EC:2.7.11.13 - FACTA Search

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 effect of a metabolite of Nocardiopsis sp. as a protein kinase C inhibitor from microbial origin was investigated on the onset and development of dextran-induced paw edema in the rat. It was published that this compound (K-252a) interferes with histamine release from mast cells, while dextran-induced paw and nose edema are induced by vasoactive agents, like histamine etc., released from the disrupted mast cells. The antiinflammatory effect of the K-252a is effectuated by the inhibition of protein kinase C. Groups of male Wistar rats with 180-200 g b.w. were used; each group consisted of 10-10 rats. The following groups were consisted: rats given orally DMSO (control), rats given 1 mg/kg, or 3 mg/kg b.w. of K-252a dissolved in DMSO and given p.o. one hour before dextran injection. Dextran (BDH Chem. LTD, molW: 200.000, England) was injected intraperitoneally in 10% solution, in a dose of one ml/100 g b.w. Volume of the hind leg was measured by a mercury plethysmometer. Time-sequence of the edema was followed. Increase in volume of hind leg paw was related to its 0-min volume in %. Results were analyzed by the Kruskal-Wallis-test. Edema of the legs and noses appeared in each of the control rats in one hour. The 1 mg/kg dose of K-252a retarded the appearance of the edema by 1 hour, the 3 mg/kg dose, however, prevented its onset for 4 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antiinflammatory effect of a protein kinase C inhibitor (K-252a) on the development of the dextran-induced paw edema in the rat (preliminary results). 128 69

In rat basophilic leukemia cells (2H3), a tumor analog of mast cells, the aggregation of IgE receptors results in histamine secretion and the increase in histidine decarboxylase activity which synthesizes histamine. Using inhibitors of protein kinases C, we studied the relationships between these events and protein kinase C which is activated by antigens. Histamine release is suppressed by inhibitors of protein kinase C, staurosporine, K252-a and H-7, in this decreasing order of effectiveness; and the IC50 values are 1.5 nM, 29.9 nM and 3.8 microM, respectively. The changes in the intracellular Ca concentration monitored by fura-2 fluorescence is not modified by staurosporine, although the histamine response is suppressed. Meanwhile, the increase of histidine decarboxylase was abolished by inhibitors of protein kinase C; staurosporine was the strongest, K-252a of moderate activity and H-7, the weakest, having IC50 values of 0.8 nM, 100 nM and 11.5 microM, respectively. The inhibitors of protein kinase C suppress both histamine secretion and synthesis. Therefore, the histamine synthesis may be stimulated via activation of protein kinase C to supplement the released histamine.
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PMID:Effects of inhibitors of protein kinase C on the release and synthesis of histamine in rat basophilic leukemia cells (2H3). 138 Oct

K-252 compounds, which share a common polyaromatic aglycon structure, are rather general and potent inhibitors of various protein kinases, including protein kinase C and tyrosine-specific protein kinases, and possibly act by interfering at or near the ATP binding site. However, chemical modifications in their sugar moiety can result in high specificity of the inhibitory action and, furthermore, can induce other stimulatory and inhibitory effects on nerve cells. These compounds are of particular interest because, in intact cells, they inhibit the actions of NGF and other neurotrophins without diminishing comparable actions of other growth factors. This effect seems to reflect a direct inhibitory action on trk neurotrophin receptor proteins. At concentrations lower than those necessary to inhibit neurotrophin actions, K-252a and K-252b have been shown to potentiate the stimulatory effects of NT-3 on different neurons in culture and on PC12 cells. The structural requirements for this effect seem to be different from those for the inhibition of neurotrophin actions. These findings raise the possibility of development of compounds of high selectivity, able to inhibit or potentiate the transduction mechanisms of individual neurotrophins, and identify K-252a and K-252b as lead compounds for the development of such selective molecules. Specific inhibitors and stimulators of neurotrophins would be valuable tools to investigate biological functions of the neurotrophins in vitro and in vivo. Furthermore, it is possible that, in the future, highly selective drugs with agonistic or antagonistic actions on neurotrophin mechanisms could become therapeutically useful in the treatment of neurological disease and injury.
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PMID:K-252 compounds: modulators of neurotrophin signal transduction. 143 89

