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)

To assess the role of calmodulin in human basophil histamine release, we triggered leukocytes with different secretagogues in the presence of putative inhibitors of calmodulin. Calcium ionophore-induced histamine release was reduced or blocked by calmidazolium, CGS 9343B, felodipine, metofenazate, and Ro 22-4839. H 186/86, a felodipine-related dihydropyridine derivative, blocked A23187-but not ionomycin-triggered histamine release, suggesting a difference in the mode of action of these ionophores. In contrast, leukocyte histamine release triggered by the purported protein kinase C (PKC) activator, 1,2-isopropylidene-3-decanoyl-sn-glycerol (IpOCOC9), was enhanced by calmidazolium, CGS 9349B and metofenazate but not affected by felodipine or Ro 22-4839, whereas the response triggered by 4 beta-phorbol 12-myristate 13-acetate (PMA) was reduced by metofenazate and Ro 22-4839 but not consistently affected by calmidazolium, CGS 9343B or felodipine. The PMA-induced histamine release was enhanced by H 186/86. Anti-IgE- and FMLP-induced responses were either unaffected or slightly enhanced by the examined calmodulin antagonists. In comparison with the calmodulin antagonists, R 59022, an inhibitor of diacylglycerol kinase, failed to reduce calcium ionophore-triggered histamine release, whereas FK506, an inhibitor of peptidyl prolyl cis-trans isomerase (PPI), reduced both anti-IgE- and ionophore-triggered responses. These results indicate that calmodulin constitutes an obligate link in signal transduction pathways leading to human leukocyte histamine release if the trigger is a calcium ionophore but not when responses are induced by anti-IgE, FMLP or PMA; a calmodulin-dependent component may rather balance responses induced by IpOCOC9.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis-trans isomerase in a secretagogue specific manner. 128 Sep 15

It was recently noted that the amino acid sequence of FK506 binding protein (FKBP-12) is nearly identical to that of an endogenous inhibitor of protein kinase C, PKCI-2. To follow up on this observation, we have tested the hypothesis that FKBP-12 is an inhibitor of PKC. The kinase activity of rat brain protein kinase C (PKC) was not inhibited by the presence of up to 700 micrograms recombinant human FKBP-12 per ml, in either the presence or absence of FK506. FKBP-12 also did not affect PMA-induced phosphorylation of an endogenous PKC substrate, an 80 kDa protein, in permeabilized cells. To test whether FKBP-12 could account for endogenous PKC inhibitory activity in cells, Jurkat cell lysate was chromatographed on an anion exchange column. A peak of PKC inhibitory activity was eluted at approximately 200 mM NaCl. As shown by both Western blots and FK506 binding activity, FKBP-12 was eluted only in the flow-through and wash fractions. These results demonstrate that FKBP-12 is clearly distinct from endogenous PKC inhibitory activity.
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PMID:FKBP-12 is not an inhibitor of protein kinase C. 137 89

A computer-assisted sequence analysis of the ryanodine receptor pointed to a 15-residue peptide, "KC7", reported to have been purified from a proteolytic digest of the 565 kDa rabbit skeletal muscle protein. Sequence comparisons, however, showed that this peptide probably originated from a much smaller protein which copurified with the ryanodine receptor. Peptide KC7 (excluding its unknown N-terminal residue) was identical to the N-terminus of a 12 kDa immunophilin (immunosupressant-binding protein), human T-cell FK506- binding protein (FKBP), which has recently been identified as an inhibitor of protein kinase C. There was no other sequence similarity between FKBP and the ryanodine receptor. It is suggested that in vivo interaction of the ryanodine receptor and FKBP may play a role in the modulation of calcium release in muscle.
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PMID:Sequence analysis of the ryanodine receptor: possible association with a 12K, FK506-binding immunophilin/protein kinase C inhibitor. 187 49

The WEHI-231 B lymphoma cell line expresses the phenotype of immature B cells. Cross-linking of surface IgM induces programmed cell death (PCD) with typical features of apoptosis demonstrated by the decrease of cell DNA content, chromatin condensation, and nuclear fragmentation. Activation of protein kinase C (PKC) by phorbol esters was reported to protect WEHI-231 cells against apoptosis induced by ligation of antigen receptors. It was therefore hypothesized that PCD could result from a defect in PKC response with an imbalance in the phosphoinositide pathway in favor of Ca2+ mobilization. In support of this hypothesis, we show here that apoptosis can be readily triggered by the calcium ionophore ionomycin. Furthermore, pretreatment of cells with cyclosporin A or FK506 which inhibit selectively the phosphoprotein calcineurin, a calcium-and calmodulin-dependent serine/threonine phosphatase, protects WEHI-231 cells against apoptosis induced by ionomycin or ligation of surface IgM. Unlike phorbol esters, cyclosporin A did not impair the rise of intracellular Ca2+ induced by cross-linking of antigen receptors. Altogether, the data indicate that the phosphorylation status of yet undefined key cellular substrates controls the cellular response to calcium-dependent apoptotic signals in this B cell lymphoma.
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PMID:Cyclosporin A and FK506 inhibit activation-induced cell death in the murine WEHI-231 B cell line. 751 1

