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 antiallergic and antiinflammatory effects of the new protein kinase C and calmodulin inhibitor K-252a (8R, 9S, 11S)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]cycl oocta [cde] trinden-1-one) were investigated in animal models, and the following results were obtained: 1. Oral administration of K-252a, ketotifen or oxatomide showed a dose-dependent inhibition on 48 h homologous passive cutaneous anaphylaxis in rats and anaphylactic bronchoconstriction in passively sensitized guinea pigs. 2. K-252a (1-100 mg/kg p.o.) exerted a dose-dependent protection against platelet-activating factor (PAF)-induced mortality in mice. This protective effect of K-252a was sustained for 7 h. 3. K-252a (1-100 mg/kg p.o.), as well as dexamethasone (1 mg/kg s.c.), showed remarkable inhibitory effects on rat paw edema induced by carrageenin, zymosan, PAF, and antigen-antibody reaction (passive Arthus reaction) and on the croton oil-induced rat ear edema. On the other hand, indomethacin (10 mg/kg p.o.) significantly inhibited carrageenin-induced edema, but did not inhibit edema induced by other phlogistic agents. Based on these results it is suggested that K-252a, by oral administration, has antiallergic and antiinflammatory effects.
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PMID:Antiinflammatory and antiallergic effects of a novel metabolite of Nocardiopsis sp. as a potent protein kinase C inhibitor from microbial origin. 297 91

K-252 compounds (K-252a and b isolated from Nocardiopsis sp. (1) and their synthetic derivatives) were found to inhibit cyclic nucleotide-dependent protein kinases and protein kinase C to various extents. The inhibitions were of the competitive type with respect to ATP. K-252a was a non-selective inhibitor for these three protein kinases with Ki values 18-25 nM. K-252b showed a comparable potency for protein kinase C (Ki, 20nM), whereas inhibitory potencies for cyclic nucleotide-dependent protein kinases were reduced. KT5720 and KT5822 selectively inhibited cAMP-dependent (Ki, 60nM) and cGMP-dependent (Ki, 2.4nM) protein kinases, respectively.
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PMID:K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. 302 14

K-252a, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetr ahy dro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadi benzo[a,g]cycloocta[c,d,e]triden-1-one, an indole carbazol compound isolated from microbial origin, potently inhibits protein kinase C in partially purified enzyme and intact platelets. We examined the effects of this compound on platelet-activating factor [1-O-alkyl-alpha-acetyl-sn-glycero-phosphocholine (AGEPC)] induced protein phosphorylation, serotonin release and a rise in intracellular free calcium using washed rabbit platelets. In Ca2+-containing medium (1 mM CaCl2), AGEPC at 10(-10) and 10(-9) M markedly phosphorylated two proteins having molecular weights of 40,000 daltons (40 K protein) and 20,000 daltons (20 K protein) and evoked a marked rise in cytosolic free calcium. K-252a at 3 and 10 microM caused a concentration-dependent inhibition in the 20 K protein phosphorylation but caused only slight inhibition in the 40 K protein phosphorylation. K-252a inhibited the basal phosphorylation of 20 K protein obtained in non-stimulated platelets, and caused no significant alteration in the rise of intracellular free calcium evoked by AGEPC. It can be considered, from this evidence, that K-252a may act directly on myosin light chain kinase, resulting in the inhibition of 20 K protein phosphorylation. In Ca2+-free medium [1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)], AGEPC at 10(-8) M predominantly phosphorylated 40K protein, although phosphorylation of 20K protein and cytosolic free calcium were increased slightly. K-252a at 1-10 microM caused a concentration-dependent inhibition in the 40K protein phosphorylation. These results indicate that K-252a functions as an inhibitor of both protein kinase C and myosin light chain kinase in rabbit platelets. In AGEPC-stimulated platelets, the inhibition of 20K protein phosphorylation in Ca2+-containing medium and of 40K protein phosphorylation in Ca2+-free medium was closely correlated with the inhibition of serotonin release by K-252a. These results strongly suggest that the phosphorylation of these two proteins may be a prerequisite for serotonin release in AGEPC-stimulated platelets.
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PMID:Parallel inhibition of platelet-activating factor-induced protein phosphorylation and serotonin release by K-252a, a new inhibitor of protein kinases, in rabbit platelets. 312 96

K-252a, a metabolite isolated from the culture broth of Nocardiopsis sp. K-252a, was found to exhibit an extremely potent inhibitory activity on protein kinase C. The IC50 value was 32.9 nM.
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PMID:K-252a, a potent inhibitor of protein kinase C from microbial origin. 375 57

Nocardiopsis sp. K-290 was found to produce novel metabolites, designated K-252b, c and d, which were structurally related to K-252a. These compounds were isolated from the culture broth and the physico-chemical and biochemical properties were examined. The compounds strongly inhibited protein kinase C. IC50 values (the concentrations causing 50% inhibition) for the effects of K-252b, c and d on the rat brain enzyme were 38.3, 214, and 337 nM, respectively.
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PMID:K-252b, c and d, potent inhibitors of protein kinase C from microbial origin. 375 58

The structures of four new protein kinase C inhibitors of microbial origin, K-252a, b, c and d were determined by spectral studies and chemical conversion.
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PMID:The structures of the novel protein kinase C inhibitors K-252a, b, c and d. 375 59

