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)

We previously proposed that intracellular cyclic AMP accumulation induces a putative, rapidly turning over protein inhibitory to further hormone activation of adenylate cyclase. In the present study, 2-aminopurine, which has been reported to selectively block c-fos gene expression, was used to test the hypothesis that c-fos protein might be involved in the desensitization to catecholamines was observed in 2-aminopurine-treated C6-2B rat glioma cells. However, we found 2-aminopurine to inhibit, in a concentration-dependent manner, total cellular RNA and protein synthesis in C6-2B, HeLa, Swiss 3T3 and BALB/c cells. mRNA synthesis was also markedly reduced in 2-aminopurine-treated cells. These unexpected findings, while supporting our hypothesis of a protein synthesis-sensitive step in the development of refractoriness, raise concern about the specificity of action of 2-aminopurine to inhibit c-fos induction and thus any cellular process, including desensitization, which might be regulated by c-fos gene expression.
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PMID:2-Aminopurine inhibits RNA and protein synthesis and reduces catecholamine desensitization in C6-2B rat glioma cells. 137 Apr 21

In A-431 cells, platelet-activating factor (PAF) induces the expression of c-fos and TIS-1 genes in both the absence and the presence of cycloheximide in a structurally specific and receptor-coupled manner. We have now investigated the molecular mechanisms of this response, particularly in relation to the role of protein kinases. Pretreatment of cells with genistein or methyl-2,5-dihydroxycinnamate (tyrosine kinase inhibitors) or staurosporine (a protein kinase C inhibitor) for 20 min abolished the c-fos expression induced by PAF. Interestingly, when genistein was added 90 s after addition of PAF, no inhibition was observed. Similarly, staurosporine did not inhibit c-fos expression when added 8 min after PAF addition to the cells. These inhibitions were dose-dependent (IC50 for staurosporine was 180 nM, and for genistein 50 microM). Simultaneous addition of PAF and phorbol 12-myristate 13-acetate (PMA) did not give a synergistic effect on c-fos expression. Pretreatment of cells with PMA had no effect on [3H]PAF binding, but abolished the PAF-induced gene expression. PAF-stimulated gene expression was desensitized if cells were pretreated with PAF. Interestingly, epidermal growth factor was able to stimulate c-fos expression in PAF-desensitized cells, and thus indicated involvement of distinct mechanisms for the two stimuli. Forskolin, an activator of adenylate cyclase, did not induce c-fos expression and had no effect on the PAF response. Exposure of cells to PAF for as little as 1 min, followed by its removal, was sufficient to activate the gene expression and demonstrated the rapidity and the exquisite nature of the signalling involved in this process. It is concluded that activation of PAF receptor (a proposed G-protein-coupled receptor) causes rapid production of signals which induce the expression of c-fos gene and that this is mediated via tyrosine kinase and protein kinase C.
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PMID:Involvement of tyrosine kinase and protein kinase C in platelet-activating-factor-induced c-fos gene expression in A-431 cells. 138 9

We studied the involvement of the cAMP pathway in the regulation of beta TC1 cell growth with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the activator of adenylate cyclase forskolin. We examined the effect of the increase in cAMP content on the serum-induced resumption of the cell cycle of quiescent cells. IBMX and forskolin both inhibited the mitogenic effect of serum in a concentration-dependent manner. Intracellular cAMP levels were, respectively, enhanced 3.0- and 8.6-fold by IBMX (0.5 mM) and forskolin (20 microM) within 1 h. IBMX and forskolin were also inducers of insulin release, indicating that the growth-arrested beta TC1 cells have retained the essential characteristics of the normal differentiated beta-cells. The effects of IBMX and forskolin were correlated with a modulation of cell cycle-related gene expression. IBMX induced expression of the c-fos gene, which was further enhanced by the simultaneous addition of serum, whereas forskolin alone elicited maximal induction of this gene. Interestingly, c-jun expression was only enhanced with forskolin. We also studied the effects of IBMX and forskolin on the expression of the simian virus-40 T-antigen controlled by the rat insulin II promoter in beta TC1 cells. IBMX and forskolin inhibited the serum-induced accumulation of simian virus-40 T-antigen mRNA in quiescent as well as exponentially growing beta TC1 cells.
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PMID:Modulation of growth-related gene expression and growth inhibition by cyclic adenosine 3',5'-monophosphate-elevating agents in the insulin-producing cell line beta TC1. 138

