Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Prostaglandin E2 (PGE2) release from primary cultures of mouse epidermal cells was markedly stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein and 1-oleoyl-2-acetyl-glycerol but not by 4 alpha-phorbol-12,13-di-decanoate in low Ca2+ (50 microM) medium. TPA-evoked PGE2 release was inhibited by mepacrine, indomethacin and H-7 but not by HA1004. These findings suggest that TPA stimulates PGE2 release through activation of protein kinase C, phospholipase A2 and the cyclooxygenase pathway. Of the non-TPA type of tumor promoting agents, i.e. anthralin, chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, only anthralin stimulated PGE2 release. Anthralin-evoked PGE2 release was not inhibited by H-7. In normal Ca2+ (1.8 mM) medium, PGE2 release increased markedly compared to the release in low Ca2+ medium. In normal Ca2+ medium, PGE2 release was stimulated by TPA, anthralin and okadaic acid but not by other tumor promoting agents. In mouse peritoneal macrophages, TPA, palytoxin and okadaic acid stimulated PGE2 release, but other tumor-promoting agents failed to stimulate it. These results suggest that skin tumor promoting agents are not necessarily effective stimulators of prostaglandin production either in macrophages or in epidermal cells, the target cells of skin tumor promotion.
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PMID:Differential effects of various skin tumor-promoting agents on prostaglandin E2 release from primary cultures of mouse epidermal cells. 211 11

We assessed the effects of the peptide agonist, bradykinin (BK), and phorbol myristate acetate (PMA) on prostaglandin E2 (PGE2) production, cyclooxygenase (COX) activity and mass, and arachidonic acid (AA) release in Madin Darby canine kidney (MDCK) cells. PMA stimulated PGE2 production by increasing both AA release and the activity of COX. Using [35S]methionine labeling and immunoprecipitation, we demonstrated that the increased COX activity is due to new COX synthesis. Actinomycin D and cycloheximide blocked the PMA-stimulated COX activity but not AA release. Both PMA-stimulated AA release and COX activity were reduced by the protein kinase C inhibitor staurosporine (STP). Glucocorticoids failed to alter PMA- or BK-stimulated PGE2 production was reduced by STP, indicating BK acts in part through protein kinase C activation. BK increased PGE2 production in PMA-treated cells, suggesting a protein kinase C-independent mechanism of action as well. BK did not stimulate any change in COX activity. We conclude that in MDCK cells PMA, but not BK, can stimulate both AA release and COX synthesis. Stimulation of COX synthesis requires either prolonged activation of protein kinase C and/or an additional nonprotein kinase C-mediated effect of PMA.
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PMID:Regulation of eicosanoid biosynthesis by phorbol ester in Madin Darby canine kidney cells. 212 Oct 48

IL-1 stimulates PGE2 production in human fibroblasts by stimulating arachidonic acid (AA) mobilization and cyclooxygenase synthesis. Cyclooxygenase is the first enzyme in the pathway that converts AA to PGE2. To examine the role of protein kinase C (PKC) in IL-1-mediated PGE2 production, we treated cells with PMA, which stimulated PGE2 production suggesting a positive role for PKC activation in the regulation of PGE2 synthesis. Therefore, we tested the effect of sphingosine, a PKC inhibitor, on IL-1-induced PGE2 production. Alone, sphingosine had little effect on PGE2 production. However, when sphingosine was added with IL-1, or IL-1 was added to sphingosine-pretreated cells, PGE2 production increased severalfold, suggesting that the inhibition of PKC results in enhanced IL-1-mediated PGE2 production; structural analogs of sphingosine did not potentiate the IL-1 effect. In cells made deficient in PKC by prolonged exposure to PMA, IL-1-mediated PGE2 production was enhanced compared with normal cells, further suggesting that functional PKC is not required for, and may down-modulate, IL-1-mediated PGE2 production. These findings also suggest that PMA and IL-1 stimulate PGE2 synthesis via fundamentally different pathways. In separate studies on the effect of IL-1 on AA mobilization, we found that IL-1 induced an increase in phospholipase A2 (PLA2) activity and that cycloheximide blocked the increase, suggesting the requirement for new protein synthesis. We also found that the PLA2 activity increased as a result of IL-1 exposure was further stimulated by sphingosine. Thus, in addition to its primary effects on the cell, which are likely mediated via PKC, we present evidence suggesting that sphingosine may also play a role in potentiating an IL-1-induced PLA2 activity, resulting in increased availability of AA for conversion to PGE2.
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PMID:Sphingosine potentiates IL-1-mediated prostaglandin E2 production in human fibroblasts. 212 39

