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)

Modulation of renin synthesis by lipoxygenase products has been studied in cultured human mesangial cells under basal conditions and in the presence of prostaglandin (PG) E2. Total renin and cyclic AMP productions were stimulated in a dose-dependent manner (0.1-10 microM) by PGE2. The stimulatory effect of PGE2 on renin production was inhibited by 12-hydroxyeicosatetraenoic acid (12-HETE) between 0.1 and 100 nM. Extracellular and intracellular renin were affected similarly. Neither basal and PGE2-dependent cyclic AMP nor basal cyclic GMP productions were modified. 15-Hydroxyeicosatetraenoic acid (15-HPETE), 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 15-hydroperoxyeicosatetraenoic acid (15-HPETE) had the same effects as 12-HETE. Intracellular calcium concentration was not modified in the presence of 12-HETE. Since oleyl-2-acetylglycerol (OAG), an analog of diacylglycerol, also inhibited PGE2-stimulated renin production, it is hypothesized that the effect of the lipoxygenase products is mediated via protein kinase C stimulation.
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PMID:Modulation of renin synthesis by lipoxygenase products in cultured human mesangial cells. 254 91

This study was undertaken to examine the role of phospholipase A2 and protein kinase C in the potentiation of beta-adrenoceptor-mediated cyclic AMP formation by alpha-adrenoceptors in rat cerebral cortical slices. Inhibition of arachidonic acid metabolism by a range of cyclooxygenase and lipoxygenase inhibitors had no effect on the potentiation of isoprenaline-stimulated cyclic AMP. Conversely, stimulation of leukotriene formation had no effect on the response to isoprenaline. The phospholipase A2 activator, melittin, stimulated cyclic AMP and potentiated the effect of isoprenaline, but these responses were not influenced by cyclooxygenase or lipoxygenase inhibitors. Indomethacin was also ineffective against the potentiation of vasoactive intestinal peptide-stimulated cyclic AMP by noradrenaline. Phorbol ester potentiated the cyclic AMP response to isoprenaline, and this potentiation was antagonized by three different putative protein kinase C inhibitors. However, the same inhibitors did not affect the alpha-adrenoceptor-stimulated enhancement of the response to isoprenaline. We have found no evidence, therefore, to support the suggestion that arachidonic acid and its metabolites and/or protein kinase C mediate the alpha-adrenoceptor modulation of beta-adrenoceptor function.
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PMID:No role for phospholipase A2 and protein kinase C in the potentiation by alpha-adrenoceptors of beta-adrenoceptor-mediated cyclic AMP formation in rat brain. 196 88

Auranofin (AF), a lipophilic chrysotherapeutic agent, was investigated for its effect on the formation of lipoxygenase products and the activity of protein kinase C in human neutrophils. We have previously shown that inhibition of LTB4 formation by 5-lipoxygenase (5-LO) inhibitors is intimately associated with a marked increased in 15-HETE in excess of arachidonic acid. The calcium- and phospholipid-dependent protein kinase, protein kinase C, is activated in FMLP- and A23187-stimulated neutrophils, is hypothesized to stimulate superoxide generation, and plays an essential role in eicosanoid production. AF dose-dependently inhibited the generation of leukotriene B4(LTB4) in FMLP-stimulated neutrophils, the ID50 was approximately 4.5 micrograms/ml. Unlike known 5-LO inhibitors, AF did not enhance the production of 15-HETE. In neutrophils stimulated with the calcium ionophore, A23187, AF did not inhibit the generation of LTB4 nor did AF change the 15-HETE levels. AF inhibited superoxide generation in FMLP-stimulated neutrophils dose-dependently, but did not change the activation of protein kinase C in the cells. We therefore conclude, that AF inhibition of LTB4 production in neutrophils is different from 5-lipoxygenase inhibitors and is elicited at a step distal to protein kinase C activation.
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PMID:Effect of auranofin on eicosanoids and protein kinase C in human neutrophils. 255 Nov 49