Eosinophils are known to play an important role in the pathogenesis of asthma and other allergic diseases. This study demonstrated the effects of various drugs on eosinophil viability in vitro, which might help clinicians and researchers in treating and studying eosinophilic diseases. Staurosporine, a protein kinase C inhibitor, and herbimycin A, a tyrosine kinase inhibitor, at 10(-6) M and 10(-7) M significantly lowered eosinophil viability in a dose-dependent fashion (p < 0.002, p < 0.02 and p < 0.001, p < 0.002, respectively). Both staurosporine and herbimycin A reduced eosinophil survival in a time-dependent fashion at 10(-6) M and 10(-7) M. Ketotifen at 10(-4) M and theophylline at 10(-3) M, significantly decreased eosinophil viability (p < 0.001 and p < 0.001, respectively) in the presence of 100 pg/ml of recombinant human interleukin-5 (rhIL-5). Both FK506 and cyclosporin A at 10(-4) M significantly reduced eosinophil viability (p < 0.001 and p < 0.005, respectively) in the presence of 100 pg/ml of rhIL-5. Our data show that ketotifen, theophylline, FK506, cyclosporin A reduced eosinophil viability at a high concentration. Furthermore, it is suggested that protein kinase C and tyrosine kinase are involved in eosinophil survival.
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PMID:Effects of various drugs (staurosporine, herbimycin A, ketotifen, theophylline, FK506 and cyclosporin A) on eosinophil viability. 752 Jun 89

Proliferation of T lymphocytes in response to antigen/MHC complexes is dependent upon the presence of a co-stimulatory signal; in its absence, T cells are rendered unresponsive to specific antigen CD28 is a T cell surface glycoprotein that acts as a co-stimulatory molecule when combined with signals initiated by the T cell receptor CD3 complex. While the biochemical signaling events following CD28 stimulation are still poorly defined, monoclonal antibodies (mAb) directed against CD28 have been shown to transduce a variety of early signals that are different in the presence of cross-linking antibody or the presence of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Stimulation of human T cells with cross-linked anti-CD28 mAb alone resulted in the activation of 70-kDa (p70) S6 kinase, a rapamycin-sensitive serine/threonine kinase that is believed to be important for cell cycle progression. Activation of p70 S6 kinase through CD28 was inhibited by rapamycin. Activation of p70 S6 kinase also increased in response to cross-linked CD3, but followed a more rapid time course than activation via CD2. Cyclosporin A and FK506 had no effect on p70 S6 kinase activity initiated via either pathway. The combination of cross-linked CD28 and cross-linked CD3 had no more than an additive effect on the induction of p70 S6 kinase activity. Thus, recruitment of p70 S6 kinase activity appears to represent a common signal transduction event shared by both the CD28 and CD3 pathways of T cell activation.
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PMID:Cross-linking CD28 leads to activation of 70-kDa S6 kinase. 752 38

The macrolide FK506 inhibited, by up to 50%, neutrophil migration and the production of the superoxide radical in response to the formyl peptide, formyl-methionyl-leucyl-phenylalanine (FMLP). The production of the superoxide radical in response to phorbol 12-myristate 13-acetate (PMA) was unaffected by FK506. The inhibition of neutrophil functions was accompanied by a partial reversal of FMLP-induced synthesis of cellular proteins, despite a rise in intracellular Ca2+. Neutrophils treated with FK506 demonstrated a small (average 23%) though significant decrease in formyl-peptide receptor numbers but receptor binding affinity was unaffected. The effects of FK506 on neutrophil activation appear to be analogous to those in T-lymphocytes. The incomplete inhibition, by FK506, of neutrophil responses suggests further that activation by FMLP is mediated via distinct multiple signalling pathways, including protein kinase activation and protein synthesis. The inability of FK506 to reduce FMLP-induced rises in cellular Ca2+ or PMA-induced activation of neutrophils suggests that its action is distal to Ca2+ mobilization and distinct from pathways relying on PKC activation. Thus the immunosuppressive effects of FK506 in vivo might be mediated through the inhibition of inflammatory cells other than lymphocytes and the drug therefore has therapeutic potential in a variety of inflammatory conditions. The drug also has potential in vitro for the characterization of signalling pathways from the plasma membrane to the nucleus.
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PMID:Inhibition by FK506 of formyl peptide-induced neutrophil activation and associated protein synthesis. 752 4