To determine the cellular functions which are modified when interferon-beta (IFN-beta) gene expression is inhibited, a plasmid allowing the constitutive expression of RNA complementary to IFN-beta mRNA was constructed and stably introduced into L929 cells. Some of the selected clones expressing this antisense IFN-beta mRNA, named L-ASI, were unable to produce IFN-beta and lost the ability to arrest in the G0 phase of the cell cycle. Indeed, the usual transrepression of the c-fos gene observed in quiescent cells was blocked in IFN-beta antisense L-ASI clones and the c-fos gene was permanently stimulated. This overexpression of c-fos was not modified in response to protein kinase C agonists such as phorbol esters, but increased in response to the adenylate cyclase activator forskolin. In addition, the ability to induce major histocompatibility class I genes following recombinant IFN-beta treatment was impaired in antisense IFN-beta L-ASI clones, suggesting an important alteration of this cell with regard to the interferon system. Unexpectedly, the tumorigenicity of the clones was significantly diminished. We postulate that IFN-beta antisense RNA blocks the repression of the c-fos gene and thus prevents the arrest of cells in the G0 phase of the cycle.
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PMID:An antisense interferon-beta RNA abolishes repression of c-fos gene expression. 159 42

Protooncogene c-fos is induced by activation of adenylate cyclase through the major cAMP-responsive element (CRE) centered at position -60 of the promoter. cAMP induction is followed by a rapid decrease in transcriptional rate, reminiscent of down-regulation after serum stimulation. Fos protein is known to negatively autoregulate serum-induced transcription of c-fos promoter, but whether Fos is responsible for down-regulation of cAMP-induced transcription is unclear. Here we show that Fos is unable to down-regulate CRE-mediated activation. We present evidence that the transcriptional antagonist CRE modulator (CREM) can bind to c-fos CRE and heterodimerize with activator CRE-binding protein, thereby blocking cAMP induction. Furthermore, expression of antisense CREM enhances c-fos basal and cAMP-induced transcription. CREM does not antagonize serum-induced transcription; therefore, we conclude that down-regulation of c-fos is exerted by different effectors, depending upon which signal transduction pathway is activated. We speculate that, by its c-fos down-regulatory function, CREM may act as an antioncogene.
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PMID:Transcriptional antagonist cAMP-responsive element modulator (CREM) down-regulates c-fos cAMP-induced expression. 164 33

We have shown that FGF (basic or acidic) is mitogenic for quiescent hamster lung fibroblasts (CCL39 line). It is active alone but is much more efficient in synergistic combinations with G-protein-activating agents. When used alone, FGF appears to exert its mitogenic effects without involving any of the major G-protein-mediated signaling pathways. It causes no significant hydrolysis of phosphoinositides, it does not alter the activity of adenylate cyclase, and its mitogenicity is insensitive to pertussis toxin. It therefore seems likely that all pleiotropic actions of FGF are primarily mediated by the intrinsic protein tyrosine kinase of its receptors. However, FGF, acting through its receptor tyrosine kinase, and thrombin, acting through G-protein-coupled receptors, induce a common set of early responses detected within seconds or minutes at the level of membranes, cytoplasm, and nuclei. Typical examples of early responses are activation of Na/H antiporter and Na/K/Cl cotransporter, phosphorylation of ribosomal protein S6, and increased transcription of early-immediate genes (c-fos, c-jun, and c-myc). Not only various classes of growth factors acting via distinct transducing mechanisms activate common targets, but also their synergistic effects on reinitiation of DNA synthesis is reflected on the early responses. How does the coordination of these signaling events take place? A partial answer to this question is illustrated in Figure 6 in which "switch kinases" play the role of integrators of multiple extracellular signals. Raf and, perhaps more convincingly, MAP kinases that are activated by dual phosphorylation on tyrosine and threonine residues are potential good candidates for this integration. This hypothetical scheme could therefore explain, in part, the coordination and the synergy commonly observed in the mitogenic response. The synergy could be generated at the level of MAP kinases simply by dual activating phosphorylations. With the recent cloning of MAP kinases, these questions will be more easily addressed. Another important gap that will have to be filled in future studies is the identification of all the members of the kinase cascade. When used in synergistic combinations with G-protein-activating agents, FGF does exert in contrast some effects on the G-protein-mediated pathways. It potentiates the G-protein-mediated activations of both PIP2-PLC and adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mitogenic effects of fibroblast growth factors in cultured fibroblasts. Interaction with the G-protein-mediated signaling pathways. 166 81

Expression of the proto-oncogenes c-fos and c-jun was analysed in the insulin producing rat tumor cell line, RIN 5AH. Addition of fetal calf serum (FCS) to serum-starved cells in the presence of cycloheximid induced a modest increase in c-fos and c-jun mRNA levels, whereas growth hormone (GH) in the presence of cycloheximid had little or no effect, when added to RIN 5AH cells maintained in 0.5% FCS for 2 days prior to stimulation. Activation of protein kinase C by phorbol ester lead to increased c-jun and c-fos mRNA levels, whereas activation of adenylate cyclase by forskolin increased c-fos mRNA levels. These results suggest that the effects of GH on insulin producing cells are not mediated by activation of c-fos and c-jun transcription.
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PMID:Effect of growth hormone and serum on the expression of the proto-oncogenes c-jun and c-fos in insulin producing cells. 212 2

