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)

Bryostatin 1, a macrocyclic lactone, functions like the phorbol esters biochemically in binding to and activating protein kinase C. Biologically, however, although it induces some phorbol ester responses such as mitogenesis in Swiss 3T3 cells, it paradoxically blocks the effects of the phorbol esters on differentiation in HL-60 promyelocytic leukemia cells and Friend erythroleukemia cells. Since the phorbol esters induce proliferation and terminal differentiation in distinct subpopulations of epidermal basal cells, we have now examined the action of bryostatin 1 in that system. Bryostatin 1 decreased epidermal growth factor binding and induced ornithine decarboxylase activity, the latter a marker of proliferation. The magnitude of the maximal induction of ornithine decarboxylase was less than for phorbol 12,13-dibutyrate. Bryostatin 1 only transiently caused the morphological change typical of phorbol ester treatment and did not induce transglutaminase or cornified envelope production, markers of the differentiative pathway. Combined treatment with bryostatin 1 and phorbol 12,13-dibutyrate gave similar results to treatment with bryostatin 1 alone, i.e., slight reduction to complete inhibition of phorbol ester action, depending on the response. The mechanism may reflect time dependent block of the protein kinase C pathway by bryostatin 1 in this system; although bryostatin 1 inhibited epidermal growth factor binding at short incubation times (1-2 h), by 4 h of incubation its inhibition was markedly reduced and it correspondingly blocked inhibition of epidermal growth factor binding by phorbol 12,13-dibutyrate. Since induction of terminal differentiation is proposed to be an essential component of phorbol ester mediated tumor promotion in skin, our findings suggest that bryostatin 1 may function as an inhibitor of phorbol ester promotion.
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PMID:Partial parallelism and partial blockade by bryostatin 1 of effects of phorbol ester tumor promoters on primary mouse epidermal cells. 288 31

We have found many compounds that amplify the action of glucocorticoid without themselves having any glucocorticoid-like action and have proposed the concept of 'Glucocorticoid Action Biomodulators'. These biomodulators consist of 'Glucorticoid Sensitivity Amplifiers', which greatly amplify the action of glucocorticoid at doses of glucocorticoid that alone have minimal effects, and 'Glucocorticoid Potency Amplifiers', which markedly enhance the effect of glucocorticoid at doses that have maximal effects. Potent activators of protein kinase C, such as 1,2-racemic dioctanoylglycerol, 12-o-tetradecanoyl-phorbol-13-acetate, and epidermal growth factor (EGF), markedly enhanced the induction of tyrosine aminotransferase and ornithine decarboxylase by dexamethasone in adrenalectomized rats in vivo and in primary cultures of adult rat hepatocytes in vitro. They amplified enzyme induction by even a large amount of dexamethasone that had a maximal effect, but had no effect in the absence of glucocorticoid. These modes of amplification show that these compounds are 'Glucocorticoid Potency Amplifiers'. They amplified not only enzyme induction in liver but also growth inhibition by glucocorticoid of solid tumor L5178Y lymphoblasts. They specifically amplified the actions of glucocorticoids and did not amplify the actions of other steroids, such as 17-beta estradiol, glucagon and insulin. The induction of tyrosine aminotransferase by glucocorticoid and its amplification by EGF were both inhibited by 1-(5-iso-quinoline-sulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, and not by N-[2-(methylamino)-ethyl]-5-isoquinoline-sulfonamide, an inhibitor of cyclic nucleotide dependent protein kinases, suggesting that the induction and the amplification are mediated by protein kinase C.
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PMID:Studies on biomodulators of glucocorticoid actions; the nature and the modes of actions of glucocorticoid potency amplifiers. 289 Feb 79

Staurosporine, a recently described microbial alkaloid, is uniquely potent as an inhibitor of protein kinase C in vitro, being active at nM concentrations rather than the microM concentrations typical of other inhibitor classes. Like these other inhibitors, however, staurosporine exhibits only limited selectivity among different protein kinases. We report here that, in intact human neutrophils, nM concentrations of staurosporine blocked the action of the phorbol ester tumor promoters. In mouse primary epidermal cells, on the other hand, staurosporine failed to block the effects of phorbol 12,13-dibutyrate on epidermal growth factor binding and on induction of ornithine decarboxylase and epidermal transglutaminase. Unexpectedly, staurosporine induced morphological changes in keratinocytes to a dendritic shape resembling that induced by the phorbol esters. It also induced epidermal transglutaminase and cornified envelope production, markers of the differentiative pathway in the epidermal cells. We conclude that the effectiveness of staurosporine as a protein kinase C inhibitor in intact cells may depend markedly on the cell system. Other actions of staurosporine may predominate, and, in keratinocytes, its activity is suggestive of a tumor promoter rather than of an inhibitor of tumor promotion.
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PMID:Contrasting actions of staurosporine, a protein kinase C inhibitor, on human neutrophils and primary mouse epidermal cells. 289 57

