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)

Treatment of rat submandibular acinar cell extracts with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) caused the dose-dependent activation of protein kinase C (PKC), assessed by the phosphorylation of a novel and highly specific substrate. This effect was duplicated by a diacylglycerol, but not by the 4 alpha-phorbol ester 4 alpha-phorbol 12,13-didecanoate. The TPA elevation of PKC was blocked by the PKC inhibitors H-7 and sangivamycin. In intact cells, TPA caused the translocation of PKC from cytosol to membrane, consistent with its known mode of activation. The beta-adrenergic agonist, isoproterenol, stimulated cAMP levels which were significantly reduced by preactivation of PKC. This inhibitory PKC effect was reversed by H-7. When cAMP was stimulated at the post-receptor level, however, by forskolin, NaF or GTP[gamma S], PKC did not inhibit, but rather enhanced the cyclic nucleotide response. Since PKC phosphorylated an endogenous protein of 55 kDa, the size of the beta 1 receptor, these findings indicate that, as in other cell types, PKC can desensitize adenylate cyclase by direct phosphorylation of the beta receptor, but potentiate the cAMP response by a post-receptor mechanism. In mucin secretion studies in the model, TPA alone caused the cAMP-independent release of up to 44% total mucin, which was much less than additive with the isoproterenol response. When the cAMP-mucosecretory response was stimulated at the adenylate cyclase level by forskolin, however, the TPA + forskolin effects were additive. These findings on the modulation of cAMP by PKC indicate cross-talk regulation in the phosphoinositide-cAMP signal transduction pathways in submandibular acinar cells.
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PMID:Regulation of the cAMP signal transduction pathway by protein kinase C in rat submandibular cells. 132 9

The mucus producing colonic cell line, LS174T, was used as a model to study E. histolytica-induced mucin secretion. E. histolytica trophozoites in contact with the mucus layer overlying the LS174T cells and in response to PMA, a protein kinase C activator, and Ca2+ ionophore A23187 which elevates intracellular Ca2+ ([Ca]i), caused a time-dependent (0.25-2.00 h) release of mucin. PKC inhibitors, H7 and staurosporine inhibited E. histolytica (37 and 75%) and PMA (46 and 100%)-induced mucin secretion, whereas in response to Ca2+ ionophore mucin secretion was augmented (56 and 17%). Both PMA and E. histolytica-induced the translocation of the PKC enzyme from the cytoplasm to the membrane fraction with increased enzyme activity. These results suggest that even though mucin secretion can be induced by PKC and Ca(2+)-dependent pathways, E. histolytica evokes the fast release of mucins by a PKC-dependent mechanism.
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PMID:The fast release of mucin secretion from human colonic cells induced by Entamoeba histolytica is dependent on contact and protein kinase C activation. 134 Feb 98

Calcium and protein kinase C may be directly involved in exocytosis. However, in the rat submandibular gland, cAMP-mediated events appear to be required for mucin secretion. Calcium may be involved, but a direct signal-transduction role for calcium and protein kinase C in regulating such secretion has yet to be established. With dispersed rat submandibular acinar-intercalated duct complexes, endogenous protein phosphorylation and mucin secretion studies were performed to determine if 12-O-tetradecanoylphorbol 13-acetate (PMA), a specific activator of protein kinase C, could act as an effective secretagogue for mucin secretion and if specific protein phosphorylation could be assigned to protein kinase C activation. PMA did not elicit such phosphorylation and it only slightly increased mucin secretion at high concentrations; these slight increases appeared to be non-specific. Therefore, protein kinase C activation may not be directly involved in regulating rat submandibular mucin secretion.
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PMID:Evidence against a direct role for protein kinase C in rat submandibular salivary mucin secretion. 262 60

The effects of a phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and a diacylglyceride, 1-oleoyl-2-acetyl-glycerol (OAG) on the secretion of two major exocrine products by dispersed rat submandibular cells were investigated. TPA stimulated the release of acinar cell mucin and ductal cell protease (arginine esterase) in a dose- and time-dependent manner. Mucin secretion was also provoked by OAG, which, however, had no effect on arginine esterase release. The unsaturated diacylglycerol, 1,2-diolein, elicited a greater mucosecretory response than did OAG at the same concentration, while the saturated 1,2-distearin produced a smaller response. Mucin and enzyme secretion caused by TPA or OAG in the rat submandibular model was not inhibited by either of two putative antagonists, the antipsychotic drug, fluphenazine, and the antibiotic, polymyxin B. The involvement of extracellular Ca2+ in TPA-induced secretion was examined by comparing responses of cells maintained in normal or Ca2+-free medium, or in medium containing the ionophore A23187. Although extracellular Ca2+ was not an absolute requirement for a secretory response, the results indicate a synergistic relationship between TPA and Ca2+ in stimulating the release of both mucin and arginine esterase. These results suggest a role for the Ca2+-, phospholipid-dependent enzyme, protein kinase C in the secretory mechanism of mucous and serous cells in the submandibular gland. This is consistent with the proposal that receptor-mediated hydrolysis of membrane phosphoinositides is an initial event in stimulus-response coupling in exocrine cells.
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PMID:Effects of a phorbol ester and diacylglycerols on secretion of mucin and arginine esterase by rat submandibular gland cells. 308 75

