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)

Recruitment of inflammatory cells to the lung capillaries has been proposed as an important step in the sequence of events that lead to acute lung injury. Frequently, in the clinical setting, bacteremia and sepsis syndrome precede the acute lung failure and endotoxin priming may represent a comparable paradigm, useful for experimental pursuit. Following addition of the chemotactic tripeptide FMLP (10(-9) to 10(-6) M) to the cell-free, salt solution perfusate of isolated rat lungs, only a small degree of vasoconstriction was observed. However, in lungs isolated from rats that received 2 mg/kg intraperitoneal Salmonella enteritidis endotoxin 2 h before lung perfusion, FMLP dose dependently caused a large, transient pulmonary pressor response, edema formation, and release of large amounts of thromboxane and leukotriene B4. Since in vitro priming with endotoxin, direct vascular injury by neutrophil elastase, nor direct stimulation with FMLP of pulmonary artery rings from endotoxin-pretreated rats, mimicked the effects of in vivo endotoxin priming, we conclude that the presence of inflammatory cells in the lung capillaries accounted for the large amount of eicosanoids produced by the lungs after FMLP stimulation. In fact, by retrograde lavage of the lung circulation with a collagenase solution, previously adherent cell clumps were mobilized and identified. These cell clumps, composed of red blood cells, neutrophils, and platelets, were not seen in the vascular lavage sediment obtained from unprimed control lungs. Indomethacin, a thromboxane antagonist, AA861, a 5-lipoxygenase inhibitor, and WEB 2086, a platelet-activating factor (PAF) antagonist, reduced the thromboxane synthesis and release after FMLP (10(-7) M) in in vivo endotoxin-primed lungs. None of the inhibitors employed exclusively inhibited only one particular eicosanoid mediator but rather affected the release of several mediators, suggesting a close link between the different synthetic arachidonic acid pathways. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), NCDC, but not an inhibitor of phospholipase D (Wortmannin) or of protein kinase C (staurosporine) inhibited the FMLP-stimulated pulmonary pressure rise and eicosanoid release in endotoxin-primed lungs in vivo. Our data suggest that eicosanoids (in particular thromboxane) released from cells trapped in the lung circulation, but not from constitutive lung cells, contribute to vasoconstriction and edema formation caused by the chemoattractant FMLP in endotoxin-primed lungs.
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PMID:FMLP causes eicosanoid-dependent vasoconstriction and edema in lungs from endotoxin-primed rats. 154 53

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

Both 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) and 3,4,2',4'-tetrahydroxychalcone inhibited 12-lipoxygenase of mouse epidermis. The IC50 of AA861 and 3,4,2',4'-tetrahydroxychalcone for epidermal 12-lipoxygenase were 1.9 and 0.2 microM, respectively. These agents showed very weak inhibitory actions on epidermal cyclooxygenase, with the potency of inhibition for cyclooxygenase less than 1/50 of that for lipoxygenase. Induction of epidermal ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate (TPA; 10 nmol/mouse) was potently inhibited by these agents in a dose-dependent manner (1-30 mumol/mouse). TPA (5 nmol/mouse)-induced skin tumor formation was also strongly suppressed by these agents (15 mumol/mouse). Both AA861 and 3,4,2',4'-tetrahydroxychalcone failed to inhibit partially purified epidermal protein kinase C activity. These results support the proposed involvement of lipoxygenase product(s) of arachidonic acid in TPA-induced skin tumor promotion.
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PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-mediated epidermal ornithine decarboxylase induction and skin tumor promotion by new lipoxygenase inhibitors lacking protein kinase C inhibitory effects. 309 75

Four structurally unrelated inhibitors of lipoxygenase (LO), i.e. nordihydroguaiaretic acid (NDGA), Esculetin, AA861 and 5,8,11,14-eicosatetraynoic acid (ETYA) suppressed mitogen induced proliferation of human peripheral blood lymphocytes in a dose-dependent manner. The degree of suppression was influenced by the type of the mitogenic stimulus. Receptor mediated stimulation, i.e. through phytohemagglutinin or the anti-CD3 antibody OKT3, was overall less susceptible, whereas proliferation initiated by direct activation of protein kinase C (PKC), i.e. through phorbol myristate acetate or indolactam V, was profoundly suppressed (up to 90%). The effect of the LO inhibitors was not due to non-specific interference with intracellular radical intermediates, because AA861 and ETYA showed no radical scavenging activity. Two PKC inhibitors, H-7 and H-8, similarly suppressed lymphocyte proliferation and showed essentially the same suppressive pattern as LO inhibitors. The results clearly indicate that LO product(s) participate in signal transduction mechanisms in T lymphocytes, possibly via stimulation of PKC activity and cell proliferation.
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PMID:Lipoxygenase inhibitors counteract protein kinase C mediated events in human T lymphocyte proliferation. 943 65

