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

1. In this study, the underlying mechanism of stimulation of respiratory burst by kazinol B, a natural isoprenylated flavan, in rat neutrophils in vitro was investigated. 2. Kazinol B concentration-dependently stimulated the superoxide anion (O2*-) generation, with a lag but transient activation profile, in neutrophils but not in a cell-free system. The maximum response (13.2+/-1.4 nmol O2*- 10 min(-1) per 10(6) cells) was observed at 10 microM kazinol B. 3. Pretreatment of neutrophils with phorbol 12-myristate 13-acetate (PMA) or formylmethionyl-leucyl-phenylalanine (fMLP) significantly enhanced the O2*- generation following the subsequent stimulation of cells with kazinol B. 4. Cells pretreated with EGTA or a protein kinase inhibitor staurosporine effectively attenuated the kazinol B-induced O2*- generation. However, a p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and a phosphoinositide 3-kinase (PI3K) inhibitor wortmannin had no effect on the kazinol B-induced response. 5. Kazinol B significantly stimulated [Ca2+]i elevation in neutrophils, with a lag and slow rate of rise activation profile, and this response was attenuated by a phospholipase C (PLC) inhibitor U73122. Kazinol B also stimulated the inositol bis- and trisphosphate (IP2 and IP3) formation with a 1 min lag time. 6. The membrane-associated PKC-alpha and PKC-theta but not PKC-iota were increased following the stimulation of neutrophils with kazinol B. It was more rapid and sensitive in the activation of PKC-theta than PKC-alpha by kazinol B. Kazinol B partially inhibited the [3H]phorbol 12,13-dibutyrate ([3H]PDB) binding to the neutrophil cytosolic PKC. 7. Neither the cellular mass of phosphatidic acid (PA) and phosphatidylethanol (PEt), in the presence of ethanol, nor the protein tyrosine phosphorylation were stimulated by kazinol B. In addition, the kazinol B-induced O2*- generation remained relatively unchanged in cells pretreated with ethanol or a tyrosine kinase inhibitor genistein. 8. Collectively, these results indicate that the stimulation of the respiratory burst by kazinol B is probably mediated by the synergism of PKC activation and [Ca2+]i elevation in rat neutrophils.
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PMID:The signal transduction mechanism involved in kazinol B-stimulated superoxide anion generation in rat neutrophils. 980 35

We recently reported that bile salts play a role in the regulation of mucin secretion by cultured dog gallbladder epithelial cells. In this study we have examined whether bile salts also influence mucin secretion by the human epithelial colon cell line LS174T. Solutions of bile salts were applied to monolayers of LS174T cells. Mucin secretion was quantified by measuring the secretion of [3H]GlcNAc labeled glycoproteins. Both unconjugated bile salts as well as taurine conjugated bile salts stimulated mucin secretion by the colon cells in a dose-dependent fashion. Hydrophobic bile salts were more potent stimulators than hydrophilic bile salts. Free (unconjugated) bile salts were more stimulatory compared with their taurine conjugated counterparts. Stimulation of mucin secretion by LS174T cells was found to occur at much lower bile salt concentrations than in the experiments with the dog gallbladder epithelial cells. The protein kinase C activators PMA and PDB had no stimulatory effect on mucin secretion. We conclude that mucin secretion by the human colon epithelial cell line LS174T is regulated by bile salts. We suggest that regulation of mucin secretion by bile salts might be a common mechanism, by which different epithelia protect themselves against the detergent action of bile salts, to which they are exposed throughout the gastrointestinal tract.
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PMID:Mucin secretion by the human colon cell line LS174T is regulated by bile salts. 988 2

