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)

Using tunicamycin, we have investigated the role of glycoproteins in membrane transport. Tunicamycin is a glucosamine-containing antibiotic that specifically inhibits dolichol pyrophosphate-mediated glycosylation of asparaginyl residues of glycoproteins. Inhibition of protein glycosylation in chick embryo fibroblasts by tunicamycin or other inhibitors of glycosylation resulted in defective transport of glucose, uridine, and amino acid analogs (alpha-aminoisobutyrate and cycloleucine). The defect in glucose transport is accompanied by decreased glucose metabolism, as determined by rates of CO2 and lactate production. In contrast, tunicamycin treatment did not affect other membrane-associated processes, such as secretion of fibronectin and procollagen, uptake of glucose by passive diffusion, Na+/K+ ATPase and adenylate cyclase activities, or stimulation of adenylate cyclase by prostaglandin and cholera toxin. Two glucose/glycosylation-regulated membrane proteins with apparent subunit molecular weights of 95,000 and 75,000 were induced by tunicamycin treatment. Our results indicate that glycoprotein glycosylation is required for membrane transport.
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PMID:Evidence for role of glycoprotein carbohydrates in membrane transport: specific inhibition by tunicamycin. 21 20

The cellular origin of estrogen-induced kidney tumors in male Syrian hamsters has been repeatedly the subject of controversy. Several authors have proposed that the tumors arise from proximal tubules, from a combination of tubular and interstitial stromal cells, or solely from interstitial cells. Because of the model character of this tumor for hormone-associated cancer, it was further investigated in this study with respect to morphology, enzyme and intermediate filament pattern, the expression of alpha-smooth muscle actin and the extracellular matrix proteins fibronectin and tenascin. These analyses were carried out with early and late tumors as well as metastases to determine possible changes in expression of biochemical parameters during the development and progression of this neoplasm. The enzyme histochemical and intermediate filament patterns were usually the same as those described previously for proliferative foci and early tumors, i.e. highly elevated activities of glucose-6-phosphate dehydrogenase, adenylate cyclase and alkaline phosphatase, a lack of glucose-6-phosphatase and gamma-glutamyltransferase and coexpression of vimentin and desmin, alpha-smooth muscle actin could not be detected in early lesions. In five of 24 advanced tumors inclusions of kidney tubules were found which showed various degrees of alteration in their morphology and enzyme histochemical pattern, but were often directly connected with tubular segments of normal appearance outside the tumor. Like the normal tubules, the enclosed tubular segments were strongly positive for cytokeratin but never expressed vimentin or desmin. Among the 24 tumors studied, two contained cysts which expressed cytokeratin and sometimes also vimentin but not desmin. The enzyme histochemistry of the cells lining the cysts was similar to that of the surrounding tumor mass, except adenylate cyclase was lacking and alkaline phosphatase was not uniformly distributed. In tumors containing cytokeratin-positive cysts, there often were cytokeratin-positive, vimentin-negative and desmin-negative tumor formations in close contact to these cysts. With the exception of cyst formation, the pattern of metastases were identical to that of the primary tumors. All large tumors and the main component of the metastases expressed vimentin, desmin and fibronectin. Mesothelia surrounding metastatic tumor complexes were positive for vimentin, desmin, alpha-smooth muscle actin, fibronectin, cytokeratin and tenascin. It was concluded from these and previous observations on early stages of tumor development that the estrogen-induced hamster kidney tumor originates from mesenchymal interstitial cells (probably pericytes) which may rarely acquire an epithelial phenotype by metaplastic transformation during tumor progression.
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PMID:Changes in the cellular phenotype and extracellular matrix during progression of estrogen-induced mesenchymal kidney tumors in Syrian hamsters. 171 81

The regulation of cellular growth and proliferation is perhaps the most investigated and elusive problem in cell biology and seems to be possible to solve from almost any angle of study chosen. Among the non-systemic factors that have been discussed are genetic damage, genomic control, regulation by stimulatory and inhibitory peptide factors such as EGF, chalones, and fibronectin, protein kinase activation with tyrosine phosphorylation, adenylylcyclase and cAMP, cGMP, membrane perturbations and specifically in tumours the failure of the Pasteur effect in control of glycolysis, excessive membrane ATPase activity, and excessive hydrolytic and proteolytic activities at the cell surface. This article focuses on the central role of fluxes within the plasma membrane and re-examines the possibility that changes of flux of metabolites, ions, and reducing equivalents may be the common denominator regulating cellular proliferation.
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PMID:A unifying model of the cell proliferation emphasizing plasma membrane fluxes. 214 43

