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)

Exogenous C(2)-ceramide has been shown to inhibit polymorphonuclear leukocyte (PMN) phagocytosis through inhibition of phospholipase D (PLD) and downstream events, including activation of extracellular signal-regulated kinases 1 and 2, leading to the hyphothesis that the sphingomyelinase pathway is involved in termination of phagocytosis. Here it is postulated that increased PLD activity generating phosphatidic acid and diacylglycerol (DAG) is essential for superoxide release and degranulation and that ceramide, previously shown to be generated during PMN activation, inhibits PLD activation, thereby leading to inhibition of PMN function. When PMNs were primed with granulocyte colony-stimulating factor (G-CSF) and then activated with N-formyl-methionyl-leucyl-phenylalanine (FMLP), C(2)-ceramide (10 microM) completely inhibited release of superoxide, lactoferrin, and gelatinase; the DAG analog sn-1,2-didecanoylglycerol (DiC10) (10 microM) restored oxidase activation and degranulation in the ceramide-treated cells. Similarly, C(2)-ceramide inhibited oxidase activity and degranulation of PMNs treated with cytochalasin B followed by FMLP, and DiC10 restored function. In contrast, C(2)-ceramide did not inhibit phosphorylation of p47phox or p38 mitogen-activated protein kinase, or translocation of p47phox, PLD-containing organelles, adenosine diphosphate-ribosylation factor 1, RhoA, protein kinase C (PKC)-beta or PKC-alpha to the plasma membrane in G-CSF or cytochalasin B-treated, FMLP-activated PMNs. PLD activity increased by 3-fold in G-CSF-primed PMNs stimulated by FMLP and by 30-fold in cytochalasin B-treated PMNs stimulated by FMLP. Both PLD activities were completely inhibited by 10 microM C(2)-ceramide. In conclusion, superoxide, gelatinase, and lactoferrin release require activation of the PLD pathway in primed PMNs and cytochalasin B-treated PMNs. Ceramide may affect protein interactions with PLD in the plasma membrane, thereby attenuating PMN activation.
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PMID:Regulation of polymorphonuclear leukocyte degranulation and oxidant production by ceramide through inhibition of phospholipase D. 1183 Apr 97

To better understand the intracellular signaling mechanism that causes the association of insulin resistance and hyperlipidemia with cardiovascular diseases, we specifically looked at the ability of lysophosphatidylcholine (lysoPC) to inhibit the Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells. LysoPC inhibited the insulin-induced phosphorylation of Akt at Ser473, and the inhibition was concentration dependent. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, inhibited the insulin-induced phosphorylation of Akt. LysoPC stimulated PKC phosphorylation at Ser660, which was inhibited by the PKC inhibitor GF109203X. The PKC-alpha/beta-selective inhibitor Go6976 also blocked the PMA- and lysoPC-induced inhibition of Akt phosphorylation by insulin. PKC-alpha, but not PKC-beta, is expressed in vascular smooth muscle cells, and overexpression of PKC-alpha, but not PKC-beta or PKC-delta, inhibited insulin-induced Akt activation. LysoPC rapidly stimulated PKC-alpha translocation to the membrane. In contrast, pretreatment with the p42/44 mitogen-activated protein kinase kinase inhibitor PD98059 or the p38 mitogen-activated protein kinase inhibitor SB203580 did not block the lysoPC-induced inhibition of Akt phosphorylation by insulin. In addition, lysoPC inhibited the insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 but not that of the insulin receptor beta subunit or insulin binding. PMA treatment or PKC-alpha overexpression also inhibited the tyrosine phosphorylation of IRS-1. From these data, we conclude that lysoPC negatively regulates the insulin signal at the point of IRS-1 through PKC-alpha in the vasculature, which may explain the association of hyperlipidemia with hyperinsulinemia in cardiovascular diseases.
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PMID:Lysophosphatidylcholine inhibits insulin-induced Akt activation through protein kinase C-alpha in vascular smooth muscle cells. 1188 99

