(1-34) in avian systems (chicken renal plasma membranes and 19 day chick embryonic bone cells) and mammalian systems [canine renal plasma membranes and rat osteosarcoma cells (UMR-106-H5)]. In both avian and mammalian systems the binding affinity of [36Tyr]cPTHrP(1-36)NH2 (0.8-3.4 nM) was approximately one-half that of hPTHrP(1-34)NH2 (0.4-1.1 nM). The potencies of [36Tyr]cPTHrP(1-36)NH2 and hPTHrP(1-34)NH2 for activation of adenylate cyclase were similar in canine renal membranes (5.2 and 6.7 nM) and chick bone cells (1.0 nM). In UMR-106 cells and chicken renal membranes the potency of [36Tyr[cPTHrP(1-36)NH2 for activation of adenylate cyclase was about one-half that of [36Tyr]hPTHrP(1-36)NH2. Binding of 125I-[36Tyr]cPTHrP(1-36)NH2 to chick bone cells and chicken renal membranes was completely displaced by bPTH(1-34) and hPTHrP(1-34)NH2: thus there was no evidence for a distinct chicken PTHrP receptor. In general, [36Tyr]cPTHrP(1-36)NH2 and hPTHrP(1-34)NH2 activated adenylate cyclase similarly despite their sequence differences in the 25-32 region.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional properties of a synthetic chicken parathyroid hormone-related protein 1-36 fragment. 794 50

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