We have investigated the regulation of the intestinal mucin gene MUC2 in HT29 cells. Surprisingly, sodium butyrate, an effective inducer of aspects of colonic cell differentiation in HT29 cells, fails to induce MUC2 during short-term exposure, despite the fact that it has been used to select stably differentiated clones of HT29 that resemble goblet cells and produce mucin. However, 12-O-tetradecanoylphorbol-13-acetate and forskolin, which trigger the protein kinase C- and A-dependent signal transduction pathways, respectively, are potent inducers of MUC2 gene expression. 12-O-Tetradecanoylphorbol-13-acetate and forskolin operate through distinct mechanisms, with the former requiring de novo protein synthesis and the latter not. Experiments using specific protein kinase inhibitors suggest that both inducers operate by triggering their respective signal transduction pathways. Nuclear runoff analyses suggest that post-transcriptional (rather than transcriptional) mechanisms are important in the accumulation of MUC2 mRNA. Finally, we show that in several cell lines from human mucinous tumors, characterized by elevated levels of mucin production, MUC2 expression is very high and constitutive compared to forskolin-treated HT29 cells. Thus, the different regulation of MUC2 in HT29 cells and in mucinous tumor cell lines may reflect molecular pathways that characterize colon carcinomas of different histology and pathology.
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PMID:Regulated expression of an intestinal mucin gene in HT29 colonic carcinoma cells. 768 47

Platelet-activating factor (PAF), a proinflammatory lipid mediator, is a potent airway mucin secretagogue. This study assessed the role of protein kinase C (PKC) in PAF-induced mucin release from primary cultures of feline tracheal epithelial cells (FTEC). Mucin secretion was quantitated by enzyme-linked immunosorbent assay using a monoclonal antibody raised against airway mucin-type glycoproteins. Coincubation of FTEC with PAF (5 microM) and pharmacologic PKC inhibitors, sphingosine, H7, or calphostin C, inhibited PAF-induced mucin secretion at 30 min. The PKC inhibitors produced a concentration-dependent, noncytotoxic inhibition. Exposure of FTEC with the PKC activator phorbol 12-myristate 13-acetate (PMA), failed to increase the release of mucin. Stimulation of FTEC with PAF caused a transient increase of membrane-bound PKC activity after 5 min of stimulation. PMA also induced the translocation of PKC activity from the cytosol to the membrane fraction, which was still present after 15 min of exposure. Determination of the specific PKC isozyme(s) involved in PAF-induced mucin release was performed by immunoblot analysis of the subcellular fractions using a battery of antibodies against various PKC isozymes (anti-PKC alpha, beta, delta, gamma, epsilon, and zeta). We found that PKC zeta (mol wt approximately 70 kD) was a major identifiable PKC isozyme present in the cytosolic fraction of FTEC. Furthermore, PKC zeta isozyme was also found to translocate to the membrane fraction following PAF exposure. Thus, these results demonstrate the crucial role of PKC in the intracellular events that culminate in mucin release following PAF stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet-activating factor induces airway mucin release via activation of protein kinase C: evidence for translocation of protein kinase C to membranes. 804 80

The relationship between the adenosine 3',5'-cyclic monophosphate-mediated protein kinase A (PKA)-dependent stimulatory pathway for mucin secretion and Ca(2+)-mediated and protein kinase C (PKC)-mediated secretion was studied in T84 cells, using the postreceptor secretagogues forskolin, A-23187, and phorbol 12-myristate 13-acetate (PMA), the protein kinase inhibitors staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), high- and low-Ca2+ media, and the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Staurosporine (10(-5) M) inhibited both PMA and forskolin at their maximally effective concentrations, whereas H-7 (5 x 10(-5) M) inhibited only PMA. Stimulation of mucin secretion by forskolin (5 x 10(-5) M) was not significantly affected by the reduction of medium Ca2+ to 47 and 129 nM, equivalent to published values for intracellular Ca2+ concentration ([Ca2+]i). Stimulation by forskolin was reduced by preloading cells with BAPTA, but to a much smaller extent than Ca(2+)-dependent stimulation by A-23187. A-23187-mediated mucin secretion from BAPTA-loaded cells was augmented by high doses of forskolin. Similar concentrations of forskolin had no effect on A-23187-stimulated secretion in calcium-replete cells. Our results indicate that forskolin does not stimulate mucin secretion by increasing Ca2+ entry or releasing Ca2+ from intracellular stores. Forskolin can stimulate mucin secretion in a Ca(2+)-independent manner but is apparently inhibited by high levels of intracellular Ca2+ induced by Ca2+ ionophores in 1.0 mM Ca2+ media.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of mucin secretion in T84 adenocarcinoma cells by forskolin: relationship to Ca2+ and PKC. 817 99