The regulation of fibronectin (FN) biosynthesis by dexamethasone (a synthetic glucocorticoid), forskolin (an activator of adenylate cyclase), and transforming growth factor beta (TGF-beta) was examined in six human cell lines. Dexamethasone treatment produced the largest increase in FN biosynthesis in the fibrosarcoma cell line, HT-1080 (approximately 45-fold). This seems to result from a dexamethasone-mediated increase in FN mRNA stability which increases the message half-life from approximately 11 to 26 h. The relative instability of FN mRNA in the fibrosarcoma (t1/2 11 h) compared to normal fibroblasts (70 h) appears to result from the particular transformed phenotype of the HT-1080 cells. Forskolin and TGF-beta increase the rate of FN gene transcription in most of the cell lines. These effects (four- to six-fold) occur rapidly and do not require protein synthesis in the responsive cell lines which include normal fibroblasts. However, in the fibrosarcoma (HT-1080), a surprisingly large induction (20-30-fold) is observed and this induction is different from that in the normal fibroblasts and the other cell lines in that both protein synthesis and a lag period are required. Synergism is seen with dexamethasone and either forskolin or TGF-beta in HT-1080 cells increasing the rate of FN biosynthesis approximately 200-fold to a level similar to normal fibroblasts. This seems to result from a combination of FN mRNA stabilization (dexamethasone) and increased transcription (forskolin and TGF-beta).
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PMID:Regulation of fibronectin biosynthesis by dexamethasone, transforming growth factor beta, and cAMP in human cell lines. 245 32

The role that the intracellular mediators, cAMP and Ca2+/phosphatidylserine-dependent protein kinase C, play in the regulation of endothelial cell (EC) motility was investigated. The adenylate cyclase activator, forskolin, at 10 microM induced rapid and reversible alterations in the shape of cultured human EC, disappearance of actin bundles and the concentration of F-actin at cell borders. Actin reorganization provoked by forskolin coincide with redistribution of vinculin to the cell periphery and rapid elimination of surface-associated fibronectin. A protein kinase C activator, phorbol 12-myristate 13-acetate (PMA) at 10-100 microM induced no visible alterations of cell shape, but enhanced the effect of forskolin. PMA stimulated formation of "stress fibers" and increased the number of vinculin plaques in central areas of the cell. A decrease in the amount of the surface-associated fibronectin in PMA-treated cells has also been observed, but, this effect was considerably slower than that produced by forskolin. Forskolin, but not PMA stimulated phosphorylation of the major intermediate filament protein, vimentin.
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PMID:Effects of forskolin and phorbol-myristate-acetate on cytoskeleton, extracellular matrix and protein phosphorylation in human endothelial cells. 254 28

We investigated the effect of agents which raise intracellular levels of cyclic AMP (cAMP) on the secretion of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) by cultured human umbilical-vein endothelial cells. Significant inhibition of baseline (unstimulated) t-PA and PAI-1 secretion was observed in response to several agents which, when added exogenously, cause increased intracellular cAMP: cholera toxin, 1-methyl-3-isobutylxanthine (MIX), dibutyryl-cAMP, and prostaglandin E1. These agents also significantly reduced or abolished the previously reported stimulatory effects of thrombin and histamine on t-PA secretion, and, with the exception of MIX, significantly reduced the previously reported stimulatory effect of thrombin on PAI-1 secretion. MIX at a concentration (10 microM) below that required to inhibit t-PA and PAI-1 secretion when tested alone, significantly increased the inhibitory effects of cholera toxin, dibutyryl-cAMP, and prostaglandin E1 on both t-PA and PAI-1 secretion. The data suggest that elevated intracellular levels of cAMP inhibit both spontaneous endothelial secretion of t-PA and PAI-1, and secretion induced by agents (thrombin and histamine) which stimulate endothelial phosphoinositide metabolism, consistent with bidirectional regulation of endothelial fibrinolytic protein secretion by the adenylate cyclase and phosphoinositide signal transduction pathways. The inhibitory effects of cAMP do not appear to be specific for t-PA and PAI-1, since cholera toxin and MIX also inhibited endothelial secretion of the adhesive protein, fibronectin. Significant inhibition of baseline endothelial t-PA and PAI-1 secretion was also caused by the stable prostacyclin analogue iloprost (ZK 36 374) and by arachidonic acid, which is converted by endothelial cells to prostacyclin, suggesting that prostacyclin produced endogenously by endothelial cells may inhibit secretion of fibrinolytic proteins by increasing intracellular cAMP.
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PMID:Inhibition of endothelial secretion of tissue-type plasminogen activator and its rapid inhibitor by agents which increase intracellular cyclic AMP. 254 66