Glucocorticoids stimulate the prostaglandin E2 production of confluent amnion cell cultures, but have no stimulatory effect on the PGE2 output of freshly isolated human amnion cells. Since protein phosphorylation may modify the responsiveness of target cells to steroids, and activators of protein kinase C (PKC), as well as corticosteroids, promote amnion cell PGE2 output by stimulating the synthesis of prostaglandin endoperoxide H synthase (PGHS), we investigated the possibility that PKC is involved in the glucocorticoid-induction of PGE2 synthesis in cultured amnion cells. The dexamethasone-induced PGE2 output of arachidonate-stimulated cells was blocked by the protein kinase inhibitors staurosporine, K-252a, H7, HA1004, and sphinganine, in a manner consistent with their effect on PKC. However, dexamethasone increased the PGE2 production of cultures treated with maximally effective concentrations of the PKC-activator compound TPA. Moreover, dexamethasone stimulated PGE2 synthesis in cultures which were desensitized to TPA-stimulation by prolonged phorbol ester treatment. Concentration-dependence studies showed that staurosporine completely (greater than 95%) blocked glucocorticoid-provoked PGE2 synthesis at concentrations which did not inhibit TPA-stimulated prostaglandin output, and that K-252a inhibited the effect of TPA by more than 95% at concentrations which decreased the effect of dexamethasone only moderately (approximately 40%). Dibutyryl cyclic AMP had no influence on the basal- or dexamethasone-stimulated PGE2 production, and on the staurosporine inhibition of the steroid effect. These results show that glucocorticoids and phorbol esters control amnion PGE2 production by separate regulatory mechanisms. It is suggested that the response of human amnion cells to glucocorticoids is modulated by protein kinase(s) other than phorbol ester-sensitive PKC and cyclic AMP-dependent protein kinase.
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PMID:Glucocorticoid stimulation of amnion cell prostaglandin synthesis: suppression by protein kinase C inhibitors and independence of phorbol ester-sensitive protein kinase C. 150 1

Novel derivatives of 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-triazadibe nzo[a,g]-cycloocta[cde]trinden-1-one, an inhibitor of protein kinases and calmodulin-dependent phosphodiesterase, were synthesized and evaluated for their antitumor activity in vitro and in vivo. Of ten derivatives tested, four were active against the P388 murine leukemia i.p.-i.p. system, although K-252a was inactive. Among these derivatives, KT6124 was selected for further biological evaluation studies because its efficacy was the highest. KT6124 was also active against sarcoma 180 and B16 melanoma. It exerted a relatively broad spectrum of antiproliferative activity against 20 human tumor cell lines in vitro. To determine the mechanism(s) of action underlying the antitumor activity of KT6124, we tested the drug for inhibition of protein kinases, including Ca(2+)- and phospholipid-dependent protein kinase (PKC), in intact A431 human epidermoid carcinoma cells in comparison with the PKC-inhibitory activity of K-252a. KT6124 did not antagonize the action of phorbol 12-myristate 13-acetate (PMA) in A431 cells, whereas K-252a did, suggesting that KT6124 may not act on protein kinases in the cells. The interaction of KT6124 with DNA in living cells was examined by the alkaline elution method. KT6124 apparently exhibited DNA scission both dose- and time-dependently in the target cells. The DNA breakage was dependent on proteinase K treatment, suggesting its possible interaction with DNA-related enzyme(s). These results indicate that KT6124 exerts antitumor activity by acting on DNA or on DNA-related enzyme(s) in tumor cells rather than via the inhibition of protein kinases.
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PMID:Antitumor effect of KT6124, a novel derivative of protein kinase inhibitor K-252a, and its mechanism of action. 153 71