7-Bromomethylbenz[a]anthracene (BrMBA) has been shown to have a tumor-promoting action in mouse skin without an initial direct interaction with protein kinase C, which is believed to be a receptor for phorbol ester tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA). An application of BrMBA to mouse dorsal skin caused epidermal ornithine decarboxylase (ODC) induction in a dose-dependent manner with a peak of activity at 12 h after the application. A single topical application of BrMBA failed to induce mouse ear edema formation, i.e. inflammation. However, repeated applications of BrMBA, i.e. twice a week for 3-4 times, caused a significant edema. Unlike TPA, BrMBA failed to stimulate the superoxide anion generation of rabbit peritoneal polmorphonuclear leukocytes. Lipoxygenase inhibitors such as 3,4,2',4'-tetrahydroxychalcone, nordihydroguaiaretic acid, quercetin and 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) effectively inhibited BrMBA-caused epidermal ODC induction and ear edema formation. In addition, BrMBA-caused skin tumor promotion was also potently inhibited by 3,4,2'4'-tetrahydroxychalcone and quercetin. These results indicate that a mechanism susceptible to lipoxygenase inhibitors plays a role not only in the TPA-caused but also in the BrMBA-caused epidermal ODC induction, skin inflammation and tumor promotion. It seems unlikely that superoxide anion generation is involved in the mechanism of BrMBA-caused skin tumor promotion.
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PMID:Inhibition by lipoxygenase inhibitors of 7-bromomethylbenz[a]anthracene-caused epidermal ornithine decarboxylase induction and skin tumor promotion in mice. 255 89

Treatment of hepatocytes with 2,5-di-(tert-butyl)-1,4-benzohydroquinone (tBuBHQ), a novel mobilizer of the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool, produces a sustained elevation of [Ca2+]i (Kass, G. E. N., Duddy, S. K., and Orrenius, S. (1989) J. Biol. Chem. 264, 15192-15198). Exposure of hepatocytes to the Ca2(+)-mobilizing hormones, vasopressin, angiotensin II, or ATP following [Ca2+]i elevation by tBuBHQ produced a rapid return of [Ca2+]i to basal or near basal levels. Release of the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool by tBuBHQ following pretreatment with vasopressin or angiotensin II resulted in a [Ca2+]i transient and not the sustained [Ca2+]i elevation observed in the absence of the Ca2(+)-mobilizing hormones. The G-protein activator, NaF plus AlCl3, mimicked both effects of the Ca2(+)-mobilizing hormones on [Ca2+]i. The mechanism for Ca2+ removal from the cytosol by Ca2(+)-mobilizing hormones did not involve cyclic nucleotides nor did it require protein kinase C activation or cyclo- and lipoxygenase-dependent metabolites of arachidonic acid. Furthermore, the hormone-mediated decrease in [Ca2+]i did not involve the pertussis toxin-sensitive Gi-protein. Removal of the tBuBHQ-mobilized Ca2+ from the cytosol of hepatocytes by Ca2(+)-mobilizing hormones was mediated by stimulation of a Ca2+ efflux pathway. Thus, in addition to initiating [Ca2+]i transients by releasing Ca2+ from the inositol 1,4,5-trisphosphate-sensitive Ca2+ store and stimulating Ca2+ influx, Ca2(+)-mobilizing hormones also regulate the termination of the [Ca2+]i transient by stimulating a Ca2+ efflux pathway.
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PMID:Ca2(+)-mobilizing hormones stimulate Ca2+ efflux from hepatocytes. 255 86

In digitonin-permeabilized bovine adrenal medullary cells, arachidonic acid and oleic acid, the cis-unsaturated fatty acids, enhanced Ca2+-induced secretion of catecholamines, whereas elaidic acid, a trans-unsaturated fatty acid and stearic acid, a saturated fatty acid, had no effect. Indomethacin, an inhibitor of cyclooxygenase and nordihydroguaiaretic acid, an inhibitor of lipoxygenase, failed to inhibit the stimulatory effect of arachidonic acid. Stimulation of catecholamine secretion by arachidonic acid was abolished by the removal of adenosine 5'-triphosphate and Mg2+ from the incubation medium. Pretreatment of the cells with phorbol 12-myristate 13-acetate, an activator of protein kinase C, enhanced Ca2+-induced catecholamine secretion. In cells pretreated with phorbol 12-myristate 13-acetate, the stimulatory effect of arachidonic acid on Ca2+-induced catecholamine secretion was greatly reduced. In digitonin-permeabilized cells, arachidonic acid and oleic acid enhanced Ca2+-induced activation of tyrosine hydroxylase in the presence of adenosine 5'-triphosphate and Mg2+, whereas elaidic acid and stearic acid did not activate the enzyme. In a soluble fraction of adrenal medullary cells, 32P incorporation to histone by protein kinase C was increased by arachidonic acid and oleic acid, but not by elaidic acid and stearic acid. These results suggest that cis-unsaturated fatty acids modulate Ca2+-induced catecholamine secretion and tyrosine hydroxylase activity by activation of protein kinase C in adrenal medullary cells.
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PMID:cis-unsaturated fatty acids stimulate catecholamine secretion, tyrosine hydroxylase and protein kinase C in adrenal medullary cells. 256 57

