Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin E2 (PGE2, 5 ng/ml to 5 micrograms/ml) induced a dose-dependent increase in cAMP accumulation, inositol phosphates (IPs) accumulation, and cytoplasmic free Ca2+ ([Ca2+]i) in a clonal osteoblast-like cell line, MOB 3-4. In contrast, prostaglandin F2 alpha (PGF2 alpha, 5 ng/ml to 5 micrograms/ml) stimulated increases in IPs accumulation and [Ca2+]i without stimulating an increase in cAMP accumulation. Both PGE2 (greater than 0.5 micrograms/ml) and PGF2 alpha (greater than or equal to 5 micrograms/ml) increased cytoplasmic pH (pHi) from approximately 7.15 to 7.35 in BCECF-loaded cells. A tumor promotor, phorbol 12-myristate 13-acetate (PMA, 0.1-100 nM) also increased pHi without effect on phosphoinositide hydrolysis. Both PGE2-(5 micrograms/ml) and PMA- (100 nM) induced cytoplasmic alkalinization was inhibited by removal of extracellular Na+, or by pretreatment of the cells with amiloride (0.5 mM), an inhibitor of Na+/H+ exchange, or H-7 (100 microM), a nonspecific inhibitor of protein kinase C. Thus, MOB 3-4 cells appeared to possess PGE2 receptors and PGF2 alpha receptors: the former are coupled to adenylate cyclase and phospholipase C, and the latter are predominantly coupled to phospholipase C. Also the cells appeared to possess an amiloride-sensitive Na+/H+ exchange activity, which increases pHi in response to PGE2 and PGF2 alpha, as well as to PMA. Long-term (48 hr) exposure of the cells to PGE2 at a high concentration (5 micrograms/ml), but not to PGF2 alpha and PMA, decreased DNA synthesis in the serum-deficient medium. Thus, cytoplasmic alkalinization appeared insufficient for cell replication. At least in MOB 3-4 cells, the inhibitory effect of PGE2 on DNA synthesis may be due to the cAMP messenger system.
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PMID:Effects of prostaglandin E2 and F2 alpha on cytoplasmic pH in a clonal osteoblast-like cell line, MOB 3-4. 184 35

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

Galanin, an ubiquitous neuropeptide, was recently shown to inhibit somatostatin release by the rat islet tumor cell line, Rin-m. By using the clonal pancreatic delta cell line Rin14B, originating from Rin-m cells, we were able to identify the presence of one type of specific galanin-binding site of high affinity (Kd = 1.6 nM; maximal binding capacity = 270 fmol/mg protein) and high specificity for the peptide. Binding of 125I-galanin to these receptors was time-dependent and highly sensitive to guanine nucleotides. Using the cross-linker disuccinimidyl tartrate, covalent linking of the galanin receptor to 125I-galanin in membranes from Rin14B cells, followed by SDS/PAGE analysis of membrane proteins, indicated that the galanin receptor is a protein of 54 kDa. 0.1-100 nM galanin also exerted a marked inhibitory effect on the cAMP-production system under basal conditions, as well as in the presence of the pancreatic peptide glucagon. At a maximal dose, galanin induces a 90-100% decrease of basal and glucagon-stimulated cAMP production levels, with a median inhibition concentration (IC50) of 3 nM galanin. The direct inhibitory effect of galanin on the adenylate cyclase activity in Rin14B cell membranes was also demonstrated (IC50 = 3 nM galanin). The inhibitory effect of galanin on the basal and glucagon-stimulated cAMP production in Rin14B cells was reversed by pertussis toxin. The toxin was also shown to specifically ADP-ribosylate a protein of 41 kDa in membranes from Rin14B cells. Taken together, these data show that the pancreatic delta cell line Rin14B expresses high affinity galanin receptors negatively coupled to a pertussis-toxin-sensitive cAMP-production system.
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PMID:A clonal rat pancreatic delta cell line (Rin14B) expresses a high number of galanin receptors negatively coupled to a pertussis-toxin-sensitive cAMP-production pathway. 184 83

Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha-1 and beta-2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC), the density was examined of alpha-1 and beta-2 adrenoceptors with their affinity and coupling of beta-2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age-matched and sex-matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty-two HCC had a decrease of about 72% in alpha-1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha-1 adrenoceptor density compared with healthy livers. Twenty-three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase, as evidenced by a guanosine triphosphate-mediated right shift in (-)-isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (-)-isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha-1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the "healthy" part of the liver in HCC patients and that an increase in beta-2 and a decrease in alpha-1 adrenoceptor densities characterize the tumor part of the liver in human HCC.
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PMID:Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma. 184 89

Anterior pituitary POMC transcription and peptide release are negatively regulated by glucocorticoids and stimulated by CRF. Although pretreatment of corticotrope cells with CRF markedly inhibits subsequent glucocorticoid effects, the mechanism of this action is unclear. We have thus used a mouse corticotrope tumor (AtT20) cell line, to examine the effects of CRF on glucocorticoid receptor (GR) messenger RNA levels and on GR capacity/nuclear translocation. GR mRNA levels were measured by solution hybridization/S1 nuclease protection, and both total cell binding and nuclear binding were determined with [3H]dexamethasone ([3H]DEX). CRF treatment of AtT20 cells led to a rapid time-dependent decrease in GR mRNA levels which preceded a dose- and time-dependent decrease in GR binding capacity. Scatchard analysis showed a single class of high affinity binding sites (GR) in both control and CRF-treated cultures, and a decrease in the total number of GR after CRF treatment. The relative proportion of nuclear vs. cytoplasmic localized [3H]DEX-bound GR did not differ between control and CRF-treated cultures, indicating that CRF does not interfere with GR nuclear translocation. To investigate whether CRF regulates GR expression through the adenylate cyclase system, as it does POMC, AtT20 cells were treated with either forskolin or 8-bromo-cAMP, and specific nuclear GR binding was determined. Both drugs mimic the CRF-induced decrease in GR binding, and in addition forskolin decreased GR mRNA levels; in contrast, forskolin had no effect on GH3 cell GR levels. These results suggest that CRF can decrease the cellular concentration of GR, and thus potentially the response to glucocorticoids, through the same mechanism by which it stimulates anterior pituitary POMC expression.
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PMID:Adrenocorticotropin-releasing factor down-regulates glucocorticoid receptor expression in mouse corticotrope tumor cells via an adenylate cyclase-dependent mechanism. 185 64

There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase), verapamil (calcium antagonist), forskolin (stimulator of platelet adenylate cyclase), and indomethacin (inhibitor of cyclooxygenase) were examined, alone and in combination, to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically, and the animals were divided into control, single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore, when these agents were combined, similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008), while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also, the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.
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PMID:Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse. 189 Aug 39

The radiation leukemia virus-induced murine Cyc- T lymphoma cell line TL2-9 expressed one homogeneous population of beta 2-adrenoceptors based on competition curves of [125I]cyanopindolol with the specific antagonist ICI 118.551 and three beta-adrenergic agonists. These receptors were uncoupled from adenylate cyclase due to the absence of Gs. The catalytical unit was directly stimulated by MnCl2, forskolin, and even more markedly in the simultaneous presence of both reagents. In contrast, the enzyme was inhibited in the presence of Gpp[NH]p, probably through interaction with Gi. Indeed, this inhibitory effect was constrained by preincubating cells in the presence of pertussis toxin and a 41 kDa protein was specifically ADP-ribosylated in the presence of the toxin. This cell line was therefore analogous to the Cyc- cell line derived from the murine S49 lymphoma cell line. When added to the culture medium, butyrate (2 mM) induced beta 2-adrenoceptors, the expression of these uncoupled receptors depending on protein synthesis, as judged by inhibitory effects of cycloheximide. In contrast, dBcAMP (1 mM) and TPA (tumor-promoting agent phorbol ester) increased the rate of disappearance of beta 2-adrenoceptors. Butyrate, dBcAMP and TPA systematically decreased adenylate cyclase activity. Besides, TPA (but neither butyrate nor dBcAMP) reduced the efficacy of Gpp[NH]p in inhibiting adenylate cyclase, suggesting a proportionately higher alteration of Gi. We conclude that beta 2-adrenoceptors, uncoupled from adenylate cyclase, are regulated independently from the catalytical unit and Gi, in this Cyc- T lymphoma cell line.
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PMID:Divergent regulation of beta 2-adrenoceptors and adenylate cyclase in the Cyc- mouse T lymphoma cell line TL2-9. 198 Feb 64