In the present study, we investigated how chrysotile-stimulated macrophages generate superoxide using murine peritoneal macrophages, with special attention to the modulatory role of phospholipase A(2) (PLA(2)). We examined the effects of the following inhibitors and antagonists for signaling molecules on the superoxide anion (O(2)(-)) production of chrysotile-stimulated macrophages: p-bromophenacyl bromide (pBPB) and mepacrine for PLA(2); islet-activating protein (IAP) for G-protein; H-7 for protein kinase C (PKC); AA861 for 5-lipoxygenase (5-LO); indomethacin for cyclo-oxygenase (COX); ETYA for both 5-LO and COX; hexanolamine PAF for platelet-activating factor (PAF). The PLA(2) and PKC inhibitors effectively inhibited the chrysotile-induced superoxide anion production of macrophages, but not the G-protein inhibitor, the 5-LO and COX inhibitors, and the PAF antagonist. We also examined the effects of the PLA(2) inhibitors on macrophages stimulated by phorbol 12-myristate 13-acetate (PMA) which directly activates PKC. The two structurally different PLA(2) inhibitors showed differential effects on the PMA-induced superoxide generation: pBPB inhibited it but mepacrine did not. These results suggested that (1) PLA(2) and PKC modulate the chrysotile-induced O(2) production, and (2) two different kinds of PLA(2) work upstream and downstream of PKC, but (3) G-protein, 5-LO and COX metabolites, and PAF have no modulatory role in the reaction.
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PMID:Phospholipase A2-mediated superoxide production of murine peritoneal macrophages induced by chrysotile stimulation. 1085 8

Dietary fats, which increase the risk of prostate cancer, stimulate release of intestinal neurotensin (NT), a growth-promoting peptide that enhances the formation of arachidonic acid metabolites in animal blood. This led us to use PC3 cells to examine the involvement of lipoxygenase (LOX) and cyclooxygenase (COX) in the growth effects of NT, including activation of EGF receptor (EGFR) and downstream kinases (ERK, AKT), and stimulation of DNA synthesis. NT and EGF enhanced [3H]-AA release, which was diminished by inhibitors of PLA2 (quinacrine), EGFR (AG1478) and MEK (U0126). NT and EGF phosphorylated EGFR, ERK and AKT, and stimulated DNA synthesis. These effects were diminished by PLA2 inhibitor (quinacrine), general LOX inhibitors (NDGA, ETYA), 5-LOX inhibitors (Rev 5901, AA861), 12-LOX inhibitor (baicalein) and FLAP inhibitor (MK886), while COX inhibitor (indomethacin) was without effect. Cells treated with NT and EGF showed an increase in 5-HETE levels by HPLC. PKC inhibitor (bisindolylmaleimide) blocked the stimulatory effects of NT, EGF and 5-HETE on DNA synthesis. We propose that 5-LOX activity is required for NT to stimulate growth via EGFR and its downstream kinases. The mechanism may involve an effect of 5-HETE on PKC, which is known to facilitate MEK-ERK activation. NT may enhance 5-HETE formation by Ca2+-mediated and ERK-mediated activation of DAG lipase and cPLA2. NT also upregulates cPLA2 and 5-LOX protein expression. Thus, the growth effects of NT and EGF involve a feed-forward system that requires cooperative interactions of the 5-LOX, ERK and AKT pathways.
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PMID:Involvement of arachidonic acid metabolism and EGF receptor in neurotensin-induced prostate cancer PC3 cell growth. 1633 Jan 12

We used shotgun proteomics to identify plasma membrane and lipid raft proteins purified from B cells obtained from mantle cell lymphoma (MCL) patients in leukemic phase. Bioinformatics identified 111 transmembrane proteins, some of which were profiled in primary MCL cases, MCL-derived cell lines, and normal B cells using RT-PCR and Western blotting. Several transmembrane proteins, including CD27, CD70, and CD31 (PECAM-1), were overexpressed when compared with normal B cells. CD70 was up-regulated (>10-fold) in three of five MCL patients along with its cognate receptor CD27, which was up-regulated (4-9-fold) in five of five patients, suggesting that MCL cells may undergo autocrine stimulation via this signaling pathway. Activated calpain I and protein kinase C betaII were also detected in the plasma membranes, suggesting that these proteins are constitutively active in MCL. Protein kinase C betaII has been associated with lipid rafts, and shotgun proteomics/protein profiling revealed that key lipid raft proteins, raftlin (four of five patients) and CSK (C-terminal Src kinase)-binding protein (Cbp)/phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) (four of four patients) were down-regulated in MCL. Levels of other known lipid raft proteins, such as Lyn kinase and flotillin 1, were similar to normal B cells. However, 5-lipoxygenase (5-LO), a key enzyme in leukotriene biosynthesis, was associated with lipid rafts and was up-regulated approximately 7-fold in MCL compared with normal B cells. Significantly inhibitors of 5-LO activity (AA861) and 5-LO-activating protein (FLAP) (MK886, its activating enzyme) induced apoptosis in MCL cell lines and primary chronic lymphocytic leukemia cells, indicating an important role for the leukotriene biosynthetic pathway in MCL and other B cell malignancies. Thus, using shotgun proteomics and mRNA and protein expression profiling we identified a subset of known and unknown transmembrane proteins with aberrant expression in MCL plasma membranes. These proteins may play a role in the pathology of the disease and are potential therapeutic targets in MCL.
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PMID:Protein profiling of plasma membranes defines aberrant signaling pathways in mantle cell lymphoma. 1934 16