Endothelial cells have the capacity to metabolize several important lipids; this includes the ability to store and then metabolize arachidonate, as well as the capacity to synthesize platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine). Arachidonate is predominantly metabolized via cyclooxygenase to PGI2 although the spectrum of prostaglandins may vary depending upon the source of the endothelial cell. Biosynthesis of eicosanoids and PAF are likely to be an important physiologic function of the endothelial cell as these potent lipids appear to have a role in maintaining vascular tone and mediating interactions of the endothelium with circulating inflammatory cells. In addition to production of eicosanoids and PAF, endothelial cells metabolize exogenous arachidonate and arachidonate metabolites and other fatty acids such as linoleate to bioactive compounds (HODEs). There is also evidence that small amounts of arachidonate are metabolized via a lipoxygenase. The physiologic significance of these minor lipid pathways is not known at this time. Production of eicosanoids and PAF is not a constitutive function of the endothelial cell. Lipid biosynthesis by endothelial cells is one component of the early activation response that occurs in response to stimulation with pro-inflammatory and vasoactive hormones or to pathologic agents such as oxidants and bacterial toxins. A central mechanism for activation of the relevant pathways is a rise in cellular calcium concentrations that can be mediated by hormone-receptor-binding or by direct permeabilization of the cell membrane to calcium (Fig. 3). Regulatory mechanisms distal to the calcium signal are unknown, but current evidence suggests that calcium directly or indirectly activates phospholipases that release arachidonate from phospholipids and hydrolyze a specific phospholipid to the immediate precursor of PAF. There is evidence that protein kinase C may, in part, regulate this process, but the role of other potential regulatory components, such as other protein kinases or G-proteins is not known. As noted above, the most direct mechanism for initiation of PAF biosynthesis and arachidonate release would be activation of a phospholipase A2 as shown in Fig. 3. Activation of other phospholipases (e.g. phospholipase C) may contribute to the total amount of arachidonate released, although the magnitude of that contribution is not yet known. In addition to generation of PAF and eicosanoids, activation of endothelial cell phospholipases generates second messengers that are important in intracellular signaling (Fig. 4). Activation of phospholipase C, in response to hormonal stimulation, generates diacylglycerol and inositol phosphates from phosphatidylinositol. Each of these is a potent intracellular second messenger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lipid metabolism and signal transduction in endothelial cells. 212 4

LPS has been identified as a potent activator of mononuclear phagocytes. This activation is associated with TNF gene expression. The intracellular signaling mechanisms responsible for this effect, however, are unknown. The present studies demonstrate that LPS induces TNF transcripts in HL-60 promyelocytic leukemia cells. Because previous studies have demonstrated that eicosanoids are involved in the regulation of TNF gene expression in these cells, we examined the effects of LPS on activation of the arachidonic acid cascade. The results demonstrate that LPS stimulates phospholipase A2 activity and the hydrolysis of both 1,2-dipalmitoyl phosphatidylcholine and 1-steroyl 2-arachidonoyl phosphatidylcholine. In contrast, there was no detectable effect of LPS on activation of protein kinase C. We also demonstrate that inhibition of phospholipase A2 activity with bromophenacyl bromide or quinacrine blocks the induction of TNF transcripts by LPS. These findings suggested that LPS induces TNF gene expression through formation of arachidonic acid metabolites. Indeed, similar results were obtained with mellitin, a known activator of phospholipase A2 and eicosanoid production. Previous studies have also suggested that TNF mRNA levels are increased in HL-60 cells by the 5-lipoxygenase pathway and, in the present work inhibitors of this enzyme blocked LPS-induced TNF expression. Moreover, the cyclooxygenase metabolite, PGE2, as well as dibutyryl cAMP, inhibited the induction of TNF transcripts by LPS. Taken together, these results suggest that LPS induces TNF gene expression through activation of phospholipase A2 and that the level of this induction is regulated by activity of the 5-lipoxygenase and cyclooxygenase pathways.
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PMID:Effects of lipopolysaccharide on phospholipase A2 activity and tumor necrosis factor expression in HL-60 cells. 215 30