Nerve growth factor (NGF) causes pheochromocytoma cells (PC12) to undergo a number of physiological changes which mimic the differentiated neuronal cell, including neurite extension. We have examined protein kinase C (Ca2+/phospholipid-dependent enzyme) as a potential signaling mechanism in NGF-stimulated neurite outgrowth and induction of the enzyme ornithine decarboxylase. Phorbol 12-myristate 13-acetate (PMA) can activate protein kinase C and induce ornithine decarboxylase in PC12 cells with kinetics which are similar to those of NGF induction, but only to levels about 10-fold lower. The induction of ornithine decarboxylase by both NGF and PMA is inhibited by cycloheximide and actinomycin D suggesting that both agents increase enzyme activity by increasing gene transcription. The evidence presented here, however, shows that the induction produced by the two agents is through two different pathways. First, maximal induction by NGF is increased when PMA is included in the media showing that the two effects are synergistic. Second, NGF does not cause induction of ornithine decarboxylase in the mutant PC12nnr5 cell line (Green, S.H., Rydel, R.E., Connolly, J.L., and Greene, L.A. (1986) J. Cell Biol. 103, 1967-1978) while added PMA does produce an induction of the enzyme. Finally, when protein kinase C is down-regulated by incubating PC12 cells with PMA in serum-containing or serum-free medium for 24 h, the induction by PMA is completely inhibited, while the NGF induction is not affected. A recent study (Hall, F.L., Fernyhough, P., Ishii, D.N., and Vulliet, P.R. (1988) J. Biol. Chem. 263, 4460-4466) using sphingosine inhibition concluded that protein kinase C was required for NGF-stimulated neuritogenesis. In contrast, results presented here show that down-regulation of protein kinase C also has no effect on NGF-mediated neurite extension in PC12 cells grown in serum-free medium. Our data demonstrate that induction of ornithine decarboxylase and formation of neurites in PC12 cells by NGF does not require a protein kinase C-mediated pathway.
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PMID:The lack of a role for protein kinase C in neurite extension and in the induction of ornithine decarboxylase by nerve growth factor in PC12 cells. 291 63

When guinea pig lymphocytes were cultured with 1-oleoyl-2-acetyl-glycerol (OAG), A23187, and cholera toxin, ornithine decarboxylase activity was induced synergistically, peaking at 6 h. Addition of 12-O-tetradecanoyl-phorbol 13-acetate (TPA), A23187, and dibutyryl cAMP caused the same kind of induction. Cholera toxin potentiated the ability of A23187 to induce ornithine decarboxylase, but not that of OAG. Dibutyryl cAMP augmented the induction caused by A23187 but not by TPA. These results suggest that both the activation of Ca++-sensitive, phospholipid-dependent protein kinase (protein kinase C) and the increase in intracellular levels of Ca++ and cAMP are necessary for this induction. cAMP may potentiate the induction by modulating a Ca++ messenger system other than that for protein kinase C activation.
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PMID:Synergistic induction of ornithine decarboxylase by diacylglycerol, A23187, and cholera toxin in guinea pig lymphocytes. 299 66

We reported previously that 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], a hormonally active form of vitamin D3, markedly enhanced methylcholanthrene-induced transformation of BALB 3T3 A31-1-1 cells. When the cells were treated with methylcholanthrene (1 microgram/ml) for 72 h and then with 1 alpha,25(OH)2D3 (5 ng/ml) for 2 wk, the transformation frequency was 1.95 +/- 0.73 (SD) foci/dish in 8 independent experiments, which was about 20 times that in cultures treated with methylcholanthrene only. Even at a physiological concentration in plasma, i.e., 0.05 ng/ml, 1 alpha,25(OH)2D3 enhanced the transformation frequency significantly (P less than 0.001). 1 alpha,25(OH)2D3 was not cytotoxic but slightly inhibited growth of the cells. Cells treated with 1 alpha,25(OH)2D3 were thin and became arranged in a meshwork with wide intercellular spaces. These morphological changes were reversible. 1 alpha,25(OH)2D3 induced DNA synthesis in quiescent BALB 3T3 cells dose and time dependently, but this effect was less than that of 12-O-tetradecanoylphorbol-13-acetate. Unlike 12-O-tetradecanoylphorbol-13-acetate, 1 alpha,25(OH)2D3 did not interfere with the binding of epidermal growth factor or phorbol dibutyrate. 1 alpha,25(OH)2D3 did not induce ornithine decarboxylase. Moreover, it did not activate protein kinase C in quiescent BALB 3T3 cells or this enzyme isolated from mouse brain. BALB 3T3 cells and their transformants contain a specific cytosol receptor for 1 alpha,25(OH)2D3, but the binding sites of the transformants were fewer and had lower affinity than those of untransformed BALB 3T3 cells. These effects of 1 alpha,25(OH)2D3 were specific, because other derivatives of vitamin D3 induced the same effects only at 200 times or more higher concentrations.
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PMID:Enhancement by 1 alpha,25-dihydroxyvitamin D3 of chemically induced transformation of BALB 3T3 cells without induction of ornithine decarboxylase or activation of protein kinase C1. 300 May 80

