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)

Cyclic AMP may be involved in the modulation of cell growth. The present work sought to further define differences between normal cells and tumor cells in their cyclic AMP system. Mouse embryo fibroblasts and murine bladder transitional epithelium tumor cells were grown in vitro; at various times, adenyl cyclase activity was assayed by measuring the conversion of [alpha32P]ATP to cyclic AM32P; stimulation by prostaglandin E1 or sodium fluoride was also determined. Base line and fluoride-stimulated enzyme activity were significantly greater in normal cells than tumor cells (P less than 0.01), and reached a peak at day 2; at confluency, levels in both systems decreased. Prostaglandin E1-stimulated levels, in contrast, were greater in tumor cells, there being a 10 fold greater relative stimulation in these cells compared to normal cells (P less than 0.01). Findings of a possibly greater sensitivity in these tumor cells may be important in a therapeutic modulation of tumor growth.
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PMID:Differences in adenylate cyclase activities in murine normal cells and bladder tumor cells in tissue culture. 18 32

Some of the regulatory mechanisms of cyclic adenosine monophosphate (AMP) production in human brain tumors were investigated by assessing both cyclic AMP levels and adenyl cyclase activity. A large disparity was found between the levels of cyclic AMP of normal brain and brain-tumor tissue. Cyclic AMP levels were much lower in brain tumors (25.8 pmoles (picomoles)/mg protein) than in normal brain (98.8 pmoles/mg protein). These studies also show that the abnormally low levels of cyclic AMP in tumors parallel those of adenyl cyclase. The mean adenyl cyclase activity of brain tissue was found to be 111.0 pmoles of cyclic AMP/min/mg protein, while that of the tumor was only 23.0 pmoles/min/mg protein. Levels of cyclic AMP and adenyl cyclase activity were inversely related to the degree of malignancy. Attempts to stimulate adenyl cyclase in homogenates of human brain and brain tumors resulted in a similar response in both tissues. Norepinephrone was the most effective stimulant and produced a two- to threefold increase in cyclic AMP production, while histamine had no effect. It is concluded that one of the factors governing tumor growth may be a defect in the adenyl cyclase system.
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PMID:Cyclic AMP and adenyl cyclase in brain tumors. 19 76

Dimethylbenzanthracene-induced rat carcinomas possess activities binding cyclic adenosine 3':5'-monophosphate (cAMP) and estrogen. When dimethylbenzanthracene-induced tumors regress after ovariectomy of the host, a change in the specific binding of cAMP and estrogen occurs in the tumors. Six days after ovariectomy, cAMP binding increases 5-fold in the nuclei and 2-fold in the cytosol of tumors, while nuclear and cytoplasmic estrogen binding decreases by 80% and 50%, respectively. These changes in activities binding cAMP and estrogen are detectable within 1 day after ovariectomy and the changes are reversed when resumption of tumor growth is induced by the injection of 17beta-estradiol. When dimethylbenzanthracene-induced tumors fail to regress after ovariectomy, the change in activities binding cAMP and estrogen does not occur. Significant increases in the cAMP level as well as in adenylate cyclase and cAMP-phosphodiesterase activities are also found in the regressing tumors. Concomitant with the increase of cAMP-binding activity is an increase in histone kinase activity in the regressing tumor. These data suggest the involvement of cAMP in the growth control of a hormone-dependent mammary rumor.
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PMID:Cyclic AMP-binding proteins: inverse relationship with estrogen-receptors in hormone-dependent mammary tumor regression. 20 18

An osteogenic sarcoma was induced in an inbred strain of the Sprague Dawley rat using seven serial injections of 32P-orthophosphate. The tumor was maintained by transplantation over a 3-year period in the same inbred strain. During this time it retained its bone-like differentiation. Tumor membranes and freshly isolated tumor cells also retained responsiveness to parathyroid hormone and to prostaglandins of adenylate cyclase and cyclic nucleotide formation respectively. The potencies of these agents and their analogues and metabolites were found to be proportional to their efficacies as bone resorbing agents. Thus, the tumor was shown to be a model for the study of hormone-responsiveness for tumor growth and differentiation, and also of the effects of agonists which act on bone-like cells.
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PMID:Radiation induced osteogenic sarcoma in the rat as a model of hormone-responsive differentiated cancer. 33 78