To evaluate the regulation and effects of pancreatic islet lipoxygenase, adult rat islets were permeabilized, using digitonin or staphylococcal alpha-toxin, and then were studied in a medium simulating an intracellular milieu at fixed ambient concentrations of Ca2+. Permeabilized islets retained 12-lipoxygenase activity, as indicated by conversion of tritiated arachidonic acid to a predominant peak of [3H]12-hydroxyeicosatetraenoic acid (12-HETE); this activity was inhibited (89-98%) by the lipoxygenase blockers nordihydroguaiaretic acid (35 microM), BW755c (250 microM) or ETYA (35 microM). Lesser amounts of compounds coeluting with 15- and 11-HETE (but little or no 5-HETE) were formed; however, 11-HETE (and possibly some 15-HETE) was probably synthesized (at least in part) via cyclooxygenase, as suggested by the partial synthesis blockade induced by 50 microM ibuprofen. The production of 12-HETE did not require the presence of Ca2+, Mg2+ or ATP; it also was not stimulated by addition of cyclic AMP, a phorbol ester, or calmodulin. However, it was augmented modestly by provision of a basal cytosolic free Ca2+ concentration of 60-80 nM, with no further increase at physiologically elevated levels of 260-530 nM. Elevations in cytosolic free Ca2+ concentrations induced insulin release which was inhibited by cooling, epinephrine or protein kinase inhibitors and, therefore, was exocytotic in nature. Lipoxygenase inhibitors blocked this insulinotropic effect of calcium at submaximal or saturating Ca2+ concentrations (with or without its potentiation by 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C) by 53-82%. However, they did not reduce the Ca2+-independent secretory effects (at subnanomolar Ca2+ concentrations) of the phorbol ester alone. Similar results were seen using dibutyryl cyclic AMP to activate protein kinase A. The alpha 2-adrenergic agonists epinephrine or clonidine inhibited Ca2+-, TPA- or cyclic AMP-induced insulin release without reducing HETE formation. We conclude that (1) islet lipoxygenase is constitutively expressed and is not physiologically regulated by alpha 2-adrenergic agonism, Ca2+ or protein kinases; (2) lipoxygenase modulates insulin release; HETE production is not merely an epiphenomenon reflecting the activation (or inhibition) of exocytotic secretion; (3) islet lipoxygenase inhibitors reduce insulin secretion, at least in part, by blocking the direct effects of Ca2+ on exocytosis and/or its synergism with Ca2+-binding proteins such as protein kinase C; and (4) these same inhibitors do not directly poison protein kinase C or A, or the exocytotic apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blockade by lipoxygenase inhibitors of Ca2+-dependent insulin secretion from permeabilized rat islets. A molecular mechanism distinct from that of alpha 2-adrenergic agonists. 256 95

The mechanism of human interleukin (IL)-1 beta-mediated cytolysis was studied in a human melanoma cell line, A375.6. Purified recombinant human IL-1 beta produced 50% cytocidal activity at 50 pg/ml. A variety of compounds were tested for their ability to interfere with A375.6 lysis. Compounds were added simultaneously with IL-1 beta (100 pg/ml), and tumor cytolysis was measured after 72 hr of culture by release of 125I from DNA of A375.6 cells labeled with [125I]-dUrd. A variety of anti-inflammatory/immunosuppressive agents (including auranofin, chloroquine, cyclosporin A, d-penicillamine) and several cyclooxygenase/lipoxygenase inhibitors (AA-861, BW755c, and indomethacin) lacked protective activity. Similarly, phospholipase inhibitors (mepacrine and 4-bromophenacyl bromide), putrescine, inhibitors of lysosomal activity (chloroquine and NH4Cl), calcium channel blockers (nifedipine and verapamil), calmodulin inhibitors (W-7 and calmidazolium), and inhibitors of ADP ribosylation (nicotinamide and 3-aminobenzamide) were inactive. In contrast, corticosteroids (dexamethasone, hydrocortisone, and paramethasone acetate), tilorone, and protein kinase C inhibitors (1-[5-isoquinolinyl-sulfonyl]-2-methylpiperazine and staurosporine) significantly inhibited IL-1 beta-mediated A375.6 cytolysis. These compounds also interfered with tumor necrosis factor-mediated lysis of A375.6, suggesting common mechanisms of tumor cytotoxicity by these monokines. This model may be useful for delineating intracellular biochemical events integral to IL-1 action.
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PMID:Potent inhibition of interleukin 1 beta-mediated human melanoma (A375.6) lysis by corticosteroids, staurosporine, and tilorone. 262 25