We have shown previously that in rat tracheal epithelial 2C5 cells the induction of ornithine decarboxylase (ODC) activity and the reduction in the binding of epidermal growth factor (EGF) by diacylglycerol is related to the activation of protein kinase C. In this paper we analyse the action of retinoic acid (RA) on these two parameters in order to determine whether RA acts on the level of protein kinase C. RA inhibits the induction of ODC activity by diacylglycerol (sn-1,2-dioctanoylglycerol) in a dose- and time-dependent manner. A biologically inactive analog of RA has no effect on this induction. RA does not affect the activation of protein kinase C by diacylglycerol in an in vitro assay. In contrast to the effect on ODC induction, RA does not counteract the reduction in EGF binding induced by diacylglycerol. These results are consistent with the concept that RA does not act at the level of protein kinase C and inhibits ODC induction during a stage following protein kinase C activation.
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PMID:Action of retinoic acid on the diacylglycerol-induced ornithine decarboxylase activity, reduction in EGF binding and protein kinase C activation in rat tracheal epithelial 2C5 cells. 301 43

The activation of protein kinase C and protein phosphorylation by tumor promoters were examined using quiescent cultures of BALB/3T3 and C3H/10T1/2 cells, because in these cells tumor promoters enhance chemically induced transformation and also induce DNA synthesis and ornithine decarboxylase. The cytosol and membrane fractions were partially purified, and the activity of protein kinase C was assayed. In quiescent cells, protein kinase C activity was found only in the cytosol fraction. Treatment with 100 ng of 12-O-tetradecanoylphorbol-13-acetate or teleocidin B per ml caused rapid translocation of protein kinase C from the cytosol to the membrane fraction. The activity in the cytosol disappeared almost completely after 15 min when the activity in the membrane reached a peak. The membrane activity gradually decreased to the control level after 6 h, while no activity reappeared in the cytosol within 6 h. Under these circumstances, a membrane protein with a molecular weight of 90,000 and pl of 4.0-4.4 (termed p90) was specifically phosphorylated, possibly by the activated protein kinase C, in both cell-free and intact-cell systems. On treatment of quiescent BALB/3T3 cells with 100 ng of 12-O-tetradecanoylphorbol-13-acetate, p90 phosphorylation increased 2-fold in 1 min, reaching a peak in 15 min of 3.4-fold the initial value. The phosphorylation of p90 increased with increase in the concentrations of 12-O-tetradecanoylphorbol-13-acetate between 0.1 and 10 ng/ml and reached a plateau at 10 ng/ml. p90 phosphorylation also occurred on exposure of the cells to non-phorbol ester tumor promoters (mezerein and teleocidin B) and growth factors, such as platelet-derived growth factor and fibroblast growth factor. p90 was not immunoprecipitated by antibody against the insulin receptor. Phosphorylation of p90 occurred at a serine residue. The present study suggests that activation of protein kinase C and phosphorylation of p90 by it are early events leading to tumor promotion.
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PMID:Activation of protein kinase C and specific phosphorylation of a Mr 90,000 membrane protein of promotable BALB/3T3 and C3H/10T1/2 cells by tumor promoters. 308 Feb 29

Palmitoylcarnitine, which has been reported to be an inhibitor of calcium-activated, phospholipid-dependent protein kinase (protein kinase C), inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase in mouse skin in a dose-dependent manner. Neither acetylcarnitine nor palmitic acid inhibited TPA-caused ornithine decarboxylase induction. In addition, palmitoylcarnitine markedly inhibited skin tumor promotion induced by TPA. Palmitoylcarnitine inhibited epidermal protein kinase C activity which was stimulated by Ca2+ in the presence of phosphatidylserine but failed to inhibit the enzyme activity which was stimulated by TPA in the presence of either phosphatidylserine or Ca2+ plus phosphatidylserine. Therefore, it seems unlikely that the potent anti-tumor-promoting action of palmitoylcarnitine, which is shown in the present study, is explained solely by its effect on protein kinase C.
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PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and epidermal ornithine decarboxylase activity in mouse skin by palmitoylcarnitine. 308 Dec 51

N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) inhibited epidermal ornithine decarboxylase (ODC) induction caused either by 12-O-tetradecanoylphorbol-13-acetate (TPA) or teleocidin in CD-1 mice. Inhibitory effect of W-7 on TPA-caused ODC induction was also observed in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated skin and even after repetitive TPA treatment. TPA-induced skin tumor promotion was also suppressed by W-7. Meanwhile, W-7 showed only slight inhibitory effects on calcium-activated, phospholipid-dependent protein kinase (protein kinase C) activity of mouse epidermis stimulated either by Ca2+ or TPA in the presence of phosphatidylserine. Thus, it is unlikely that the anti-ODC-inducing and anti-tumor-promoting actions of W-7 are due to its inhibitory effect on protein kinase C. It may be possible that a calmodulin-mediating process is involved in the mechanism of epidermal ODC induction and tumor promotion caused by tumor promoters such as TPA and teleocidin.
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PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and tumor promotion by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) in mouse skin. 308 37


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