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)

The role of protein kinase C (PKC) in the desensitization of muscarinic receptor-mediated responses in bovine ciliary muscle was examined. Exposure of the bovine ciliary muscle to phorbol esters, used to activate PKC, resulted in antagonism of muscarinic receptor-mediated contraction. On the other hand, staurosporine, a known PKC inhibitor, caused a significant potentiation of the contractile effect induced by carbachol. Staurosporine reduced the desensitization induced by repeated additions of carbachol and completely suppressed that induced by phorbol esters. The results also indicate that desensitization mediated by phorbol esters as well as that mediated by muscarinic receptor agonists is heterologous.
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PMID:Evidence for protein kinase C modulation of the ciliary muscle response to carbachol and desensitization. 172 56

Insulin and insulin-like growth factor I promote the growth of rat neuronal cells in primary culture. In order to investigate the mechanism of hormone signalling in this biological system, we studied the effect of cyclic AMP agonists and a protein kinase C stimulator on basal and hormone-induced RNA synthesis. Agents elevating endogenous cyclic AMP levels (forskolin, dibutyryl cyclic AMP, cholera toxin) blocked the stimulatory effects of both insulin and the growth factor; dibutyryl cyclic AMP, however, altered the binding of neither hormone. Although, unlike the aforementioned agents, phorbol ester significantly elevated basal RNA synthesis; it nevertheless inhibited the stimulation by insulin; this latter effect probably being mediated by an increase in intracellular cyclic AMP levels, as has been found in other cell types. Staurosporine, an inhibitor of protein kinase C, also blocked the effects of insulin on RNA synthesis.
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PMID:Insulin and IGF-I stimulated RNA synthesis in primary cultures of neuronal cells: involvement of cyclic AMP and protein kinase-C. 172 9

A polyclonal antiserum raised against an oligopeptide with an amino acid sequence corresponding to a sequence of the myristoylated alanine-rich C-kinase substrate (MARCKS) from mouse macrophages and rat brain recognizes the 80-kDa C-kinase substrate from Swiss 3T3 fibroblasts. Using this antiserum for quantitative determination of the 80-kDa MARCKS-related protein, we found that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a rapid down-regulation of this protein in the fibroblasts. In accordance with earlier reports, TPA causes phosphorylation of the 80-kDa protein which can be inhibited by staurosporine. Staurosporine also suppresses the TPA-induced down-regulation, possibly indicating that the down-regulation of the MARCKS-related protein is dependent on its phosphorylation by protein kinase C.
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PMID:Phorbol ester-induced down-regulation of the 80-kDa myristoylated alanine-rich C-kinase substrate-related protein in Swiss 3T3 fibroblasts. Inhibition by staurosporine. 173 May 92

We assessed the specificity of staurosporine, a putative protein kinase C inhibitor, for the enzyme in intact porcine coronary arteries by examining its effects on changes in intracellular free calcium level ([Ca++]i) and force induced by a phorbol ester, high KCl and caffeine. [Ca++]i was measured simultaneously with force by the fura-2 microfluorimetric method. Phorbol 12,13-dibutyrate (PDBu, 10(-6) M) produced a slowly developing and sustained contraction; however, [Ca++]i only increased slightly and transiently in the initial phase and then decreased gradually. On the other hand, 90 mM KCl elicited a contraction with a sustained increase in [Ca++]i. Staurosporine (10(-10) to 10(-7) M) applied 20 min before the addition of PDBu inhibited the PDBu-induced changes in [Ca++]i and force in a concentration-dependent manner. In contrast, staurosporine only at 10(-7) M reduced an increase in [Ca++]i and contractile force produced by 90 mM KCl. The inhibitory effects of staurosporine on PDBu- and KCl-induced contractions depended on exposure time. The [Ca++]i-force relationship obtained with variable concentrations of KCl was shifted slightly to the right by staurosporine at 10(-7) M. Furthermore, staurosporine even at 10(-7) M did not affect an increase in [Ca++]i by caffeine (25 mM), although it slightly attenuated a caffeine-induced contraction. These results suggest that staurosporine is a relatively specific inhibitor of protein kinase C in intact arteries at lower concentrations. At higher concentrations it may have actions unrelated to its inhibitory effect of protein kinase C, which include the inhibition of calcium influx into smooth muscle cells through the voltage-dependent Ca++ channel.
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PMID:Is staurosporine a specific inhibitor of protein kinase C in intact porcine coronary arteries? 176 58