Bombesin is a potent mitogen for Swiss 3T3 cells and can stimulate DNA synthesis in the absence of any other growth factor. This effect is mediated by multiple synergistic signaling pathways, including an accumulation of intracellular cyclic AMP (cAMP) and an increase in c-fos mRNA expression. The cyclooxygenase inhibitor indomethacin abolished prostaglandin E2 release and substantially depressed cAMP levels induced by bombesin (EC50 congruent to 10 nM). In contrast, indomethacin at 1 microM did not affect 80K phosphorylation or Ca2+ mobilization by bombesin, indicating that cAMP synthesis can occur through a phospholipase C-independent pathway. Indomethacin caused a 30 to 35% decrease in c-fos induction and DNA synthesis in cells treated with bombesin (EC50 congruent to 40 nM). Significantly, the inhibitory effect of indomethacin was reversed in the presence of forskolin, a direct activator of adenylate cyclase. We conclude that cAMP plays a regulatory role in c-fos induction and mitogenesis in Swiss 3T3 cells treated with bombesin.
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PMID:Bombesin stimulation of c-fos expression and mitogenesis in Swiss 3T3 cells: the role of prostaglandin E2-mediated cyclic AMP accumulation. 217 Jan 55

Serum mitogens, fibroblast growth factor (FGF), and type beta transforming growth factor (TGF-beta) suppress differentiation of the mouse muscle cell line BC3H1; however, the signal transduction pathways whereby these growth factors exert their effects on this system are unknown. The goal of this study was to determine whether the program for differentiation of BC3H1 cells was susceptible to negative regulation by signaling pathways involving cAMP or protein kinase C and whether these intracellular effectors participate in the mechanism by which growth factors prevent establishment of the myogenic phenotype. Exposure of BC3H1 cells to dibutyryl cAMP, 8-bromo-cAMP, or compounds that stimulate adenylate cyclase, i.e. forskolin, prostaglandin E1, and cholera toxin, prevented up-regulation of muscle-specific gene products following growth arrest in mitogen-deficient medium. Conversely, addition of cAMP to differentiated BC3H1 myocytes caused down-regulation of muscle-specific mRNAs. In contrast to the ability of cAMP to block differentiation, chronic exposure to O-tetradecanoylphorbol-13-acetate, the potent activator of protein kinase C, exhibited no apparent effects on expression of muscle-specific gene products. The proto-oncogenes c-myc and c-fos were up-regulated rapidly by cAMP in a manner similar to that observed previously by serum, FGF, and TGF-beta. However, these growth factors failed to increase intracellular cAMP levels, and they did not induce ornithine decarboxylase, which was subject to positive regulation by cAMP and O-tetradecanoyl-13-acetate. Together, these data indicate that differentiation of BC3H1 cells is subject to negative regulation through a cAMP-dependent pathway and that serum mitogens, FGF, and TGF-beta inhibit differentiation through a mechanism independent of cAMP or protein kinase C.
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PMID:Regulation of differentiation of the BC3H1 muscle cell line through cAMP-dependent and -independent pathways. 246 41

We have studied the effect of increased intracellular levels of cyclic AMP on the growth response to platelet-derived growth factor (PDGF) of human foreskin fibroblasts in culture. It was found that forskolin, a potent stimulator of adenylate cyclase activity, inhibits the stimulatory effect of PDGF on 3H-thymidine incorporation with a dose dependence similar to that observed with regard to cyclic AMP formation. A time-course study indicated that forskolin has no effect on ongoing DNA synthesis but affects events in the prereplicative phase. The cell-cycle block induced by forskolin was found to be reversible; after removal of the drug, DNA synthesis was initiated after a lag period, similar to that of the prereplicative phase of control cells. Forskolin had no effect on PDGF binding, receptor autophosphorylation, or c-fos mRNA expression. However, a reduction in PDGF-induced c-myc mRNA expression was observed in cultures given forskolin. Forskolin was also found to have a marked stimulatory effect on the expression of interferon-beta 2 mRNA expression. However, we were unable to demonstrate that the growth-inhibitory effect of forskolin is mediated by interferon-beta. In conclusion, an increase in cAMP levels leads to a reversible inhibition of PDGF-induced DNA synthesis in human fibroblasts, which may be related to an inhibition of c-myc mRNA expression.
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PMID:Induction of cyclic AMP synthesis by forskolin is followed by a reduction in the expression of c-myc messenger RNA and inhibition of 3H-thymidine incorporation in human fibroblasts. 253 35


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