The present study investigated the effects of 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17,20 B-P) on (1) ovulation of isolated perch follicles in which the extrafollicular (EF) ovarian tissue had been removed; (2) prostaglandin F (PGF) and prostaglandin E (PGE) synthesis in EF tissue and intact (= follicles attached to EF tissue) and isolated follicles by radioimmunoassay and [14C]arachidonic acid incorporation; and (3) proteolysis in EF tissue and intact and isolated follicles by substrate sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In addition, the ovulatory and proteolytic effects of the phorbol ester, phorbol-12-myristate-13-acetate (PMA), and the calcium ionophore A23187 on 17,20B-P-stimulated follicles were also studied in the presence/absence of indomethacin (IM) and nordihydroguaiaretic acid (NDGA). Ultrastructural analyses revealed that the preparation of isolated follicles also removed the surface epithelium of the follicle. While 17,20B-P stimulated ovulation and an increase in PGF and PGE in incubates of intact perch follicles, it did not in incubates of isolated follicles. In contrast, PMA, A23187, and a combination of PMA and A23187 stimulated ovulation of these isolated follicles. PMA/A23187-induced ovulation could be blocked by NDGA but not IM, and two hydroxyeicosatetraenoic acids (11- and 15-HETEs) were capable of partially reversing the NDGA block. Incorporations with [14C]arachidonic acid revealed that the EF tissue had a significant potential to produce PGF; however, 17,20B-P did not stimulate an increase in PGF or PGE (measured by RIA) in incubates of EF tissue alone. In addition, neither ovulation nor an increase in prostaglandins was observed in cocultures of isolated follicles and EF tissue. One major protease (66 kDa) was observed in the medium during incubation of intact and isolated perch follicles. No protease activity was present in incubates of EF tissue alone. Protease activity in 17,20B-P-stimulated incubates of intact tissue was significantly higher than in steroid-stimulated incubates of isolated follicles. Protease activity increased in the medium during incubation with PMA or a combination of PMA and A23187. This activity was blocked by NDGA but not IM. The NDGA block was partially reversed by 11-HETE. The combined results suggest that there is an interaction of EF tissue and follicle that is necessary, particularly for the stimulation of ovulation and prostaglandin production. Further, the results with phorbol esters and NDGA suggest that the follicular control of ovulation in perch may involve protein kinase C acting through the production of a lipoxygenase product.
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PMID:In vitro ovulation, prostaglandin synthesis, and proteolysis in isolated ovarian components of yellow perch (Perca flavescens): effects of 17 alpha,20 beta-dihydroxy-4-pregnen-3-one and phorbol ester. 279 31

Exposure of isolated SENCAR mouse epidermal cells to the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) in vitro resulted in the production of oxidant species detected as chemiluminescence. This oxidant response can be inhibited by superoxide dismutase and copper complexes but not catalase or scavengers of hydroxyl radical or singlet oxygen, suggesting that the oxidant is superoxide anion. Inhibitors of various parts of the arachidonate cascade affect the TPA-induced oxidant response in a manner that corresponds to their effects on in vivo tumor promotion experiments. Agents that inhibit lipoxygenase activity, i.e. nordihydroguaiaretic acid, benoxaprofen, but not agents that are cyclooxygenase inhibitors, i.e. indomethacin, are effective in suppressing the oxidant response to TPA. Phospholipase C but not phospholipase A2 or D produced an oxidant response kinetically similar to that elicited by TPA. The inhibitors of TPA-induced oxidants inhibited the phospholipase C response to the same extent, suggesting that TPA and phospholipase C may produce an oxidant species through a common mechanism, via phospholipid turnover-protein kinase C activation. The relevance of oxidant production to the tumor promotion process is suggested by the ability of exogenous xanthine/xanthine oxidase, a superoxide anion-generating system, to induce ornithine decarboxylase, a characteristic of TPA-treated cells. In addition, oxidant production is significantly lower in cells from the TPA-promotion resistant C57BL/6J mouse. These studies provide further support for a role for reactive oxygens in the tumor promotion process.
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PMID:Reactive oxygen in the tumor promotion stage of skin carcinogenesis. 284 22


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