Basic Fibroblast Growth Factor (bFGF) is shown to be a potent mitogen for cultured glomerular mesangial cells. bFGF induces an increase in cell number and stimulates DNA synthesis measured by [3H]thymidine incorporation in normal as well as in protein kinase C-depleted cells. The ED50 observed in both cases are nearly identical (approximately 0.04 nM) and maximal responses are obtained at 1 nM. Staurosporine, a potent protein kinase C inhibitor, does not prevent bFGF from inducing mitogenesis. On the contrary, the tumour promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and the bradykinin derivative Des-Arg9bradykinin that we have previously shown as mitogens for mesangial cells, fail to trigger DNA synthesis or cell proliferation upon staurosporine treatment or in protein kinase C-depleted cells. bFGF is unable to induce the association of the enzyme to membranes, the so-called translocation process, although the growth factor induces a slight production of diacylglycerol. Using a highly resolutive two-dimensional electrophoresis, we show that bFGF, in contrast to TPA, is unable to stimulate the phosphorylation of a Mr 80,000/pI 4.5 protein, a major and specific protein kinase C substrate. By contrast, bFGF stimulates the phosphorylation of a Mr 28,000/pI 5.7-5.9 protein in normal as well as in protein kinase C-depleted cells while TPA induces this protein phosphorylation only in normal cells. Our results suggest that bFGF exerts its proliferative action on mesangial cells through a protein kinase C-independent pathway and that the growth factor does not activate anyway the enzyme in this cell type.
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PMID:Basic fibroblast growth factor stimulates glomerular mesangial cell proliferation through a protein kinase C-independent pathway. 177 35

Human U-937 leukemia cells differentiate along the monocytic lineage following 3-day exposures to 12-O-tetradecanoylphorbol-13-acetate (TPA). This induction of differentiation is accompanied by adherence and loss of proliferation, as well as expression/repression of differentiation-associated genes. Long term culture of TPA-differentiated U-937 cells in the absence of phorbol ester for 32-36 days resulted in a process of retrodifferentiation. The retrodifferentiated cells detached from the substrate and reinitiated proliferation. Other cellular parameters, such as glycosidase activities, cytokine release, and filament expression, returned to levels similar to that observed in uninduced cells. Treatment of U-937 cells with TPA resulted in a rapid translocation of protein kinase C (PKC) from the cytosol to cell membrane fractions within 2-8 min. Increased levels of membrane-associated PKC activity persisted until 17-29 days. However, longer periods of incubation were associated with a return to the distribution of PKC in control cells. Activation of PKC has been implicated in the regulation of certain immediate early response genes, and in the present studies, TPA rapidly induced c-fos and c-jun gene expression. Levels of c-fos and c-jun transcripts remained elevated during periods of PKC activation and also returned to levels observed in control cells by 30-36 days, when the cells entered retrodifferentiation. Staurosporine, a nonspecific inhibitor of PKC, partially blocked TPA-induced adherence and growth inhibition and concomitantly prevented TPA-induced c-fos and c-jun gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C activation and protooncogene expression in differentiation/retrodifferentiation of human U-937 leukemia cells. 181 34

When rat pleural mononuclear leukocytes were stimulated with 1 microM phorbol myristate acetate (PMA), platelet-activating factor (PAF)-like activity was detected in the supernatant and the cellular fractions of the incubation mixture, as measured by rabbit platelet aggregation. C16PAF activity peaked at 30 min in both fractions. Acetyltransferase activity in the microsomal fraction of the stimulated cells also increased rapidly and showed a peak at 10 min. A protein kinase C inhibitor, staurosporine, and an inhibitor of phospholipase A2, p-bromophen-acylbromide, inhibited stimulated PAF formation in both fractions. Staurosporine also inhibited PMA induced acetyltransferase activity. The data suggest that PMA stimulates PAF synthesis by the remodeling pathway in rat pleural cells through activation of both phospholipase A2 and acetyltransferase, and that the acetyltransferase, in turn, may be activated through activation of protein kinase C.
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PMID:Phorbol ester stimulates PAF synthesis via the activation of protein kinase C in rat leukocytes. 181 89