Treatment of human endothelial cells with thrombin, histamine, or dioctanoylglycerol (DiC8), a synthetic diacylglycerol, resulted in the rapid and transient phosphorylation of a Mr = 29,000 protein (P29) in a dose-dependent manner. Various tumor promoters also promoted P29 phosphorylation while the adenylate cyclase activator, forskolin, did not. The level of phosphorylation with all three agonists was similar (2.5-4 fold), and analysis of P29 by two-dimensional gel electrophoresis revealed identical patterns in each case. Receptor specificity was demonstrated for the histamine-stimulated changes; pyrilamine (10(-6) M; H1) but not cimetidine (10(-4); H2) blocked the response. The thrombin effect was active site-dependent. Phosphorylation induced by thrombin and histamine occurred within 1 min, peaked between 5 and 10 min, and returned to control levels by 1 h. DiC8-induced phosphorylation occurred more slowly but was also reduced by 1 h while phorbol ester treatment prolonged phosphorylation for at least 4 h. Treatment of these cells with thrombin or histamine for 1 h desensitized P29 to further phosphorylation by the homologous agonist although secondary phosphorylation could occur with heterologous compounds. However, if the primary agonist was removed following the onset of a desensitized state, secondary phosphorylation of P29 could be stimulated by the same compound. These same results were observed with two other phosphoproteins Mr = 18,000 (P18) and 80,000 (P80) which became more highly phosphorylated in response to thrombin treatment and with histamine/thrombin-stimulated prostaglandin I2 production. In contrast, homologous down-regulation of P29 phosphorylation was not observed with DiC8-treated cells, and the decline in phosphorylated P29 was associated with the loss of functional DiC8. The protein kinase inhibitors staurosporine and H-7 blocked P18 and P80 phosphorylation by thrombin but had no effect on P29 phosphorylation by histamine, thrombin, or DiC8 suggesting distinct pathways leading to the phosphorylation of these different proteins. These data suggest that multiple and independent thrombin/histamine-induced events are susceptible to receptor occupancy-dependent homologous down-regulation.
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PMID:Thrombin- and histamine-induced signal transduction in human endothelial cells. Stimulation and agonist-dependent desensitization of protein phosphorylation. 198 91

Crude plasma membranes were prepared from the liver of control rats or of rats submitted to an initiation by diethyl-nitrosamine and selection with 2-acetylaminofluorene and carbon tetrachloride (group IS) or of rats submitted to an initiation-selection protocol followed by a promotion with phenobarbital (group IS PB). In control rats, the diterpene forskolin and glucagon stimulated the activity of adenylate cyclase 6- to 7-fold. Guanosine-5'-O-(2-thiodiphosphate) (GDP beta S) inhibited the stimulation by both agents and the non-hydrolyzable GTP analog, guanyl-5'-yl-imidodiphosphate [Gpp(NH)p], potentiated the stimulatory effect of glucagon. In rats of the IS group, no modification of the activity of the liver cyclase was found, except for an increased response to forskolin and glucagon. In the IS PB group, for the rats without tumor, the only effect of adding phenobarbital was to increase the sensitivity of the cyclase to forskolin. In tumoral tissue, the response to Gpp(NH)p, glucagon and forskolin were increased when compared to the surrounding tissue. In contrast to the surrounding tissue, GDP beta S potentiated the stimulatory effect of forskolin. When the affinity of the glucagon receptors for the hormone was measured in binding experiments, no difference was observed among the rats of the various groups, except for a higher affinity in tumoral tissue. Similarly, GTP inhibited the binding of glucagon with the same potency in each group. It is concluded that during hepatocarcinogenesis, the sensitivity of the adenylate cyclase towards glucagon increases secondarily to a better binding of the hormone to its receptor and to an impairment of the inhibitory regulatory site.
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PMID:Adenylate cyclase activity in crude liver membranes during chemical hepatocarcinogenesis. 201 30

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


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