Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous reports, we have provided evidence indicating that newly formed histamine is an intracellular messenger in human platelets. The involvement of protein kinase C (PKC) and intracellular calcium (Ca2+i) in the synthesis of histamine was investigated. Human platelets were stimulated by phorbol 12-myristate 13-acetate (PMA), collagen and the Ca2+ ionophore A23187, with or without the PKC inhibitor staurosporine. Aggregation, histamine synthesis and phosphorylation of pleckstrin (47 kDa; P47) and myosin light chain (20 kDa; P20) proteins were monitored. Staurosporine inhibited PMA- and collagen-induced aggregation, histamine synthesis and phosphorylation of 47 kDa and 20 kDa proteins in a dose-dependent manner. For PMA, median inhibitory concentrations (IC50 values) for staurosporine inhibition of aggregation, histamine synthesis and phosphorylation were similar, suggesting that histamine synthesis induced by this agonist may be a consequence of PKC activation. Conversely, collagen-stimulated histamine synthesis was inhibited by staurosporine at concentrations significantly higher than those required to inhibit aggregation (P less than 0.005) or pleckstrin phosphorylation (P less than 0.01), indicating the possible involvement of non-PKC mechanism(s) in the synthesis of histamine induced by this agonist. A23187 failed to induce the synthesis of intracellular histamine in platelets, whereas staurosporine blocked A23187-induced aggregation and phosphorylation of the 20 kDa protein at significantly higher concentrations than those needed to inhibit PKC. When platelets were stimulated with a combination of A23187 and PMA, the increase in platelet histamine was less than that with PMA alone. The results provide evidence that the synthesis of intracellular histamine in platelets occurs as a consequence of PKC activation and may be down-regulated under conditions where there is a substantial rise in [Ca2+]i.
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PMID:Synthesis of intracellular histamine in platelets is associated with activation of protein kinase C, but not with mobilization of Ca2+. 189 34

Calcitriol-induced differentiation of U937 mononuclear phagocytes is known to have divergent effects on the synthesis of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-2 (PAI-2). In this study, we sought to determine whether calcitriol affects the expression of these proteins by modulating intermediate signal transduction involving intracellular calcium and protein kinase C (PKC). U937 cells were stimulated with calcitriol (50 nM) for 6-72 hr, inducing a transient increase in specific binding of [3H]phorbol dibutyrate ([3H]PDBu), seen only after 24 hr. Staurosporine (2 nM), a PKC inhibitor, had no effect on calcitriol-induced secretion of plasminogen activator (PA) activity. However, staurosporine significantly (P less than 0.05) inhibited the ability of calcitriol to enhance phorbol myristate acetate (PMA)-induced secretion of PA inhibitor activity, indicating that this priming effect of calcitriol requires expression of PKC. The calcium ionophore A23187 (0.1 microM) induced a modest increase in secreted PA inhibitor activity, in contrast to the secretion of PA activity which is consistently seen in response to calcitriol. Northern blot analysis demonstrated that A23187 induced an increase in PAI-2 mRNA and a marked reduction in uPA mRNA, while calcitriol induced opposite changes in both mRNA species. We conclude that calcitriol modulates uPA and PAI-2 expression by multiple mechanisms that are both PKC dependent and PKC independent. Our studies also demonstrated that increased intracellular calcium alters the synthesis of both uPA and PAI-2 in a manner which favors expression of PA inhibitor activity.
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PMID:Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2. 190 5