Previous experiments have demonstrated that double-stranded RNAs (dsRNAs) can exert an antiproliferative effect on human tumor cells, independent of interferon (IFN) induction. However, the mechanism by which dsRNAs inhibit tumor growth has not been elucidated. As a first step in determining the molecular events responsible for growth arrest, we have explored the role of signal transduction through the cAMP system in the antiproliferative effect of the mismatched dsRNA, r(I)n.r(C12,U)n (Ampligen). These studies utilized the human glioma cell line A1235, which does not produce detectable levels of IFN-alpha, -beta, or -gamma in response to mismatched dsRNA treatment. Treatment of A1235 cells with mismatched dsRNA in combination with either 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), which inhibits cAMP-dependent protein kinase and protein kinase C, or N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), which preferentially inhibits the cAMP-dependent protein kinase, yielded an antagonism of the mismatched dsRNA-induced antiproliferative effect. Measurement of adenylate cyclase activation showed a dose-dependent increase in activity at antiproliferative mismatched dsRNA concentrations, but not at lower, nonantiproliferative doses. This increase in activity was rapid, seen as early as 30 sec after initiation of treatment, and it was sustained at peak levels for 1-2 hr. Analysis of the intracellular cAMP concentration gave similar kinetics of induction. Exposure of cells to the stable cAMP analogue dibutyryl cAMP yielded dose-dependent inhibition of cell growth. The cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also inhibited proliferation. In contrast, neither H-7 nor HA1004 had an effect on growth inhibition induced by human natural IFN-alpha treatment. In addition, antiproliferative doses of IFN-alpha did not increase cAMP concentrations. These results indicate that the cAMP system is utilized by mismatched dsRNA as an early signal transduction mechanism for growth control. Furthermore, the antiproliferative effects induced by mismatched dsRNA and IFN can occur by different mechanisms of action.
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PMID:Cyclic AMP mediates the direct antiproliferative action of mismatched double-stranded RNA. 184 67

Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Resistance to bromocriptine in prolactinomas. 276 Jan 67

Synergistic increases in the survival of mice bearing an L1210 leukemia tumor have been demonstrated previously after treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea together with theophylline over those treated with either agent alone. These results imply that manipulation of cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels in L1210 cells may result in alteration of sensitivity to chemotherapy and alterations in tumor growth. In the present study, we have shown that in vivo treatment of L1210 cells with theophylline results in changes in intracellular cyclic AMP-dependent protein kinase activity levels as well as in an apparent redistribution of both the nuclear and cytoplasmic isozymes. Biochemical events in the tumor cells immediately after administration of theophylline in vivo or a cyclic AMP analog (8-parachlorophenylthio cyclic adenosine 3':5'-monophosphate in vitro were independent of the presence of 1,3-bis(2-chloroethyl)-1-nitrosourea. The changes apparently involve signal transduction via the adenylate cyclase system and manifest as: (a) increased sensitivity of cyclic AMP-dependent protein kinase to activation by cyclic AMP after treatment of L1210 cells with theophylline; (b) decrease in endogenous nuclear protein phosphorylation sites; and (c) protein kinase isozyme redistribution between nuclear and extranuclear compartments, i.e., a relative increase of the type I isozyme activity in the nuclear and of the type II isozyme activity in the 900 x g supernatant fractions after treatment of the mice with theophylline. The relative activity increases are accompanied by a relative decrease of type II activity from the nucleus and type I isozyme activity from the 900 x g extranuclear supernatant fraction. These events appear temporally related to changes in nuclear RNA metabolism as evidenced by altered kinetics of RNA precursor uptake and incorporation into tumor cell RNA after treatment. These results imply that the cyclic AMP-dependent phosphorylative modification of intracellular proteins may play a regulatory role in tumor cell growth and in theophylline-mediated tumor regression.
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PMID:Cyclic adenosine 3':5'-monophosphate-dependent protein phosphorylation and the control of leukemia L1210 cell growth. 628 49