Acute intensive insulin therapy is an independent risk factor for diabetic retinopathy. Here we demonstrate that acute intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae of diabetic rats. Retinal nuclear extracts from insulin-treated rats contain higher hypoxia-inducible factor-1alpha (HIF-1alpha) levels and demonstrate increased HIF-1alpha-dependent binding to hypoxia-responsive elements in the VEGF promoter. Blood-retinal barrier breakdown is markedly increased with acute intensive insulin therapy but can be reversed by treating animals with a fusion protein containing a soluble form of the VEGF receptor Flt; a control fusion protein has no such protective effect. The insulin-induced retinal HIF-1alpha and VEGF increases and the related blood-retinal barrier breakdown are suppressed by inhibitors of p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol (PI) 3-kinase, but not inhibitors of p42/p44 MAPK or protein kinase C. Taken together, these findings indicate that acute intensive insulin therapy produces a transient worsening of diabetic blood-retinal barrier breakdown via an HIF-1alpha-mediated increase in retinal VEGF expression. Insulin-induced VEGF expression requires p38 MAPK and PI 3-kinase, whereas hyperglycemia-induced VEGF expression is HIF-1alpha-independent and requires PKC and p42/p44 MAPK. To our knowledge, these data are the first to identify a specific mechanism for the transient worsening of diabetic retinopathy, specifically blood-retinal barrier breakdown, that follows the institution of intensive insulin therapy.
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PMID:Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. 1190 Nov 89

Solubilization of a number of membrane proteins occurs by the action of cell-surface proteases, termed secretases. Recently, the activity of these secretases has been reported to be controlled by the extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and the p38 mitogen-activated protein kinase (MAPK) routes. In the present paper, we show that shedding of membrane-anchored growth factors (MAGFs) may also occur through MAPK-independent routes. In Chinese-hamster ovary cells, cleavage induced by protein kinase C (PKC) stimulation was largely insensitive to inhibitors of the ERK1/ERK2 and p38 routes. Other reagents such as sorbitol or UV light stimulated MAGF cleavage independent of PKC. The action of sorbitol on cleavage was only partially prevented by the combined action of inhibitors of the p38 and ERK1/ERK2 routes, indicating that sorbitol can also stimulate shedding by MAPK-dependent and -independent routes. Studies in cells devoid of activity of the secretase tumour necrosis factor-alpha-converting enzyme (TACE) indicated that this protease had an essential role in PKC- and ERK1/ERK2-mediated shedding. However, secretases other than TACE may also cleave MAGFs since sorbitol could still induce shedding in these cells. These observations suggest that cleavage of MAGFs is a complex process in which multiple secretases, activated through different MAPK-dependent and -independent routes, are involved.
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PMID:Mitogen-activated protein kinase-dependent and -independent routes control shedding of transmembrane growth factors through multiple secretases. 1193 48

Hypoxia and ischemia regulate the expression of several important genes at the level of transcription and of mRNA stability. Two isoforms of a 40-kDa poly(C)-binding protein, previously identified as RNA-binding proteins, bind to a hypoxia-inducible protein-binding site in the 3'-untranslated region of erythropoietin and tyrosine hydroxylase mRNAs and regulate mRNA stability. To determine if poly(C)-binding proteins show changes in expression -- which might regulate mRNA stability -- in hypoxic or ischemic neuronal cells, we examined poly(C)-binding protein 1 and poly(C)-binding protein 2 expression in hypoxic cortical neuron cultures and in rat cerebral cortex after focal ischemia. Reverse transcription-polymerase chain reaction and western blotting showed hypoxic up-regulation of poly(C)-binding protein 1, and down-regulation of poly(C)-binding protein 2, mRNA and protein expression. Hypoxia-inducible expression of poly(C)-binding protein 1 was mediated by p38 mitogen-activated protein kinase, while hypoxia-reducible expression of poly(C)-binding protein 2 was mediated by protein kinase C. Immunostaining showed that poly(C)-binding protein 1, but not poly(C)-binding protein 2, expression was increased in the ischemic boundary zone (penumbra) of the frontal cortex after 90 min of ischemia, and persisted for at least 72 h after reperfusion. These results demonstrate that poly(C)-binding protein 1 and poly(C)-binding protein 2 in cortical neurons are differentially affected by hypoxic/ischemic insults, suggesting that there are functional differences between poly(C)-binding protein isoforms. Since we observed no poly(C)-binding protein expression in astroglia, alternative mRNA stability mechanisms may exist in these cells.
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PMID:Expression of poly(C)-binding proteins is differentially regulated by hypoxia and ischemia in cortical neurons. 1195 62