The activation of protein kinase C by endotoxic lipid A was observed with both intact platelets and in a cell-free system [Romano & Hawiger (1990) J. Biol. Chem. 265, 1765-1770]. We have now studied the action of lipid A on intracellular Ca2+ concentration ([Ca2+]i). Lipid A induced a concentration-dependent rise in [Ca2+]i in human platelets loaded with fura-2, which reached a maximum at 37.1 +/- 3.8 s (tmax). Maximum [Ca2+]i levels, observed at 30 microM lipid A, were 432 +/- 60 nM. EGTA (2 mM) or NiCl2 (1 mM) each decreased the lipid A-dependent elevation of [Ca2+]i by 50-60% without significant modification of tmax, but shortening the time for 50% recovery (t50) from greater than 400 s to 113.1 +/- 29.1 s and 54 +/- 2.1 s, respectively. Quenching of the fura-2 signal was also observed in lipid A-stimulated platelets resuspended with MnCl2 (1 mM), suggesting that both mobilization and external influx of Ca2+ occur. Intracellular Ca2+ mobilization depended on release from Ins(1,4,5)P3-sensitive stores, since Ins(1,4,5)P3 accumulation was detected in lipid A-activated platelets. Staurosporine, an inhibitor of protein kinase C, blocked the [Ca2+]i rise generated by lipid A in platelets [concn. giving 50% inhibition (IC50) = 0.1 microM], prolonging the tmax. to 54.7 +/- 5.1 s, but decreasing the t50 to 157.5 +/- 31.8 s. Staurosporine also suppressed InsP3 accumulation (IC50 = 0.15 microM). These results suggest that platelet activation by lipid A involves an interaction between [Ca2+]i elevation and protein kinase C activation.
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PMID:Endotoxic lipid A induces intracellular Ca2+ increase in human platelets. 190 16

The mechanisms whereby bacterial endotoxins stimulate arachidonic acid metabolism in macrophages are uncertain. Both protein kinase C activation and de novo protein synthesis occur in macrophages in response to endotoxin. In this study we evaluated the time course and role of protein kinase C and de novo protein synthesis in endotoxin stimulated arachidonic acid metabolism in resident rat peritoneal macrophages. Thromboxane (TX) B2 was measured as the representative arachidonic acid metabolite synthesized in response to Salmonella enteritidis endotoxin, calcium ionophore A23187, or phorbol 12-myristate 13-acetate (PMA). The effect of inhibition of protein kinase C by 1-(5-isoquinolinsulfonyl)-2-methylpiperazine dihydrochloride (H-7) and staurosporine on endotoxin- and A23187-induced TXB2 synthesis was examined. The potential roles of transcriptional and translational events in endotoxin- and A23187-stimulated TXB2 synthesis were determined by utilizing the transcriptional inhibitors camptothecin (10 microM) or actinomycin D (0.08 microM), and the translational inhibitor cycloheximide (0.1 microM). Whereas, A23187 stimulated maximal TXB2 synthesis within 15 min, endotoxin showed a more prolonged time course with a 12-fold increase in TXB2 synthesis above basal levels after 3 h (P less than 0.05). PMA induced an approx. 8-fold increase above basal TXB2 levels that was blocked by inhibition of transcription with actinomycin D. H-7 (10 microM to 50 microM) inhibited endotoxin- and A23187-stimulated eicosanoid synthesis. Staurosporine (0.2 microM) produced a selective 66% inhibition of endotoxin, but not A23187-stimulated TXB2 synthesis. Endotoxin-induced TXB2 production was significantly (P less than 0.05) inhibited by staurosporine, camptothecin, actinomycin D or cycloheximide at intervals from 30 min prior to, through 60 min after endotoxin stimulation. These studies suggest a role for protein kinase C activation and de novo protein synthesis in endotoxin signal transduction events leading to increased macrophage arachidonic acid metabolism. These intracellular events are essential in sustaining the prolonged inflammatory response to endotoxin.
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PMID:Endotoxin-induced arachidonic acid metabolism requires de novo protein synthesis and protein kinase C activation. 190 97