The relationship between striatal dopamine-stimulated adenylate cyclase (DAC) and 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors was studied. An inverse correlation between activity of this enzyme and the number and growth of tumors was observed in several strains and substrains of rats. Chronic, but not acute, restraint stress inhibited tumor growth and increased DAC activity. No correlation between enzyme activity and the number of tumors was found in the stress study. Increased DAC activity appears to protect or inhibit DMBA mammary tumor development in rats.
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PMID:Striatal dopamine-stimulated adenylate cyclase activity reflects susceptibility of rats to 7,12-dimethylbenz[a]anthracene-induced mammary tumor development. 642 70

We have identified pituitary adenylate cyclase activating peptide (PACAP) receptors on small cell lung cancer cell line NCI-N417 in a previous study. In this study, the role of PACAP in the growth and signal transduction of non-small cell lung cancer cells was investigated. Northern blot analysis with a full-length human PACAP receptor cDNA probe revealed a major 7.5-kb hybridizing transcript when total RNA extracted from NCI-H838 cells was used. PACAP bound with high affinity (Kd = 1 nM) to a single class of sites (Bmax = 14,000/cell) when NCI-H838 cells were used. Specific 125I-labeled PACAP binding was inhibited with high affinity by PACAP-27 and PACAP-38, with moderate affinity by PACAP(6-38), and with low affinity by vasoactive intestinal polypeptide, PACAP(28-38), and PACAP(16-38). PACAP-27 elevated cAMP in a dose-dependent manner, and the increase in cAMP caused by PACAP was reversed by PACAP(6-38). PACAP-27, but not vasoactive intestinal polypeptide, elevated cytosolic Ca2+ in individual NCI-H838 cells. PACAP-27 stimulated arachidonic acid release, and the increase caused by PACAP was reversed by PACAP(6-38). PACAP-27 stimulated colony formation in NCI-H838 cells, whereas the PACAP antagonist PACAP(6-38) reduced colony formation in the absence or presence of exogenous PACAP-27. In nude mice bearing NCI-H838 xenografts, PACAP(6-38) slowed tumor growth significantly. These data suggest that biologically active type 1 PACAP receptors are present on human non-small cell lung cancer cells, which exhibit dual signal transduction pathways and regulate cell proliferation.
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PMID:Pituitary adenylate cyclase activating peptide receptors regulate the growth of non-small cell lung cancer cells. 758 25

PTH-related peptide (PTHrP) has been shown to be the major mediator of hypercalcemia of malignancy, but may also exert effects on cell growth and differentiation. The Leydig cell tumor H-500, when implanted in Fischer rats, produces abundant PTHrP and eventually causes the death of the host animal. In the present study we have used antisense RNA technology to block the effects of PTHrP in H-500 Leydig tumor cells in vivo. The full-length rat PTHrP complementary DNA encoding amino acid -36-->141 was subcloned as an EcoRI-BglII insert in the antisense orientation into the mammalian expression vector pRc/CMV to produce the plasmid pRc-PAS. This plasmid was then stably transfected into the H-500 Leydig tumor cells with a Lipofectin reagent. After selection with the neomycin derivative G-418, a stable cell line, H-500-PTHrP-AS, was obtained which showed 80% inhibition of endogenous PTHrP messenger RNA compared to wild-type or vector-only transfected H-500 cells. Conditioned culture medium from these experimental cells showed a marked decrease in PTHrP immunoreactivity and in the ability of the medium to stimulate adenylate cyclase in UMR-106 rat osteosarcoma cells. Furthermore, inhibition of PTHrP production resulted in a significant increase in the doubling time of the H-500 cells. Transfection of the experimental plasmid into Rat-2 fibroblasts, which do not produce PTHrP, had no effect on cell growth. Control and experimental cells were then implanted sc into male Fischer rats. Animals were killed at timed intervals, and their tumor volumes were determined. Experimental animals receiving cells transfected with antisense PTHrP plasmid showed near-normal levels of plasma calcium and decreased expression of tumoral PTHrP messenger RNA. These animals also showed a 30-70% lower tumor volume during the course of the experiment compared to control animals. These studies have demonstrated that PTHrP can play a role as a promoter of tumor growth in vitro and in vivo.
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PMID:Regulation in vivo of the growth of Leydig cell tumors by antisense ribonucleic acid for parathyroid hormone-related peptide. 758 90


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