T84 adenocarcinoma cells were stimulated to secrete mucin by the phorbol ester phorbol 12-myristate 13-acetate (PMA) and Ca2+ ionophores A23187 and ionomycin. In Ca(2+)-containing media, maximal stimulation by PMA was significantly inhibited by staurosporine, but maximal A23187-stimulated secretion was not affected. Downregulation of protein kinase C (PKC) reduced maximal PMA-stimulated secretion without affecting the response to A23187. Thus PKC activation is not required for maximal Ca(2+)-mediated mucin secretion. PMA stimulated secretion in low-Ca2+ media, with and without intracellular chelation of Ca2+ by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Surprisingly, Ca2+ ionophores also stimulated secretion under the same circumstances. Persistent A23187-stimulated secretion was strongly inhibited by the protein kinase inhibitors staurosporine and H-7. Secretion in Ca(2+)-containing media was also inhibited at submaximal levels of Ca(2+)-ionophore stimulation. These results indicate that PKC and Ca2+ stimulate mucin exocytosis independently. Ca2+ ionophores also stimulate secretion via a protein-kinase dependent pathway. Enhancement of protein kinase inhibition at lower Ca2+ concentrations suggests that the response could be mediated by a Ca2+ ionophore-induced depletion of an intracellular Ca2+ pool.
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PMID:Mucin secretion by T84 cells: stimulation by PKC, Ca2+, and a protein kinase activated by Ca2+ ionophore. 833 37

Cholinergic stimulation of the HT29-18N2 goblet cell line increased mucin secretion as assessed: (1) with a mucin-specific immunoassay, (2) using whole-mount immunocytochemistry, or (3) by morphometric quantification of intracellular mucous granule stores. Cholinergic stimulation did not, however, result in the apical plasmalemmal membrane cavitation that is characteristic of recent compound exocytotic activity. The response was not dependent on protein kinase C activation since it was not inhibited by the kinase C antagonist H7 or potentiated by the diacylglycerol kinase antagonist R59022. Calcium ionophore A23187 also accelerated mucin secretion by a noncompound exocytotic pathway. Activation of protein kinase C by phorbol 12-myristate 13-acetate, on the other hand, increased mucin secretion by a compound exocytotic pathway. The results provide insight into the signal transduction pathways underlying secretory responses of goblet cells observed in situ.
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PMID:Signal transduction pathways mediating mucin secretion from intestinal goblet cells. 850 99

1. Hypersecretion of gallbladder mucin has been proposed to be a pathogenic factor in cholesterol gallstone formation. Using cultured gallbladder epithelial cells, we demonstrated that bile salts regulate mucin secretion by the gallbladder epithelium. In the present study we have investigated whether established second messenger pathways are involved in bile salt-induced mucin secretion. 2. The effect of activators and inhibitors on mucin secretion was studied by measuring the secretion of [3H]N-acetyl-D-glucosamine-labelled glycoproteins. Intracellular cAMP content of the cells was measured using a radioimmunoassay. 3. Incubation of the cells with 10 mM taurocholate did not increase the intracellular cAMP content (25.7 versus control 22.8 pmol of cAMP/mg of protein). No stimulation of mucin secretion was observed after incubation with 1-100 microM concentrations of the calcium ionophores ionomycin and A23187. The stimulatory effect of 10 mM tauroursodeoxycholate (TUDC) on mucin secretion could not be inhibited by the addition of EDTA. Activation of protein kinase C (PKC) by 1 microgram/ml phorbol 12-myristate 13-acetate (PMA) caused an increase in mucin secretion (342% versus control 100%), comparable with the effect of 40 mM TUDC. The effect of 10 ng/ml PMA could partially be inhibited by a concentration of 2 microM of the PKC inhibitor staurosporin. Staurosporin had no inhibitory effect on mucin secretion induced by TUDC. 4. In gallbladder epithelial cells bile salts do not stimulate mucin secretion via one of the classical signal transduction pathways. We hypothesize that bile salts act on mucin secretion via a direct interaction with the apical membrane.
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PMID:Mechanism of bile salt-induced mucin secretion by cultured dog gallbladder epithelial cells. 867 Jan 65


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