Mammalian period genes have a pivotal role in generating circadian rhythms and are rapidly induced by several stimuli in mammalian cells. In the present study, we revealed that treatment with thapsigargin significantly induced transcripts of mouse period 1 and 2 (mPer1 and mPer2) but not mPer3 among circadian related genes in NIH3T3 cells. Thapsigargin-induced mPer1 and mPer2 mRNA expressions took distinct signaling pathways from protein kinase C and cAMP, but were partially inhibited by inhibitors of MEK1 and p38 mitogen-activated protein kinase, respectively. Thus, the present study suggested that intracellular calcium is one of multiple signaling stimuli triggering mPer gene expression in NIH3T3 cells.
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PMID:Intracellular calcium mobilization induces period genes via MAP kinase pathways in NIH3T3 cells. 1195 12

Ginkgolide B (GKB, BN 52021) was described as a platelet-activating factor (Paf) receptor antagonist. However, it is not known whether all GKB biological effects are mediated through Paf receptor antagonism only. To gain insight into the drug mode of action, we investigated here the effects of GKB per se on functional and signaling activities in human polymorphonuclear leukocytes (PMN). Treatment of PMN with GKB (0.5-12 microM) stimulates a rapid and weak production of reactive oxygen species determined by chemiluminescence. ROS production required the activation of protein kinase C (PKC), tyrosine kinases and p38 mitogen-activated protein kinase as indicated by inhibitory effects of, respectively, GF 109203X (IC(50) of 0.5 microM), genistein (IC(50) of 0.5 microM) and SB 203580 (IC(50) of 0.2 microM) or SB 202190 (IC(50) of 1.1 microM). GKB stimulated a Pertussis toxin-sensitive PLD activity assessed by the formation of tritiated phosphatidic acid and choline. By contrast, GKB did prevent the Paf-mediated PLD activity and CL response (IC(50) of 2 microM). Interestingly, both GKB and Paf-induced CL response were prevented by selective Paf antagonists such as CV 6209 or WEB 2086 indicating that GKB may directly activate Paf receptors. Finally, GKB potentiated the CL response induced by fMet-Leu-Phe and zymosan. These results show that GKB is the first partial agonist of the Paf receptor described so far capable of priming the polymorphonuclear leukocyte function.
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PMID:Sensitization of human neutrophil defense activities through activation of platelet-activating factor receptors by ginkgolide B, a bioactive component of the Ginkgo biloba extract EGB 761. 1196 Jun

Oxidative stress has been implicated in mediation of vascular disorders. Earlier study showed that the exposure of vascular smooth muscle cells (VSMC) to pervanadate (hydrogen peroxide plus orthovanadate) resulted in the accumulation of [3H]phosphatidylbutanol. In this study, the effect of pervanadate on the activation of p38 mitogen-activated protein kinase (p38 MAPK) was studied in the VSMC. Pervanadate treatment activated p38 MAPK in a dose-and time-dependent manner. Interestingly, specific inhibition of p38 MAPK with SB203580 attenuated pervanadate-induced PLD activation. This correlates with the finding that expression of dominant negative mutants of MKK3/6 inhibited the PLD activation. SB203580 pretreatment also inhibited other cellular stressors (i.e. high osmolarity and UV light)-induced PLD activation. The possible correlationship of p38 MAPK activation with PKC was examined since PKC is reported to be involved in the pervanadate-induced PLD activation. Calphostin C, a PKC inhibitor, suppressed pervanadate-induced p38 MAPK and PLD activation in a dose-dependent manner. These results suggest that PKC-p38 MAPK may represent an upstream pathway of PLD in the signal transduction of cellular stress.
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PMID:The p38 mitogen-activated protein kinase is involved in stress-induced phospholipase D activation in vascular smooth muscle cells. 1198 77