Identification and characterization of the cellular proteins that specifically bind to the immunosuppressive drugs, cyclosporine (CsA), FK506, and rapamycin is necessary to understand their mechanism of action. We have isolated and partially characterized a 52 kDa binding protein (BP) from calf thymus. Using 12 peptide substrates we observed very low or no cis-trans peptidyl prolyl isomerase activity. We further tested the protein for catalytic activity including kinase activity, phosphatase activity, protein kinase C regulation, and LCK tyrosine kinase regulation. The 52 kDa BP was capable of blocking the cyclic AMP dependent, protein kinase mediated, phosphorylation of histones and casein. The protein did not demonstrate kinase activity, nor did it affect the activity of protein kinase C or LCK tyrosine kinase. Microsequencing of the 52 kDa BP was performed. A comparison of known sequences indicated that the protein is unique and has not been previously characterized.
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PMID:Partial characterization of a 52 kDa CsA/FK506/rapamycin binding protein. 753 57

In T cell hybridomas, TCR/CD3 complex-mediated stimulation induces apoptosis but inhibits that induced by glucocorticoids. A combination of ionomycin (IM), a calcium ionophore, and PMA, a protein kinase C activator, mimics the effects of the TCR/CD3-mediated stimulation. Glucocorticoid-induced apoptosis is, however, markedly inhibited by IM alone, and less markedly by PMA alone. The immunosuppressant FK506 canceled the inhibition by IM but not that by PMA. As calcineurin (CN) is one of the target molecules of FK506, we examined whether CN activation might have an anti-apoptotic effect. BOG8, a T cell hybridoma, was stably transfected with a mutant CN catalytic subunit with Ca2+/calmodulin-independent, constitutive but FK506-sensitive phosphatase activity. The transfectant clones were fairly resistant to glucocorticoid-induced death. Their resistance, however, was hardly affected by FK506 when added simultaneously with glucocorticoid, but was lost after a prolonged preincubation with FK506. In the parent BOG8 cells, FK506 failed to cancel the inhibitory effect of IM on glucocorticoid-induced death when the addition of FK506 was delayed for 1 h or more. These results suggest that CN activation is required for the resistance only as an early event. The transfectant clones produced IL-2 but failed to undergo apoptosis upon stimulation with PMA alone, whereas apoptosis was induced by a combination of IM and PMA. These results suggest that activation-induced cell death may require a higher level of CN activity than IL-2 production or may require another Ca(2+)-dependent pathway.
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PMID:Calcineurin activation protects T cells from glucocorticoid-induced apoptosis. 753 18

IL-5 was produced in vitro by peripheral blood mononuclear cells (PBMC) of mite-sensitive atopic patients upon challenge with specific allergen, while PBMC of healthy controls produced essentially no IL-5. Stimuli delivered by the combination of phorbol ester and Ca2+ ionophore induced marked IL-5 production by PBMC obtained from atopic and non-atopic asthmatics, suggesting that both protein kinase C and Ca2+ influx are required for IL-5 production. CD2- or CD4-bearing cell depletion almost completely removed IL-5-producing cells while CD8-bearing cell depletion rather enriched them. These findings indicate that CD4+ T cells are the principal source of IL-5 in PBMC. The capacity of PBMC of atopic asthmatics, non-atopic asthmatics and healthy controls to produce IL-2, IL-4, IL-5 and IFN-gamma was compared, to find that cytokine-producing capacities other than that of IL-5 (IL-2, IL-4 and IFN-gamma) were not significantly different among the three groups. Dexamethasone, FK506 and cyclosporin A suppressed IL-5 production in vitro in a dose-dependent manner. Clear dose-dependent suppression of IL-5 gene expression by FK506 was also observed. Treatment of asthmatic patients with inhaled glucocorticoid (beclomethasone dipropionate) ameliorated clinical symptoms, improved lung function and markedly suppressed IL-5 production by PBMC, suggesting the essential role of IL-5 in the pathogenesis of bronchial asthma and the clinical importance of its regulation.
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PMID:IL-5 production by CD4+ T cells of asthmatic patients is suppressed by glucocorticoids and the immunosuppressants FK506 and cyclosporin A. 754 Aug 62


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