Staurosporine is an antibiotic that specifically inhibits protein kinase C. Fourteen staurosporine- and temperature-sensitive (stt) mutants of Saccharomyces cerevisiae were isolated and characterized. These mutants were divided into ten complementation groups, and characterized for their cross-sensitivity to K-252a, neomycin, or CaCl2. The STT1 gene was cloned and sequenced. The nucleotide sequence of the STT1 gene revealed that STT1 is the same gene as PKC1. The STT1 gene conferred resistance to staurosporine on wild-type cells, when present on a high copy number plasmid. STT1/stt1::HIS3 diploid cells were more sensitive to staurosporine than STT1/STT1 diploid cells. Analysis of temperature-sensitive stt1 mutants showed that the STT1 gene product functioned in S or G2/M phase. These results suggest that a protein kinase (the STT1 gene product) is one of the essential targets of staurosporine in yeast cells.
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PMID:Characterization of a staurosporine- and temperature-sensitive mutant, stt1, of Saccharomyces cerevisiae: STT1 is allelic to PKC1. 153 90

Chicken splenic cells, stimulated by concanavalin A, secreted a factor or factors into the culture medium which supported the survival of neurons from sympathetic ganglia of chick embryos. The effect of this conditioned medium (CM) was similar to the effect of nerve growth factor (NGF). However, the enhanced survival effect of CM was unaffected by K-252a, a protein kinase inhibitor which completely abolished the effect of NGF. 6-Thioguanine, an inhibitor of NGF-activated protein kinase N, blocked the survival effects of both NGF and CM on sympathetic neurons, but a dose required for the half-maximal inhibition for the survival effect of CM was 10 times higher than that for NGF. H-7, an inhibitor of protein kinase C, did not block the effect of either CM or NGF. On the other hand, the survival effect of both CM and NGF was blocked to the same extent by 5'-deoxy-5'-methylthioadenosine and LiCl. These results suggest that activated splenic cells secreted neuronal survival-promoting factor(s) into CM and that the cellular mechanisms promoting neuronal survival by CM are different from those promoting neuronal survival induced by NGF.
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PMID:Chick sympathetic neurons in culture respond differentially to nerve growth factor and conditioned medium from activated splenic lymphocytes. 164 62

A number of cell-surface proteins are anchored by a phosphatidylinositol (PI)-glycan moiety. These proteins can be released by PI-specific phospholipases C (PI-PLC). Decay-accelerating factor (DAF) is such a cell-surface protein that protects cells from inadvertent complement attack by binding to and inactivating C3 and C5 convertases. We have studied the regulation of DAF synthesis in human umbilical vein endothelial cells (HUVEC), a cell that has the highest level of surface DAF among those human cells that have been studied. HUVEC DAF was measured by immunoradiometric assay of detergent extracts and of cell supernatants after treatment of cells with a bacterial (Bacillus thuringiensis) PI-PLC. Eighty percent of the HUVEC DAF (4 to 8 x 10(5) molecules/cell) was released by exogenously added PI-PLC, indicating that it is predominantly PI-anchored. The level of PI-PLC-sensitive HUVEC DAF was increased three- to fourfold by overnight treatment of cultures with the protein kinase C activators, PMA (1 to 10 nM), phorbol-12,13-dibutyrate (10 to 100 nM), and teleocidin A (1 to 10 nM) under conditions where cell number, protein, and lactate dehydrogenase remain unchanged. This DAF synthesis was blocked by the protein kinase C inhibitor K-252a in a dose-dependent manner (ED50 = 0.06 microM). The biologically inactive phorbols, 4-alpha-phorbol-12 myristate-13-acetate (1 microM) and 4-alpha-phorbol-12, 13-didecanoate (1 microM) did not increase DAF levels. The newly expressed DAF in PMA-stimulated cells was still largely PI-anchored. In contrast, another PI-anchored protein, alkaline phosphatase, was not altered by PMA treatment, demonstrating that the PMA effect is not uniform among all surface proteins. The increased expression of DAF only was evident 8 h after PMA addition and was blocked by the RNA and protein synthesis inhibitors, actinomycin D and cycloheximide, indicating that both transcription and translation are required for DAF synthesis induced by phorbol esters. It is concluded that protein kinase C activators cause selective induction of endothelial cell DAF and that DAF synthesis involves protein kinase C activation.
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PMID:Phorbol esters increase synthesis of decay-accelerating factor, a phosphatidylinositol-anchored surface protein, in human endothelial cells. 168 81