Expression of P-glycoprotein by tumor cells confers resistance to multiple natural product drugs because of its ability to export these compounds. This transporter is a substrate for several protein kinases; however, the functional significance of its phosphorylation is not defined. We examined the effects of many activators and inhibitors of protein kinases on the activity of P-glycoprotein in drug-resistant human breast carcinoma cells (MCF-7/ADR). Several phorbol esters sensitized these cells to P-glycoprotein substrate drugs; however, there was no correlation with activation of protein kinase C. The 4 alpha- and 4 beta-isomers of phorbol 12-myristate 13-acetate were equally potent in sensitizing the cells to actinomycin D and daunomycin and in increasing the intracellular accumulation of [3H]vinblastine. These effects of 4 beta-phorbol myristate acetate required much higher concentrations than were needed to increase P-glycoprotein phosphorylation and were not antagonized by staurosporine. Similar to verapamil, the phorbol esters did not sensitize MCF-7/ADR cells to cisplatin, nor parental MCF-7 cells to any of the anticancer drugs. Mezerein, K-252a, and H-89 sensitized MCF-7/ADR cells, increased intracellular accumulation of [3H]vinblastine, and antagonized photolabeling of P-glycoprotein by [3H]azidopine. Therefore, phosphorylation does not appear to play a significant role in regulating P-glycoprotein activity in MCF-7/ADR cells.
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PMID:Circumvention of P-glycoprotein-mediated multiple drug resistance by phosphorylation modulators is independent of protein kinases. 749 4

The protein kinase inhibitors K-252a and K-252b have been shown earlier to block the actions of nerve growth factor and other neurotrophins and, at lower concentrations, to selectively potentiate neurotrophin-3 actions. In the present study we show that K-252a, but not K-252b, enhances epidermal growth factor (EGF)-and basic fibroblast growth factor (BFGF)-induced neurite outgrowth of PC12 cells at higher concentrations than required for neurotrophin inhibition. In parallel, tyrosine phosphorylation of extracellular signal-regulated kinases (Erks) elicited by EGF of bFGF was also increased in the presence of K-252a, and this signal was prolonged for 6 h. EGF- and bFGF-induced phosphorylation of phospholipase C-gamma 1 were not changed. The effect of K-252a on Erks was resistant to chronic treatment with phorbol ester, indicating that protein kinase C is not involved in this potentiation. In partial contrast to the actions of K-252a, the neurotrophin-3-potentiating effect of K-252b was accompanied by an increase in tyrosine phosphorylation of the Erks and of phospholipase C-gamma 1. Finally, although K-252a alone did not induce neurite outgrowth or tyrosine phosphorylation of Erks or phospholipase C-gamma 1, this compound alone stimulated phosphatidylinositol hydrolysis. Our findings identify activities of K-252a besides the direct interaction with neurotrophin receptors and suggest that a K-252a-sensitive protein kinase or phosphatase might be involved in signal transduction of EGF and bFGF. Our results are further compatible with the hypothesis that sustained activation of Erks may be important in PC12 differentiation.
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PMID:Epidermal growth factor induces PC12 cell differentiation in the presence of the protein kinase inhibitor K-252a. 752 86

The effect of staurosporine on the Ca2+ signalling induced by the muscarinic receptor agonist carbachol (CCh) was studied in Fura-2-loaded rat parotid acinar cells. At concentrations > 1 nM, staurosporine dose-dependently enhanced the sustained increase in cytosolic free Ca2+ concentration ([Ca2+]i), but did not affect the peak [Ca2+]i seen just after stimulation. The enhancement of the sustained increase in [Ca2+]i was not attenuated by the protein kinase C activator, 4 beta-phorbol 12-myristate 13-acetate, and not mimicked by another inhibitor of protein kinase C, K-252a, suggesting that the effect of staurosporine on the CCh-induced Ca2+ signalling may be due to a mechanism independent of the inhibitory action on protein kinase C. Staurosporine also enhanced the increases in [Ca2+]i induced by the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG) and the Ca2+ ionophore ionomycin (Iono). When the cells were stimulated by CCh, TG, or Iono in the absence of extracellular Ca2+, a transient increase in [Ca2+]i due to Ca2+ release from intracellular stores was observed. This increase in [Ca2+]i was unaffected by preincubation with staurosporine. However, when Ca2+ was added to the extracellular medium after [Ca2+]i had returned to the resting level, the increase in [Ca2+]i was significantly enhanced by staurosporine. In addition, staurosporine accelerated the Mn2+ influx following the addition of CCh, TG, or Iono. These results suggest that staurosporine modulates the Ca2+ entry system activated by depletion of intracellular Ca2+ stores in rat parotid acinar cells.
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PMID:Staurosporine enhances Ca2+ entry induced by depletion of intracellular Ca2+ stores in rat parotid acinar cells. 755 79

We have investigated the roles of tyrosine kinase and protein kinase C activity in interleukin-1 beta-induced interleukin-6 production, using the U373 human astrocytoma cell line as a model system for astrocytes. Compounds known to inhibit tyrosine kinases were tested for effects on interleukin-6 production in U373 cells stimulated with interleukin-1 beta. Complete to nearly complete inhibition of interleukin-1 beta-induced interleukin-6 production was observed with the flavonoids genistein and quercetin, the bisindole alkaloids staurosporine and K-252a, or the tyrphostin AG879. Herbimycin A was a potent inhibitor but did not induce complete inhibition at saturating dose. Calphostin C, an inhibitor of protein kinase C, also completely inhibited interleukin-6 production. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate induced interleukin-6 production, and treatment with a combination of this phorbol ester and interleukin-1 produced synergistic stimulation. Prolonged exposure to phorbol ester eliminated subsequent stimulation by phorbol ester but only partially decreased interleukin-1-induced interleukin-6 and had no effect on the activities of selected inhibitors including calphostin C. We conclude that tyrosine kinase activity is essential for interleukin-1-induced interleukin-6 production in U373 astrocytoma cells and that activity of a phorbol ester-insensitive, atypical protein kinase C isozyme may also be involved.
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PMID:Tyrosine kinase activity is essential for interleukin-1 beta--stimulated production of interleukin-6 in U373 human astrocytoma cells. 759 43


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