Studies with cultured fibroblasts have shown that plasma as well as cellular fibronectin can be organized into fibrillar structures and that this organization is mediated by sites at the cell surface. Treatment of human skin fibroblasts with cholera toxin resulted in a prompt decrease in the number of binding sites for 125I-labeled plasma fibronectin and a 125I-labeled 70-kDa amino-terminal fragment of fibronectin. This decrease was accompanied by less incorporation of labeled fibronectin into deoxycholate-insoluble extracellular matrix. Binding of 125I-fibronectin was also decreased in cultures treated with epinephrine, isoproterenol, or forskolin. These results, therefore, indicate that G proteins and the adenylate cyclase system are involved in regulation of fibronectin matrix assembly sites may be one mechanism whereby hormones or growth factors can modify extracellular matrix characteristics.
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PMID:Matrix assembly sites for exogenous fibronectin are decreased on human fibroblasts after treatment with agents which increase intracellular cAMP. 282 Oct 2

The possibility that the mitogenic effect of fibrinogen, a major plasma protein (3 mg/ml), is mediated by specific membrane receptors was studied. Specific binding analysis showed that fibrinogen receptors are present only on hemopoietic cell lines that respond to its mitogenic effect. The mitogenic fibrinogen receptor is not recognized by antibodies specific for the platelet fibrinogen receptor or is not competitively blocked by synthetic peptides containing the Arg-Gly-Asp sequence, which is common to fibronectin, fibrinogen, vitronectin, and other cell-attachment proteins. The lymphoma-derived pre-B-cells (Raji) have 149,000 receptors, whereas the lymphoma-derived T cells (JM), which are 3 times smaller, have 54,000 receptors. These receptors have a Kd of 2 X 10(-7) M. They are inducible by stimuli specific for the cell lineage: activators of the breakdown of phosphatidylinositol phosphates, such as platelet activating factor for Raji cells, and adenylate cyclase agonists and cAMP analogues for JM cells. The stimuli have no mitogenic effect in the absence of fibrinogen; they do not change the Kd. Each stimulus increases the number of fibrinogen receptors in a dose-dependent manner, which correlates strongly (r = -0.98, n = 5) with an increased growth rate of cells in the presence of fibrinogen. This correlation concludes that the mitogenic effect of fibrinogen is controlled via receptor modulation.
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PMID:Fibrinogen mitogenic effect on hemopoietic cell lines: control via receptor modulation. 301 35

Retinal pigment epithelial (RPE) cell migration has been implicated in the pathogenesis of proliferative vitreoretinopathy (PVR). Using a modified Boyden chamber assay, we have examined the effect of cyclic nucleotides on human RPE cell migration in vitro. Dibutyryl cyclic 3',5'-adenosine monophosphate (cAMP) (10(-3) mmol/L) inhibits RPE cell random migration by 83%, fibronectin-induced chemotaxis by 61%, and platelet-derived growth factor-induced chemotaxis by 68%. Random and directed migration of RPE cells is not significantly affected by 8-bromo cyclic 3',5'-guanosine monophosphate. Agents that significantly increase intracellular levels of cAMP are also inhibitors of RPE cell migration. Though there is a fairly good correlation for most drugs for their ability to stimulate cAMP production and their ability to inhibit cell migration, it is not perfect, suggesting that some drugs may modulate migration by more than one mechanism. Timolol blocked both the isoproterenol-induced stimulation of RPE adenylate cyclase and attenuated the ability of isoproterenol to inhibit RPE migration. These data suggest that cAMP may modulate RPE cell migration in an inhibitory fashion. Elucidation of the biochemical events involved in RPE cell migration could provide information that might be useful in planning a strategy to attempt pharmacologic control of proliferative vitreoretinopathy.
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PMID:Cyclic 3',5'-adenosine monophosphate modulates retinal pigment epithelial cell migration in vitro. 302 98

The effect of diterpene forskolin, a potent stimulator of cyclic AMP (cAMP) in the rat thyroid cell strain FRTL-5, was compared with that of TSH. Forskolin stimulated both the release of cAMP into the culture medium and the accumulation of cAMP in the cytoplasm in a dose-dependent manner, within the range of 0.1-1000 mumol/l. Maximum cAMP concentrations were reached within 15 min of stimulation with forskolin. This is comparable with the effects of TSH. Forskolin also induced morphological changes in cultures of FRTL-5 cells, producing conspicuous cell retraction with arborization and numerous microvilli on the cell surface, specific reorganization of the microfilaments and modulation of the distribution of tubulin and fibronectin. Morphological changes induced by forskolin were always observed 20 to 30 min earlier, and in a higher percentage of cells, than the changes induced by TSH. Cell proliferation, however, was stimulated more effectively by TSH than by forskolin. These observations suggest that TSH might exert its effect on the morphology and growth of FRTL-5 cells, at least in part, through cAMP. The control of morphology and growth might not, however, be regulated solely by the adenylate cyclase and cAMP system.
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PMID:Effects of forskolin on the morphology and function of the rat thyroid cell strain, FRTL-5: comparison with the effects of thyrotrophin. 302 25


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