Pretreatment of rat peritoneal mast cells with either staurosporine or an analog K-252a [(8R*,9S*,11S*)-(-)-9-hydroxyl-9-methoxycarbonyl-8-methyl-2,3, 9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11-atrizadibenzo- [a,g]cycloocta[cde]trinden-1-one] led to a concentration-related inhibition of histamine release when the cells were stimulated with anti-IgE (IC50: staurosporine = 110 nM; K-252a = 100 nM). In contrast, the two protein kinase C (PKC) inhibitors (1-1000 nM) partially (less than 15%) inhibited histamine release induced by compound 48/80 (0.5 to 1 micrograms/mL). Furthermore, prostaglandin E2 (PGE2) synthesis mediated by anti-IgE from rat peritoneal mast cells was also inhibited by staurosporine and K-252a (IC50 = 100 nM). Exposure of anti-arsenate IgE (anti-Ars-IgE) sensitized mouse bone marrow derived mast cells to arsenate-bovine serum albumin (Ars-BSA) led to the release of both histamine (510 +/- 12.6 ng/10(6) cells) and immunoreactive leukotriene C4 (LTC4) (27.0 +/- 2.6 ng/10(6) cells). Both histamine and LTC4 release was inhibited by staurosporine and K-252a with an IC50 of 50 nM for both compounds. We also characterized a 45K molecular weight protein which is phosphorylated by PKC after Ars-BSA or phorbol, 12-myristate, 13-acetate (PMA) stimulation. This protein is phosphorylated in a broken cell preparation in which PKC is activated by phosphatidylserine/Diolein and Ca2+. Peptide mapping by V8 protease of the phosphorylated 45K protein revealed that the 45K protein phosphorylation patterns induced by IgE or PMA or in the broken cell preparation are identical. Pretreatment of 32P-labeled mouse bone marrow derived mast cells with either staurosporine or K-252a led to a concentration-related inhibition of 45K protein phosphorylation induced by PMA or Ars-BSA. This inhibition of protein phosphorylation correlated well with the inhibition of histamine and leukotriene release in bone marrow derived mast cells.
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PMID:Differential inhibition of histamine release from mast cells by protein kinase C inhibitors: staurosporine and K-252a. 169 82

Nerve growth factor (NGF) cooperates with glucocorticoids, activators of adenylate cyclase, and lithium to induce the expression of teh gene encoding the neuropeptides neurotensin and neuromedin N (NT/N gene) in PC 12 pheochromocytoma cells. High level expression requires simultaneous treatment with three or all four inducers. To examine the mechanism underlying this complex synergism, we have examined the effects of protein kinase inhibitors and other agents which influence intracellular signal transduction on NT/N gene expression. Two structurally similar bacterial alkaloids, staurosporine and K-252a, inhibit several protein kinases in vitro, including protein kinase C and cyclic nucleotide-dependent kinases. K-252a has been reported to specifically inhibit the effects of NGF on PC12 pheochromocytoma cells. Surprisingly, staurosporine in combination with other inducers markedly potentiated NT/N gene expression. In contrast, K-252a had no effect on NT/N gene expression when added simultaneously with other inducers. Expression of the NT/N gene was also potentiated by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, which directly activates protein kinase C, and by bradykinin, which stimulates phosphatidylinositol turnover in PC12 cells, and these effects were not blocked by staurosporine. Staurosporine was generally more effective in stimulating NT/N gene expression when used in inducer combinations that did not include NGF. These results, taken together with recent evidence that staurosporine is also able to induce neurite outgrowth from PC12 cells, suggest that the effects of staurosporine and NGF may converge, in part, on a common intracellular target.
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PMID:A protein kinase inhibitor, staurosporine, mimics nerve growth factor induction of neurotensin/neuromedin N gene expression. 170 31

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