Recombinant monocyte-chemotactic and activating factor (rMCAF; alternative acronyms MCP-1, TDCF, human JE) induced migration of human monocytes across polycarbonate or nitrocellulose filters. Maximal induction of migration was observed at a concentration of 10 ng/ml (10(-9) M). Checkerboard analysis revealed that rMCAF elicited true gradient-dependent chemotactic migration, although a gradient independent chemokinetic effect was observed at low concentrations (1-5 ng/ml). rMCAF caused a rapid (less than 5 s) and transient (approximately 1.5 min) increase of free cytosolic Ca2+ ions, as assessed by the fura-2 probe. No Ca2+ increase was detected in neutrophils or lymphocytes stimulated by rMCAF. Studies conducted in the absence of extracellular Ca2+ or in the presence of Ni2+ (an inhibitor of Ca2+ influx) suggested that the increase of intracellular Ca2+ induced by rMCAF is dependent on the influx of extracellular Ca2+ through plasma membrane channels. Bordetella pertussis toxin inhibited the intracellular Ca2+ elevation and chemotaxis caused by rMCAF. The possible involvement of Ca(2+)-dependent protein kinases in rMCAF signaling pathway(s) was explored using inhibitors. Inhibitors of GMP-dependent kinase and myosin L chain kinase had no effect on rMCAF-induced monocyte migration. In contrast, protein kinase C/cAMP-dependent kinase inhibitors (such as, C-I, H-7, HA-1004, KT5720, and Staurosporine) markedly decreased rMCAF induced chemotaxis suggesting the involvement of a serine/threonine protein kinase, possibly protein kinase C, in rMCAF signaling pathway.
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PMID:The signal transduction pathway involved in the migration induced by a monocyte chemotactic cytokine. 191 57

The M current, IM, a voltage-dependent non-inactivating K current, was recorded in NG108-15 neuroblastoma x glioma hybrid cells, using the whole-cell mode of the patch-clamp technique. We studied inhibition of the M current by bradykinin, phorbol dibutyrate (PDBu), an activator of protein kinase C (PKC), and methylxanthines. Focal application of 0.1-5 microM bradykinin inhibited IM by about 60%; 5 nM bradykinin inhibited by about 40%. Bath application of 0.1 microM and 1 microM PDBu diminished IM to about half of the control value. Staurosporine, a PKC inhibitor, applied for 35-43 min in a concentration of 0.3 microM significantly reduced the effect of 1 microM PDBu. M current blockage by PDBu could be partly reversed by bath application of H-7 (51-64 microM), another PKC inhibitor. These observations suggest that the PDBu effect is really due to activation of PKC. The findings are compatible with the view [Brown DA, Higashida H (1988) J Physiol (Lond) 397:185-207] that the bradykinin effect on IM is mediated by PKC. However, three further observations suggest that this is only true for part of the bradykinin effect. When the suppression of IM by 1 microM PDBu was fully developed, 0.1 microM bradykinin produced a further inhibition of IM. Down-regulation of PKC by long-term treatment with PDBu reduced the effect of 0.1 microM bradykinin significantly but did not abolish it. Staurosporine (0.3 microM, applied for 31-46 min) failed to reduce the effect of 5 nM bradykinin significantly. The M current could be reversibly blocked by methylxanthines (caffeine, isobutyl-methylxanthine, theophylline) in the millimolar range, probably because of a direct action on the M channels.
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PMID:Inhibition of the M current in NG 108-15 neuroblastoma x glioma hybrid cells. 194 51

We have examined the effect of inhibition of protein kinase C activity by staurosporine on estradiol secretion by Sertoli cells isolated from 8-10 days old rats. Staurosporine lead to a dose-related increase in estradiol secretion independent of FSH, such that with 100 nmol/l staurosporine basal estradiol levels increased 10-fold. The maximal response seen with staurosporine alone (100 nmol/l) or in combination with FSH (0.4-8 IU/l) was similar to that seen with a saturating dose of FSH (8 IU/l). There was no evidence of synergy between FSH and staurosporine. Activation of protein kinase C by phorbol 12,13 dibutyrate (10(-7) mol/l) resulted in a 53-74% inhibition of estradiol production provoked by FSH (8 IU/l), staurosporine (5-100 nmol/l) or staurosporine in combination with FSH. Staurosporine (5-100 nmol/l), in the absence or presence of FSH, was unable to overcome inhibition of estradiol secretion by phorbol ester, indicating the presence of at least two independent binding sites on protein kinase C for these molecules. Forskolin (1 mumol/l)- and dibutyryl cAMP (1 mmol/l)-stimulated estradiol secretion was inhibited by 31 +/- 5% and 64 +/- 5% respectively, by phorbol 12,13 dibutyrate (10(-7) mol/l). We conclude that FSH-induced estradiol secretion in immature rat Sertoli cells is affected by protein kinase C activity.
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PMID:Inhibition of protein kinase C by staurosporine increases estrogen secretion by rat Sertoli cells. 195 Mar 41