A BALB/c 3T3 cell line infected with the temperature-sensitive Rous sarcoma virus strain LA90 has been used to investigate early, p60v-src-dependent changes in gene expression (protein synthesis). Giant two-dimensional electrophoresis, which can resolve greater than 3000 polypeptides from [35S]methionine-labeled cell lysates, was used to detect the induction of a p72-74 (72-74 kDa) doublet (pI 7.5) after activation of p60v-src at 35 degrees C. Antiserum against cyclooxygenase (prostaglandin synthase or prostaglandin endoperoxide synthase) specifically immunoprecipitated the p72-74 doublet. The p72-74 doublet was also induced by platelet-derived growth factor and by phorbol 12-myristate 13-acetate and was elevated in an NIH 3T3 cell line transformed by wild-type src. Activation of p60v-src caused a persistent increase in p72-74, whereas the effect of the growth factor was transient. These dissimilar kinetics of induction were paralleled by changes in cyclooxygenase activity. Down-regulation of protein kinase C inhibited subsequent induction of cyclooxygenase by phorbol myristate acetate but did not block induction by p60v-src. The glucocorticoid agonist dexamethasone inhibited induction of cyclooxygenase by p60v-src. Although induction of this enzyme may not be directly involved in transformation, the data support the view that oncogenic transformation may result, not from expression of transformation-specific genes, but from persistent changes in the expression of genes normally induced only transiently during passage from the G0 stage of the cell cycle.
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PMID:Persistent induction of cyclooxygenase in p60v-src-transformed 3T3 fibroblasts. 215 48

Alveolar macrophages (AM) differ from other macrophage (m phi) populations in their profile of eicosanoids synthesized from arachidonic acid (AA)3. Little information is available regarding possible differences in the regulation of AA metabolism among various m phi populations. In our study, we compared the ability of cultured resident rat AM and peritoneal m phi (PM) to release and metabolize AA in response to exogenous activators of protein kinase C (PKC). When stimulated with PMA, prelabeled PM released free [3H]AA in a dose-dependent manner over the concentration range 1 to 100 nM. As assessed by HPLC, PMA-stimulated PM metabolized AA to a variety of predominantly cyclooxygenase products. The dose-dependent synthesis of PGE2 by unlabeled PM stimulated with PMA was confirmed using RIA. The ability of PMA to trigger AA release and metabolism in PM was a function of its capacity to activate PKC, as indicated by the following: 1) an additional activator of PKC, oleoyl acetylglycerol, also triggered PM AA metabolism, whereas phorbol didecanoate, which lacks the ability to activate PKC, did not; 2) two structurally unrelated inhibitors of PKC activation (staurosporine and sphinganine) both abrogated PMA induced AA release in PM; and 3) pretreatment for 18 h with high dose PMA (used to deplete cellular PKC), but not phorbol didecanoate, rendered PM refractory to subsequent PMA stimulation of AA release. In contrast to PM, AM cultured in identical fashion failed to release or metabolize AA in response to either PMA or oleoyl acetylglycerol. PM and AM were also compared for their ability to release extracellular superoxide anion in response to PMA; once again, PM exhibited significantly greater release than did AM. Inasmuch as this unresponsiveness to activation of PKC distinguishes AM from other m phi populations, we conclude that it is a unique consequence of m phi differentiation in the lung. Moreover, because both AA metabolism and the respiratory burst are affected, this refractoriness appears to reflect a defect at some proximal level in PKC-mediated signaling.
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PMID:Diminished protein kinase C-activated arachidonate metabolism accompanies rat macrophage differentiation in the lung. 216 Apr 99

Phorbol 12,13-dibutyrate, an activator of protein kinase C, stimulates electrogenic anion secretion in chicken ileum. This effect can be inhibited by the cyclooxygenase inhibitor piroxicam, suggesting arachidonic acid metabolites as mediators. Phorbol 12,13-dibutyrate stimulates increases in prostaglandin E2 release and mucosal 3',5'-cyclic adenosine monophosphate content in intact mucosa. Stimulation of prostaglandin E2 release appears to come mainly from the subepithelial compartment and not from epithelial cells. Unlike its effect on anion secretion, phorbol 12,13-dibutyrate inhibition of sodium uptake by sodium-hydrogen exchange in isolated mature villus enterocytes is not inhibited by piroxicam. This study concludes that phorbol ester effects on anion secretion in chickens appear to be mediated by arachidonic acid metabolites most likely produced by cells of the lamina propria and submucosa, whereas phorbol ester effects on inhibiting upper villus cell sodium-hydrogen exchange may be a direct effect of phorbol esters.
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PMID:Phorbol ester-stimulated secretion in chicken ileum: role of arachidonic acid metabolism. 216 37