Lysophosphatidylcholine (lyso-PC), a natural product of phospholipase A2 activity, induced the secretion of both granule-associated beta-hexosaminidase and newly generated leukotriene C4 from mouse bone marrow-derived mast cells. Micromolar concentrations of lyso-PC potentiated the release of beta-hexosaminidase induced by specific antigen but not the calcium ionophore, A23187. Exogenous adenosine was relatively ineffective in enhancing beta-hexosaminidase release from cells challenged with lyso PC. Lyso-PC caused a marked increase in intracellular free-calcium levels and induced the activation of protein kinase C (PKC). These effects could not be abrogated by a prolonged preincubation with pertussis toxin. Staurosporine, an inhibitor of PKC, partially inhibited the abilities of antigen and A23187 to induce beta-hexosaminidase release but was ineffective when lyso-PC was the secretagogue. Lyso-PC appears to activate mast cell PKC, but its ability to stimulate mast cell mediator release appears to be related to its ability to elevate intracellular free calcium concentrations.
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PMID:Lysophosphatidylcholine induces mast cell secretion and protein kinase C activation. 183 66

1. Desensitization of the Ca2+ release response evoked by acetylcholine in acinar cells from rat lacrimal glands was studied using the Ca(2+)-sensitive dye Fura-2. The evolution of the amplitude and half-maximal rise time (t1/2) of the Ca2+ response was followed as a function of trial number in a series of stimulations. 2. Under control conditions repetitive applications of acetylcholine (15 s long applications every minute) led to a linear decrease of the amplitude and to a linear increase of t1/2 with trial number. Both amplitude and t1/2 recovered their control values after 20 min of washing. 3. Staurosporine (0.2-1 microM), an inhibitor of protein kinase C, was found to decrease the slopes of the variation of amplitude and t1/2 with trial number. 4. Prolonged treatment with 12-O-tetradecanoyl phorbol 13-acetate (TPA), an activator of protein kinase C (100-250 nM for 2-4 h), also led to a markedly decreased desensitization, presumably as a result of down-regulation of protein kinase C. On the other hand moderate pre-treatments with TPA (16-32 nM for 10 min) strongly inhibited the response, most probably as a result of protein kinase C activation. 5. Application of oleoylacetylglycerol (50 microM), a weaker activator of protein kinase C, inhibited the response and enhanced desensitization. These effects were, however, not obtained after down-regulation of protein kinase C with strong exposure to TPA. 6. We conclude that protein kinase C activation following the ACh-induced Ca2+ rise and the concomitant diacylglycerol production mediates desensitization of the response. 7. Arachidonic acid (100 microM) inhibited the ACh-induced response and enhanced desensitization. However, this effect did not appear to be mediated by protein kinase C since it was also obtained with docosahexaenoic acid, an analogue of arachidonic acid which does not activate protein kinase C.
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PMID:Protein kinase C-mediated desensitization of the muscarinic response in rat lacrimal gland cells. 184 45

These experiments examined the mechanism by which phenylephrine enhances beta-adrenoceptor-stimulated cyclic AMP formation in rat hypothalamic and preoptic area slices. To this end we manipulated phospholipase C. phospholipase A2, and protein kinase C activity in slices and assessed the effects of these manipulations on phenylephrine augmentation of isoproterenol-stimulated cyclic AMP generation. Since previous work indicated that estrogen enhances the alpha 1-component of cyclic AMP formation, we examined slices from both gonadectomized and estrogen-treated animals. The alpha 1-antagonist prazosin eliminated phenylephrine augmentation of the beta-response, suggesting that alpha 1-adrenergic receptors mediate the potentiation of cyclic AMP formation. Inhibition of protein kinase C by H7 attenuated the alpha 1-augmentation of beta-stimulated cyclic AMP formation. Staurosporine, a more potent protein kinase C inhibitor, completely abolished the alpha 1-augmenting response. In addition, phenylephrine potentiation of the isoproterenol response was not observed if protein kinase C was first stimulated directly with a synthetic diacylglycerol (1-oleoyl-2-acetyl-sn-glycerol) or phorbol ester (phorbol 12,13-dibutyrate). Neomycin, an inhibitor of phospholipase C, decreased alpha 1-receptor enhancement of beta-stimulated cyclic AMP formation, whereas quinacrine, an inhibitor of phospholipase A2, did not. The data suggest that the postreceptor mechanism involved in alpha 1-adrenergic receptor potentiation of cyclic AMP generation in hypothalamic and preoptic area slices includes activation of phospholipase C and protein kinase C.
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PMID:Protein kinase C and phospholipase C mediate alpha 1- and beta-adrenoceptor intercommunication in rat hypothalamic slices. 184 2


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