Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypercalcemic Walker carcinosarcoma 256 of the rat is an animal model for humoral hypercalcemia of malignancy. Previous in vivo studies suggested the production of a parathyroid hormone-related protein (PTHrP) by the Walker tumor. Therefore, we have measured immunoreactive PTHrP in serum-free conditioned medium from cells derived from this tumor using an antibody raised against human PTHrP(1-34). Walker tumor cell conditioned medium (WCM) displaced 125I-hPTHrP(1-34) from the antibody in a dose dependent manner, whereas control medium contained no immunoreactive PTHrP. In contrast, we detected no secretion of immunoreactive rat parathyroid hormone (rat PTH) by the Walker tumor cells using a midregional radioimmunoassay for rat PTH. WCM stimulated adenylate cyclase in osteoblast like cells, the dose-response curve paralleling that of hPTHrP(1-34). This effect could be inhibited by the PTH antagonist (8Nle, 18Nle, 34Tyr)bPTH(3-34) and by the addition of anti-hPTHrP(1-34) antibody. Bone resorbing activity of WCM in organ culture (calvaria of fetal rats) was not inhibited by indomethacin and glucocorticoids, suggesting a prostaglandin independent mechanism of osteoclast activation in this model.
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PMID:Osteolytic activity of Walker carcinosarcoma 256 is due to parathyroid hormone-related protein (PTHrP). 164 50

One of the strains of the Walker 256 carcinosarcoma induces in the rat a humoral hypercalcaemia of malignancy (HHM) syndrome which is similar to that reported in human patients. We have isolated from this tumour a chromatographic fraction which displays an adenylate cyclase stimulating activity in dog kidney cortical membranes, similar to that of a parathormone (PTH) related protein isolated from various HHM related tumours. In addition, this fraction stimulated initial calcium (Ca) uptake in confluent Madin-Darby canine kidney (MDCK) cell monolayers in a dose-dependent manner. Maximal stimulation of Ca uptake was associated with an enhanced Ca efflux from MDCK cells preloaded with the cation, and with an increased DNA synthesis in these cells. These activities might be involved in development of increased tubular calcium reabsorption in Walker 256 tumour-bearing rats.
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PMID:Co-purification of calcium transport-stimulating and DNA synthesis-stimulating agents with parathormone-like activity isolated from the hypercalcaemic strain of the Walker 256 tumour. 183 87

Neoplasms of the parathyroid glands are uncommon in all species of laboratory and domestic animals, but occur in low incidence in rats, Syrian hamsters, and dogs and rarely in mice. Proliferative lesions of the parathyroid gland include hyperplasia (diffuse and focal), adenomas, and carcinomas. The tumors may be functional or nonfunctional. Trophic atrophy of remaining parathyroid tissue is present around functional tumors. Humoral hypercalcemia of malignancy (HHM) is a syndrome that occurs in human and animal patients with certain malignant neoplasms and is characterized by hypercalcemia, hypophosphatemia, and increased osteoclastic bone resorption. The syndrome is thought to be due to the release of parathyroid hormone (PTH)-like factors by the tumor cells which bind to PTH receptors in bone and kidney and result in the clinical manifestations of HHM. Parathyroid hormone-related protein (PTHrP) is a newly purified and sequenced protein which originated from human tumors associated with HHM. PTHrP has been shown to stimulate in vitro and in vivo effects similar to PTH-like proteins isolated from tumors associated with HHM. Well characterized animal models of HHM include a rat Leydig cell tumor line (Rice-500), the rat Walker mammary carcinosarcoma, and the canine apocrine adenocarcinoma. All 3 models have been found to contain 3 biologic activities which are thought to be important in the pathogenesis of HHM, viz., in vitro bone resorbing activity, adenylate cyclase-stimulating activity of bone and kidney cells, and transforming growth factor activity. The first 2 activities are due to PTH-like proteins which are able to compete for binding to the PTH receptor. The complete spectrum of functional disturbances in patients with HHM may be the result of the combined effects of a PTH-like protein (i.e., PTHrP) and transforming growth factors.
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PMID:Tumors of the parathyroid gland and circulating parathyroid hormone-related protein associated with persistent hypercalcemia. 267 85

The culture media of three cell lines, a human prostate carcinoma (PC3), a rat Leydig cell tumor (Rice-500), and a rat carcinosarcoma (WRC-256), that were derived from tumors associated with humoral hypercalcemia of malignancy (HHM), were examined for stimulation of adenylate cyclase in ROS 17/2.8 osteoblastic cells and for bone resorptive activity in culture. Cells from a nonhypercalcemic variant of the WRC256 tumor served as control. Extracts from three solid human tumors, a lung adenocarcinoma from a patient with HHM and two adenocarcinoma from normocalcemic patients (lung and colon), were also examined for adenylate cyclase stimulation. We found excellent correlation between stimulation of cyclic AMP accumulation in ROS 17/2.8 cells and bone resorbing activity in culture, or production of HHM in vivo. Stimulation of adenylate cyclase by HHM factors was inhibited by the parathyroid hormone competitive inhibitor, [8norleucyl, 18norleucyl, 34tyrosinyl] bovine parathyroid hormone (3-34) amide.
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PMID:Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells. 668 37

We have investigated the regulatory role of PGI2 and its stable analogs, i.e., iloprost and cicaprost, on 12(S)-HETE- and TPA-enhanced tumor cell integrin expression and adhesion. Walker 256 carcinosarcoma cells express alpha IIb beta 3 integrin receptors, which mediate their adhesion to endothelium, subendothelial matrix and fibronectin. Adhesion is enhanced by treatment with exogenous 12(S)-HETE but not 12(R)-HETE or other lipoxygenase-derived hydroxy fatty acids, as well as by TPA. Both 12(S)-HETE and TPA enhanced alpha IIb beta 3 expression on W256 cells. PGI2 iloprost and cicaprost inhibited both 12(S)-HETE- and TPA-enhanced adhesion to endothelium and subendothelial matrix as well as alpha IIb beta 3 expression on W256 cells. The mechanism responsible for the effect of PGI2 was explored. Prostacyclin treatment of W256 cells resulted in an enhanced production of cAMP in a time- and dose-dependent manner. Pre-treatment of tumor cells with increasing concentrations of adenosine resulted in a dose-dependent decrease in the PGI2 effect on TPA or 12(S)-HETE-enhanced adhesion, suggesting that the PGI2 effect is mediated through PKA. Dibutyryl cAMP also blocked the 12(S)-HETE- or TPA-enhanced adhesion, and adenosine pre-treatment did not result in an inhibition of the dibutyryl cAMP effect. Collectively, our results suggest that the cyclooxygenase metabolite PGI2 can antagonize the lipoxygenase metabolite 12(S)-HETE- and TPA-enhanced alpha IIb beta 3 expression and tumor cell adhesion via activation of adenylate cyclase and elevation of intracellular levels of cAMP.
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PMID:Inhibition of TPA and 12(S)-HETE-stimulated tumor cell adhesion by prostacyclin and its stable analogs: rationale for their antimetastatic effects. 753 Feb 35