The effect of staurosporine, a putative inhibitor of protein kinase C (PKC), on insulin secretion induced by glucose and 4-methyl-2-oxopentanoate (KIC) was examined. In addition, the effects of staurosporine on the actions of other agonists, for which glucose acts as a conditional modifier, were also examined. At 20 nM, staurosporine caused a marked inhibition of second-phase insulin secretion, whether it was stimulated by 10 mM- or 20 mM-glucose, by 15 mM-KIC, or by carbachol or tolbutamide in islets co-perifused with 7.0 mM-glucose. In each case, the second-phase secretory response was inhibited by 70-85%. In contrast, in all cases there was no effect of staurosporine on the magnitude of the first phase of insulin secretion, nor on the time course of first-phase secretion, except when glucose alone was the secretagogue. With either 10 mM- or 20 mM-glucose, the peak of the first phase of insulin secretion was delayed. Staurosporine does not alter glucose metabolism, or the ability of glucose to activate phosphoinositide hydrolysis or to cause the translocation of alpha-PKC to the membrane. These findings support the concept that PKC activation plays an important role in fuel-induced or fuel-conditioned insulin secretion.
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PMID:Influence of staurosporine on glucose-mediated and glucose-conditioned insulin secretion. 195 75

Staurosporine, an inhibitor of protein kinase C (PKC), has been shown to inhibit the induction of two cytosolic proteins, p42 and p91, during the differentiation of HL-60 cells initiated by PMA treatment. Differentiation of these cells into macrophages was also blocked. p42 has been identified as actin by Western Blot analysis and previous studies have demonstrated p91 to be the Ca+(+)-dependent actin-binding protein gelsolin. Increased levels of these proteins may be important for the attainment of macrophage functions, e.g. phagocytosis and secretion. These studies may therefore establish a link between PKC activation and the induction of specific cellular proteins, such as actin and gelsolin, as important monocyte maturation products without which the cells will be restricted from acquiring certain macrophage activities.
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PMID:Effect of staurosporine on the induction of actin/gelsolin in PMA-treated HL-60 cells. 196 74

Considerable evidence suggests that protein kinase C activation participates in the regulation of vascular smooth muscle tone. The objective of the current study was to examine the relations between inhibition of protein kinase C (PKC) and myosin light-chain kinase (MLCK) and vasorelaxation and blood pressure regulation in spontaneously hypertensive rats (SHR). Putative PKC inhibitors from two chemical classes, staurosporinelike (staurosporine and K252A) and isoquinolinesulfonamides (H7 and HA1004), were tested for their ability to 1) inhibit PKC and MLCK from SHR aorta, 2) relax isolated SHR aorta, and 3) lower blood pressure in conscious SHR. A rank order of potency for the inhibition of PKC and MLCK was established, with the staurosporinelike compounds (staurosporine PKC IC50 = 54 nM) clearly more potent than the isoquinolinesulfonamides (H7 PKC IC50 = 128 microM). The rank order of potency for inhibition of PKC was retained for inhibition of MLCK for all compounds. Staurosporine (EC50 = 75 nM) and H7 (EC50 = 2 microM) caused concentration-dependent relaxation of SHR aorta, but only staurosporine produced vasorelaxation at concentrations consistent with the inhibition of PKC or MLCK. Dose-dependent reductions in arterial pressure of SHR were demonstrated after intravenous injection of staurosporine and HA1004. A single intravenous injection of staurosporine (0.3 mg/kg) lowered blood pressure for more than 10 hours. Staurosporine also lowered blood pressure after oral administration. The depressor response to staurosporine was unaffected by sympathetic beta-adrenergic blockade. In conclusion, the vasorelaxant and antihypertensive actions of staurosporine in SHR are consistent with the inhibition of PKC but could also be equally related to inhibition of MLCK. Not all PKC inhibitors produce vasorelaxation and lower blood pressure. Moreover, the lack of correlation between in vitro vasodilation and PKC or MLCK inhibition for the isoquinolinesulfonamide protein kinase inhibitors H7 and HA1004 suggests that these agents do not cause vasorelaxation in SHR by inhibition of these enzymes.
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PMID:Protein kinase inhibitors and blood pressure control in spontaneously hypertensive rats. 198 86


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