In this study, the underlying mechanisms of stimulation by cyclocommunin, a natural pyranoflavonoid, of respiratory burst in rat neutrophils was investigated. Cyclocommunin evoked a concentration-dependent stimulation of superoxide anion (O2*-) generation with a slow onset and long lasting profile. The maximum response (16.4+/-2.3 nmol O2*-/10 min per 10(6) cells) was observed at 3-10 microM cyclocommunin. Cyclocommunin did not activate NADPH oxidase in a cell-free system. Cells pretreated with pertussis toxin or n-butanol did not affect the cyclocommunin-induced O2*- generation. However, a protein kinase inhibitor staurosporine and EGTA greatly reduced the O2*-generation caused by cyclocommunin. Treatment of neutrophils with phorbol 12-myristate 13-acetate (PMA), but not with formylmethionyl-leucyl-phenylalanine (fMLP), for 20 min significantly reduced the O2*- generation following the subsequent stimulation of cells with cyclocommunin. Cyclocommunin did not affect the cellular mass of phosphatidic acid (PA). Neither the tyrosine kinase inhibitor, genistein, nor the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, affected cyclocommunin-induced O2*- generation. The enzyme activities of neutrophil cytosolic and membrane-associated protein kinase C (PKC) were both increased significantly with 100 microM cyclocommunin. The membrane-associated PKC-theta and PKC-beta were increased following the stimulation of neutrophils with 30 and 100 microM cyclocommunin, respectively. Cyclocommunin reduced the [3H]phorbol 12,13-dibutyrate ([3H]PDB) binding to cytosolic PKC in a concentration-dependent manner. Cyclocommunin (> or =3 microM) significantly evoked a slow and long lasting [Ca2+]i elevation in neutrophils, and a phospholipase C (PLC) inhibitor U73122 greatly inhibited these Ca2+ responses. Moreover, the increase in cellular inositol bis- and trisphosphate (IP2 and IP3) levels were observed in neutrophils stimulated with 30 microM cyclocommunin for 3 min. Collectively, these results indicate that the stimulation of respiratory burst by cyclocommunin is probably mediated by the synergism of PKC activation and [Ca2+]i elevation in rat neutrophils.
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PMID:Stimulation of respiratory burst by cyclocommunin in rat neutrophils is associated with the increase in cellular Ca2+ and protein kinase C activity. 1021 46

Previous investigations have shown that phorbol esters stimulate process extension in oligodendrocytes (OL), likely by the activation of protein kinase C (PKC). In this report, we demonstrate that treatment of OL with 4beta-phorbol-12, 13-dibutyrate (PDB; 0.1-1 microM) resulted in an increase in intracellular Ca2+ concentration ([Ca2+]i) from 94+/-2 nM (mean+/-S.E.M.) to 244+/-10 nM. This increase was produced by Ca2+ influx through a La3+-insensitive pathway. Changes in [Ca2+]i were also produced by modifying the extracellular Ca2+ concentration ([Ca2+]o) where [Ca2+]i was increased by elevations in [Ca2+]o. In parallel experiments we found that increased [Ca2+]o alone, without concurrent phorbol ester application, resulted in increased OL process extension as determined by the percent of OL with long processes (greater than 3 times the cell body diameter). These results demonstrate that increasing [Ca2+]o stimulates OL process outgrowth. Furthermore, both elevations in [Ca2+]o and PDB exposure increase [Ca2+]i, suggesting that some of the effects of phorbol esters on OL process extension are likely mediated by changes in [Ca2+]i.
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PMID:Process extension and intracellular Ca2+ in cultured murine oligodendrocytes. 1032 Jun 89

The present study used structurally distinct phorbol esters to investigate the relationship between their pharmacokinetics of binding to protein kinase C (PKC) in rat brain cortex synaptosomes, their affinity for PKC in synaptosomes and ability to enhance noradrenaline release from rat brain cortex. Affinity binding studies using [3deoxyphorbol 13-tetradecanoate (dPT)=PDB&z. Gt;12-deoxyphorbol 13-acetate (dPA)=phorbol 12,13-diacetate (PDA). In intact synaptosomes PDB, dPA and PDA rapidly displaced bound [3H]PDB whereas PMA and dPT were comparatively slow. However, the displacement rates for all the phorbol esters were equally rapid in synaptosomal membranes or synaptosomes permeabilised with Staphylococcus alpha-toxin. These results suggest that the lipophilic phorbol esters (dPT and PMA) are slower to displace [3H]PDB binding because they are hindered by the plasma membrane. In brain cortex slices it was found that the rate of displacement of [3H]PDB binding was closely correlated with the degree of elevation of transmitter noradrenaline release. Thus kinetic characteristics may determine biological responses and this may be particularly evident in events which occur rapidly or where there is fast counter-regulation.
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PMID:Structural determinants of phorbol ester binding in synaptosomes: pharmacokinetics and pharmacodynamics. 1052 37