Studies were performed to examine interactions between the adenylyl cyclase (AC) and phospholipase C (PLC) signaling systems in cultured rat inner medullary collecting duct cells. Stimulation of AC by either arginine vasopressin (AVP) or forskolin or addition of exogenous cAMP inhibits epidermal growth factor (EGF)-stimulated PLC. This inhibition is mediated by activation of cAMP-dependent kinase as it is prevented by pretreatment with the A-kinase inhibitor, N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H8) but not by the C-kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7). Exposure to EGF eliminates AVP-stimulated cAMP generation. This is not mediated by a cyclooxygenase product as inhibition by EGF is observed even in the presence of the cyclooxygenase inhibitor, flurbiprofen. Inhibition by EGF is not due to an increase in inositol trisphosphate (IP3) as exposure of saponin-permeabilized cells to exogenous IP3 is without effect. Inhibition by EGF is prevented by pretreatment with the C-kinase inhibitor, H7, but not by the A-kinase inhibitor, H8. Exposure to the synthetic diacylglycerol (DAG), dioctanoylglycerol, also inhibits AVP-stimulated AC activity; therefore, inhibition by EGF is due to activation of protein kinase C. Thus, in cultured rat inner medullary collecting duct cells, cAMP and DAG function as mutually inhibitory second messengers with each impairing formation of the other.
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PMID:Cyclic adenosine monophosphate and diacylglycerol. Mutually inhibitory second messengers in cultured rat inner medullary collecting duct cells. 216 48

The present study examined responses of cultured rat glomerular mesangial cells to exogenous exposure of epoxyeicosatrienoic acids (EET's), products of cytochrome P450 epoxygenase. One day after administration of 8,9- or 14,15-EET, cultured rat mesangial cells demonstrated significant increases in [3H]thymidine incorporation (10(-7) M 14,15-EET: 120 +/- 7% of control; n = 6; P less than 0.025; 10(-6) M 14,15-EET: 145 +/- 10%; n = 20; P less than 0.0005; 10(-6) M 8,9-EET: 167 +/- 31%; n = 9; P less than 0.05), which was not affected by addition of the cyclooxygenase inhibitor indomethacin. In addition to stimulation of [3H]thymidine incorporation, the epoxides stimulated mesangial cell proliferation. 14,15-EET administration induced intracellular alkalinization of 0.2-0.3 pH units, which was prevented by extracellular Na+ removal and blunted by amiloride (0.5 mM). Following intracellular acidification with NH4Cl addition and removal, greater than 85% of 3 mM 22Na uptake into mesangial cells was inhibited by 1 mM amiloride, indicating Na+/H+ exchange. Under these conditions, 14,15-EET stimulated Na+/H+ exchange by 42% and 8,9-EET stimulated Na+/H+ exchange by 59%. Neither protein kinase C depletion nor addition of the protein kinase C inhibitor, staurosporine, affected this stimulation. In [3H]myo-inositol loaded mesangial cells, no significant stimulation of phosphoinositide hydrolysis was detected in response to administration of 14,15-EET. Twenty-four hours after addition of [14C]14,15-EET, greater than 90% was preferentially esterified to cellular lipids, with predominant incorporation into phosphatidylinositol, phosphatidylethanolamine, and diacylglycerol. Thus, these results demonstrate epoxyeicosatrienoic acids stimulate Na+/H+ exchange and mitogenesis in mesangial cells. These effects do not appear to be mediated via phospholipase C activation. In addition, 14,15-EET was selectively incorporated into cellular lipids known to mediate signal transduction. These observations extend the potential biologic roles of c-P450 arachidonate metabolites to include stimulation of cell proliferation and suggest a role for these compounds in vascular and renal injury.
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PMID:Epoxyeicosatrienoic acids activate Na+/H+ exchange and are mitogenic in cultured rat glomerular mesangial cells. 216


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