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: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Parathyroid hormone (PTH, less than 10(-8) M) stimulated adenylate cyclase in fibroblasts, but not epithelial cells, isolated from fetal rat lung. In contrast to osteosarcoma cells (UMR 106), the response of fibroblasts to PTH was increased by pretreatment with cortisol (less than 10(-8)-10(-7) M).
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PMID:The adenylate cyclase response to parathyroid hormone in fetal lung fibroblasts is enhanced by cortisol. 348 Jul 62

In human osteosarcoma membranes, gold(III) (Au(III)) inhibits prostaglandin E2- and isoproterenol-mediated stimulation of adenylate cyclase activity without affecting basal enzyme activity. Forskolin activation of adenylate cyclase is also blocked by Au(III) with ID50 of 1-2 microM. The inhibition by Au(III) is preserved in membranes prepared from pertussis toxin-treated cells. The inhibitory effect of Au(III) is additive to inhibition of adenylate cyclase by 2',5'-dideoxyadenosine. These data provide evidence that the action of Au(III) is at or near the catalytic moiety of the cyclase system and that Au(III) does not act via the guanine nucleotide-binding inhibitory component or the adenosine P-site inhibitory pathway.
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PMID:Gold(III) inhibits activated human osteosarcoma adenylate cyclase by an action at or near the catalytic component. 349 71

The effects of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) on parathyroid hormone (PTH)-responsive adenylate cyclase were examined in clonal rat osteosarcoma cells (UMR-106) with the osteoblast phenotype. Recombinant TFG-alpha and EGF incubated with UMR-106 cells for 48 h each produced concentration-dependent inhibition of PTH-responsive adenylate cyclase, with maximal inhibition of 38-44% at 1-3 ng/ml of either growth factor. TGF-alpha and EGF also inhibited beta-adrenergic agonist (isoproterenol)-stimulated adenylate cyclase by 32%, but neither growth factor affected enzyme response to prostaglandin or basal (unstimulated) activity. Nonreceptor-mediated activation of adenylate cyclase by forskolin and cholera toxin was inhibited 18-20% by TGF-alpha and EGF. Pertussis toxin augmented PTH-stimulated adenylate cyclase, suggesting modulation of PTH response by a functional inhibitory guanine nucleotide-binding regulatory component of the enzyme. However, pertussis toxin had no effect on TGF-alpha inhibition of PTH response. Growth factor inhibition of PTH response was time-dependent, with maximal inhibition by 4-12 h of TGF-alpha exposure, and was reduced by prior treatment of UMR-106 cells with cycloheximide. TGF-alpha was not mitogenic for UMR-106 cells. The results indicate that TGF-alpha and EGF selectively impair PTH- and beta-adrenergic agonist-responsive adenylate cyclase of osteoblast-like cells. Growth factor inhibition of adenylate cyclase may be exerted at the receptor for stimulatory agonist and at nonreceptor components excluding pertussis toxin-sensitive guanine nucleotide-binding regulatory proteins. The inhibitory action of growth factors may also require protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of parathyroid hormone-responsive adenylate cyclase in clonal osteoblast-like cells by transforming growth factor alpha and epidermal growth factor. 350 Jan 68

Native bovine parathyroid hormone (bPTH) was found to be readily cleaved with human leukocyte elastase to yield the fragments bPTH(1-41) and bPTH(42-84). These were then isolated by reverse-phase HPLC and characterised by gas-phase sequencing and amino acid analysis. The biological activities of these fragments were assessed in an adenylate cyclase bioassay using the rat osteosarcoma cell line UMR106. bPTH(1-41) was found to have approximately twice the molar potency of the native hormone from which it was derived. bPTH(42-84) had no biological activity and did not modulate the adenylate cyclase response to these cells to the native hormone. The possible physiological significance of these observations is discussed.
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PMID:The biological properties of bovine parathyroid hormone (1-41), a fragment generated from the native hormone by human leukocytes. 365 Jan 10

A variety of solid tumors secrete proteins that are immunochemically distinct from parathyroid hormone (PTH) but activate PTH-responsive adenylate cyclase. Such PTH-like proteins have been proposed as mediators of the hypercalcemia and hypophosphatemia frequently associated with malignancies. We purified to apparent homogeneity a PTH-like protein with a molecular weight of 6,000, that is produced by human renal carcinoma cells. The amino-terminal sequence of the PTH-like protein and that of human PTH were found to display at least five identities in the first 13 positions. The purified protein bound to PTH receptors, activated adenylate cyclase in renal plasma membranes, and stimulated cAMP formation in rat osteosarcoma cells. The PTH-like protein reproduced two additional effects of PTH, stimulation of bone resorption in fetal rat limb bone cultures and inhibition of phosphate uptake in cultured opossum kidney cells. These properties are consistent with a role for PTH-like proteins as mediators of the syndrome of malignancy-associated hypercalcemia.
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PMID:Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. 368 May 30

We compared receptor binding and adenylate cyclase stimulation of intact bovine parathyroid hormone (bPTH)-(1-84) and the synthetic amino-terminal fragments, bPTH-(1-34) and rat PTH (rPTH)-(1-34). Radioligands for binding studies were prepared by the lactoperoxidase technique and purified by high-pressure liquid chromatography. In both canine renal membranes and cloned rat osteosarcoma cells the amino-terminal fragments bound to a single order of sites; the affinity of rPTH-(1-34) exceeded that of bPTH-(1-34), correlating with its higher potency in stimulating adenylate cyclase. In studies with oxidized bPTH-(1--84), the middle and carboxyl regions of intact PTH were found to bind to both tissues but with higher affinity to osteosarcoma cells than to renal membranes. Our results demonstrate that rPTH-(1--34) is the most favorable probe of amino-terminal PTH binding and the most potent of the PTH peptides in stimulating renal and osseous adenylate cyclase. The results also show that midregion and carboxyl determinants within intact PTH contribute to hormone binding, which does not correlate with adenylate cyclase activation and appears more significant for skeletal than for renal binding.
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PMID:Comparison of renal and osseous binding of parathyroid hormone and hormonal fragments. 386 82

We have purified peptides with PTH-like bioactivity from a rat Leydig cell tumor (H-500) and a human squamous cell carcinoma, both associated with a syndrome of humor-induced hypercalcemia. Tumor extracts were shown to be active in an in vitro renal cytochemical bioassay and in an in vitro osteosarcoma cell (UMR 108) adenylate cyclase assay; activity in both assays could be reduced by the PTH antagonist [norleucine-8,18,tyrosine-34]bovine PTH-(3-34)-amide. Partially purified extracts of both tumors and of rat tumor-conditioned culture medium were active in vivo in thyroparathyroidectomized rats in preventing hypocalcemia and increasing fractional phosphorus excretion and cAMP excretion. Ion exchange chromatography demonstrated that active peptides were basic in character. Employing reverse phase HPLC and gel permeation HPLC, active peptides of approximately 9,000 and 9,500 daltons were purified from extracts of the human and rat tumors, respectively, which had similar but not identical compositions. Two additional bioactive peptides were detected in rat tumor extract, and the more active had a mol wt of approximately 28,000. The results demonstrate that peptides that mimic PTH in a variety of in vivo and in vitro bioassays can be extracted from malignancies associated with hypercalcemia, that multiple molecular species may be detected in tumors that demonstrate PTH-like activity, and that at least one of these peptides may be similar in two tumors of highly divergent cell and species origin.
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PMID:Purification of peptides with parathyroid hormone-like bioactivity from human and rat malignancies associated with hypercalcemia. 394 72


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