Protein kinase D (PKD) is a protein serine kinase that is directly stimulated in vitro by phorbol esters and diacylglycerol in the presence of phospholipids, and activated by phorbol esters, neuropeptides, and platelet-derived growth factor via protein kinase C (PKC) in intact cells. Recently, oxidative stress was shown to activate transfected PKC isoforms via tyrosine phosphorylation, but PKD activation was not demonstrated. Here, we report that oxidative stress initiated by addition of H(2)O(2) (0.15-10 mm) to quiescent Swiss 3T3 fibroblasts activates PKD in a dose- and time- dependent manner, as measured by autophosphorylation and phosphorylation of an exogenous substrate, syntide-2. Oxidative stress also activated transfected PKD in COS-7 cells but not a kinase-deficient mutant PKD form or a PKD mutant with critical activating serine residues 744 and 748 mutated to alanines. Genistein, or the specific Src inhibitors PP-1 and PP-2 (1-10 micrometer) inhibited H(2)O(2)-mediated PKD activation by 45%, indicating that Src contributes to this signaling pathway. PKD activation by H(2)O(2) was also selectively potentiated by cotransfection of PKD together with an active form of Src (v-Src) in COS-7 cells, as compared with PDB-mediated activation. The specific phospholipase C inhibitor, partly blocked H(2)O(2)-mediated but not PDB-mediated PKD activation. In contrast, PKC inhibitors blocked H(2)O(2) or PDB-mediated PKD activation essentially completely, suggesting that whereas Src mediates part of its effects via phospholipase C activation, PKC acts more proximally as an upstream activator of PKD. Together, these studies reveal that oxidative stress activates PKD by initiating distinct Src-dependent and -independent pathways involving PKC.
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PMID:Oxidative stress induces protein kinase D activation in intact cells. Involvement of Src and dependence on protein kinase C. 1074 11

The cytokine interleukin-6 (IL-6) is increased in bone and bone cells by several resorptive stimuli, including parathyroid hormone (PTH), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha). The current studies were designed to determine the contribution of the protein kinase C (PKC) signaling pathway to the effects of these three agents to increase IL-6 in UMR-106 rat osteoblastic cells. Cells were pretreated with vehicle (dimethylsulfoxide [DMSO]) or the phorbol ester, phorbol 12,13-dibutyrate (PDB; 300 nM) for 48 h to down-regulate phorbol-sensitive PKC isozymes. Either PTH (0.1-10 nM), IL-1beta (0.1-10 nM), or TNF-alpha (5 nM and 10 nM) was then added for 24 h in the continued presence of vehicle or PDB. PKC isozymes were visualized by Western immunoblotting and IL-6 was determined by bioassay. PDB pretreatment caused a partial down-regulation of the conventional alpha-PKC and betaI-PKC isozymes and complete down-regulation of the novel delta-isoenzyme and epsilon-isozymes but it had no effect on the atypical zeta-PKC isozyme. PDB pretreatment reduced IL-6 responses to 5 nM and 10 nM PTH by 61% and 33%, respectively, reduced IL-6 responses to 5nM and 10 nM TNF-a by 54% and 42%, respectively, and failed to inhibit the IL-6 responses to 0.1-10 nM IL-1beta. The PDB pretreatment protocol significantly enhanced PTH-stimulated cyclic adenosine monophosphate (cAMP) production. The PKC inhibitor calphostin C also decreased IL-6 responses to PTH. Thus, in this osteoblast cell line, the PKC pathway is an important component of the signaling pathway for the IL-6 production stimulated by PTH and TNF-alpha but not that from IL-1beta.
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PMID:Protein kinase C involvement in interleukin-6 production by parathyroid hormone and tumor necrosis factor-alpha in UMR-106 osteoblastic cells. 1080 18

1. The ability of several phorbol ester protein kinase C (PKC) activators (phorbol 12, 13-dibutyrate, PDB; phorbol 12, 13-diacetate, PDA; and 12-deoxyphorbol 13-acetate, dPA) to down-regulate PKC was studied by assessing their effects on electrical stimulation-induced (S-I) noradrenaline release from rat brain cortical slices and phosphorylation of the PKC neural substrate B-50 in rat cortical synaptosomal membranes. 2. In cortical slices which were incubated for 20 h with vehicle, acute application of PDB, PDA and dPA (0.1 - 3.0 microM) enhanced the S-I noradrenaline release in a concentration-dependent manner to between 200 - 250% of control in each case. In slices incubated with PDB (1 microM for 20 h), subsequent acute application of PDB (0.1 - 3.0 microM) failed to enhance S-I release, indicating PKC down-regulation. However, in tissues incubated with PDA or dPA (3 microM) for 20 h, there was no reduction in the facilitatory effect of their respective phorbol esters or PDB (0.1 - 3.0 microM) when acutely applied, indicating that PKC was not down-regulated. This was confirmed using Western blot analysis which showed that PDB (1 microM for 20 h) but not PDA (3 microM for 20 h) caused a significant reduction in PKCalpha. 3. Incubation with PDB for 20 h, followed by acute application of PDB (3 microM) failed to increase phosphorylation of B-50 in synaptosomal membranes, indicating down-regulation. In contrast, tissues incubated with PDA or dPA for 20 h, acute application of their respective phorbol ester (10 microM) or PDB (3 microM) induced a significant increase in B-50 phosphorylation. 4. Acutely all three phorbol esters elevate noradrenaline release to about the same extent, yet PDA and dPA have lower affinities for PKC compared to PDB, suggesting unique neural effects for these agents. This inability to cause functional down-regulation of PKC extends their unusual neural properties. Their neural potency and lack of down-regulation may be related to their decreased lipophilicity compared to other phorbol esters. 5. We suggest that PKC down-regulation appears to be related to binding affinity, where agents with high affinity, irreversibly insert PKC into artificial membrane lipid and generate Ca(2+)-independent kinase activity which degrades and deplete PKC. We suggest that this mechanism may also underlie the ability of PDB to down-regulate PKC in nerve terminals, in contrast to PDA and dPA.
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PMID:Differential abilities of phorbol esters in inducing protein kinase C (PKC) down-regulation in noradrenergic neurones. 1115 99