3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a soluble guanylyl cyclase (sGC) activator, inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide anion (O(2)*(-)) generation and O(2) consumption in rat neutrophils (IC(50) values of 12.7+/-3.1 and 17.7+/-6.9 microM, respectively). Inhibition of O(2)*(-) generation by YC-1 was partially reversed by the cyclic GMP-lowering agent 6-anilinoquinoline-5,8-quinone (LY83583) and by the Rp isomer of 8-(4-chlorophenylthio)guanosine-3',5'-monophosphorothioate (Rp-8-pCPT-cGMPS), a cyclic GMP-dependent protein kinase inhibitor. In cell-free systems, YC-1 failed to alter O(2)*(-) generation during dihydroxyfumaric acid autoxidation, phorbol 12-myristate 13-acetate (PMA)-activated neutrophil particulate NADPH oxidase preparation, and arachidonic acid-induced NADPH oxidase activation. YC-1 increased cellular cyclic GMP levels through the activation of sGC and the inhibition of cyclic GMP-hydrolyzing phosphodiesterase activity. The plateau phase, but not the initial spike, of fMLP-induced [Ca(2+)](i) changes was inhibited by YC-1 (IC(50) about 15 microM). fMLP- but not PMA-induced phospholipase D activation was inhibited by YC-1 (IC(50) about 28 microM). Membrane-associated ADP-ribosylation factor and Rho A in cell activation was also reduced by YC-1 at a similar concentration range. Neither cytosolic protein kinase C (PKC) activity nor PKC membrane translocation was altered by YC-1. YC-1 did not affect either fMLP-induced phosphatidylinositol 3-kinase activation or p38 mitogen-activated protein kinase phosphorylation, but slightly attenuated the phosphorylation of extracellular signal-regulated kinase. Collectively, these results indicate that the inhibition of the fMLP-induced respiratory burst by YC-1 is mediated by cyclic GMP-dependent and -independent signaling mechanisms.
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PMID:Inhibition of superoxide anion generation by YC-1 in rat neutrophils through cyclic GMP-dependent and -independent mechanisms. 1199 25

We have previously shown that long-term thyroxine administration can protect the heart against ischemia. In the present study, we investigated whether thyroxine-induced cardioprotection can mimic the pattern of protection that is afforded by a well-established cardioprotective means such as ischemic preconditioning. In a Langendorff-perfused rat heart preparation, after an initial stabilization, normal and thyroxine-treated hearts were subjected to 20 minutes of zero-flow global ischemia followed by 45 minutes of reperfusion. In thyroxine-treated hearts, phospho-p38 mitogen-activated protein kinase (MAPK) was found to be less at the end of the ischemic period, whereas ischemic contracture was accelerated and postischemic recovery was increased in comparison to normal hearts. In addition, normal hearts were subjected to a four-cycle preconditioning protocol before ischemia. Phospho-p38 MAPK was found to be less at the end of the ischemic period in preconditioned hearts, whereas ischemic contracture was accelerated and postischemic functional recovery was increased in those hearts in comparison to nonpreconditioned hearts. An increase in basal expression and phosphorylation of PKCdelta was also found to occur after long-term thyroxine administration. We conclude that long-term thyroxine administration can protect the heart from ischemic injury through a pattern of protection that closely resembles that of ischemic preconditioning.
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PMID:Long-term thyroxine administration protects the heart in a pattern similar to ischemic preconditioning. 1203 58


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