We studied the effect of experimental hypercholesterolaemia/atherosclerosis on changes in coronary flow and cardiac function, induced by protein kinase C and ATP-sensitive K(+) (K(ATP)) channel modulators in isolated Langendorff-perfused rabbit hearts. Both phorbol 12-myristate-13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB, 0.1 microM each), activators of protein kinase C, decreased, whereas staurosporine, (0.1 microM), a protein kinase C inhibitor, increased coronary flow and left ventricular dP/dt, an index of ventricular contractility. Glyburide (5-50 microM), a K(ATP) channel inhibitor, blocked the effect of staurosporine. The phorbol esters were without effect in the presence of pinacidil (5 microM), a K(ATP) channel activator. Neither the protein kinase C modulators nor glyburide produced any effect on coronary flow and left ventricular contractility, when the hearts were prepared from animals either maintained on a cholesterol (1.5%)-enriched diet or treated with lovastatin (5 mg/kg/day per os). Treatment with farnesol (1 mg/kg twice a day for 7 days intravenously) restored the reactivity of hearts from either hypercholesterolaemic or lovastatin-treated animals to protein kinase C modulators. We conclude that non-cholesterol mevalonate products are necessary for the functional integrity of the protein kinase C-K(ATP) channel pathway in the rabbit heart.
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PMID:Deterioration of the protein kinase C-K(ATP) channel pathway in regulation of coronary flow in hypercholesterolaemic rabbits. 1134 93

Sodium fluoride (NaF) has previously been reported to induce a strong IL-8 response in human epithelial lung cells (A549) via mechanisms that seem to involve the activation of G proteins. In the present study the signal pathways downstream of the G proteins have been examined. NaF induced a weak, but sustained increase in PKC activity. In contrast, the PKC activator TPA induced a relatively strong, but transient effect and augmented the NaF-induced PKC activity. TPA induced a marked IL-8 response compared to NaF. PDB, another PKC activator, was less effective, but augmented the IL-8 response to NaF. Pretreatment with TPA for 20 h, or the PKC inhibitor GF109203X for 1 h, abolished the basal and NaF-induced PKC activities and partially prevented the NaF-induced IL-8 response. Inhibition of the MAP kinase p38 by SB202190 partially reduced the IL-8 response to NaF, whereas a reduction in ERK activity by PD98059 led to an increased response. The NaF-induced IL-8 response was weakly augmented by the PKA stimulator forskolin and the G(i) inhibitor pertussis toxin. The PKA inhibitor H89 seemed to reduce the NaF-induced IL-8 response, but the measured effect was not statistically significant. BAPTA-AM, KN93 and W7, that inhibit Ca(2+)-linked effects, did not affect the IL-8 response. Furthermore, the tyrosine kinase inhibitor genestein, the PI-3 kinase inhibitor wortmannin and phosphatase inhibition were without effects. In conclusion, the data suggest that NaF-induced increase of IL-8 in A549 cells involved PKC- and p38-linked pathways, whereas an ERK-dependent pathway counteracted the response. Tyrosine kinases, Ca(2+)-linked pathways, PI-3 kinase, PKA and phosphatase inhibition seem to play no or minor roles in the fluoride-induced IL-8 response.
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PMID:Mechanisms in fluoride-induced interleukin-8 synthesis in human lung epithelial cells. 1156 78


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