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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of peroxisomal motility was investigated both in CHO cells and in cells derived from human umbilical vein endothelium (HUE). The cells were transfected with a construct encoding the green fluorescent protein bearing the C-terminal peroxisomal targeting signal 1. Kinetic analysis following time-lapse imaging revealed that CHO cells respond to simultaneous stimulation with ATP and lysophosphatidic acid (LPA) by reducing peroxisomal movements. When Ca(2+) was omitted from the extracellular medium or the cells were incubated with inhibitors for heterotrimeric G(i)/G(o) proteins, phospholipase C, classical protein kinase C isoforms (cPKC), mitogen-activated protein kinase kinase (MEK) or phospholipase A(2) (PLA(2)), this signal-mediated motility block was abolished. HUE cells grown to confluency on microporous membranes responded similarly to ATP-LPA receptor co-stimulation, but only when the ligands had access to the basolateral membrane region. These data demonstrate that peroxisomal motility is subject to specific modulation from the extracellular environment and suggest a receptor-mediated signaling cascade comprising Ca(2+) influx, G(i)/G(o) proteins, phospholipase C, cPKC isoforms, MEK and PLA(2) being involved in the regulation of peroxisomal arrest.
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PMID:Receptor-mediated regulation of peroxisomal motility in CHO and endothelial cells. 1052 92

We have proposed that exposure of epithelial cell membrane lipids in the lung (mainly phospholipids) to ozone will generate lipid ozonation products (LOP), which could be responsible for the proinflammatory effects of ozone. The ozonation of phosphocholine, the principal membrane phospholipid, produces a limited number of LOP, including hydroxyhydroperoxides and aldehydes. We now report that exposure of cultured human bronchial epithelial cells to the ozonized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) product, 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PC-ALD), a phospholipase A(2) (PLA(2))-stimulatory LOP, resulted in a 113 +/- 11% increase in the amounts of tritiated platelet-activating factor ((3)H-PAF) released apically. (3)H-PAF release was also induced by 1-hydroxy-1-hydroperoxynonane of ozonized POPC (HHP-C9), a phospholipase C (PLC)- stimulatory LOP (134 +/- 40% increase in (3)H-PAF). PC-ALD at 10 microM, but not HHP-C9, induced a 127 +/- 24% increase in prostaglandin E(2) (PGE(2)) release (n = 6, p < 0.05). In contrast, HHP-C9, but not PC-ALD, induced interleukin (IL)-6 release (178 +/- 23% increase, n = 6, p < 0.05) and IL-8 release (101 +/- 23% increase, n = 8, p < 0. 05). These results suggest that LOP-dependent release of proinflammatory mediators may play an important role in the early inflammatory response seen during exposure to ozone.
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PMID:Induction of inflammatory mediators in human airway epithelial cells by lipid ozonation products. 1058 9

The studies presented here explore intracellular signals resulting from the action of repellents on growth cones. Growth cone challenge with thrombin or thrombin receptor-activating peptide (TRAP) triggers collapse via a receptor-mediated process. The results indicate that this involves activation of cytosolic phospholipase A(2) (PLA(2)) and eicosanoid synthesis. The collapse response to repellents targets at least two functional units of the growth cone, the actin cytoskeleton and substratum adhesion sites. We show in a cell-free assay that thrombin and TRAP cause the detachment of isolated growth cones from laminin. Biochemical analyses of isolated growth cones reveal that thrombin and TRAP stimulate cytosolic PLA(2) but not phospholipase C. In addition, thrombin stimulates synthesis of 12- and 15-hydroxyeicosatetraenoic acid (HETE) from the released arachidonic acid via a lipoxygenase (LO) pathway. A selective LO inhibitor blocks 12/15-HETE synthesis in growth cones and inhibits thrombin-induced growth cone collapse. Exogenously applied 12(S)-HETE mimics the thrombin effect and induces growth cone collapse in culture. These observations indicate that thrombin-induced growth cone collapse occurs by a mechanism that involves the activation of cytosolic PLA(2) and the generation of 12/15-HETE.
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PMID:Thrombin-induced growth cone collapse: involvement of phospholipase A(2) and eicosanoid generation. 1059 66

A set of radioiodinatable phosphatidylcholines (PCs) derivatized with the Bolton-Hunter reagent (BHPCs) was synthesized to probe the substrate recognition and activity of phospholipases. A common feature of this series is the presence of a bulky 4-hydroxyphenyl group at the end of the fatty acyl chain attached to position sn-2. The distance between the end group and the glycerol backbone was varied by changing the length of the intervening fatty acyl chain (3-25 atoms). Except for the shortest, this chain includes at least one amide linkage. The usefulness of this series of substrates as a molecular ruler was tested by measuring the hydrolytic activities of Naja naja naja phospholipase A(2) (PLA(2)) and Bacillus cereus phospholipase C (PLC) in Triton X-100 micelles. The activity of PLA(2) proved to be highly dependent on the length of the fatty acyl chain linker, the shorter compounds (3-10 atoms) being very poor substrates. In contrast, the PLC activity profile exhibited much less discrimination. In both cases, PCs with 16-21 atom chains at position sn-2 yielded optimal activity. We interpret these findings in terms of fatty acyl chain length-related steric hindrance caused by the terminal aromatic group, affecting the activity of PLA(2) and, to a smaller extent, that of PLC. This notion agrees with the more extended recognition of aliphatic chains inside the narrow channel leading to the catalytic site in the former case. Molecular models of these substrates bound to PLA(2) were built on the basis of the crystallographic structure of Naja naja atra PLA(2) complexed with a phospholipid analogue. Docking of these substrates necessarily requires the intrusion of the bulky 4-hydroxyphenyl group inside the binding pocket and also the failure of the amide group to form hydrogen bonds inside the hydrophobic substrate channel.
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PMID:Mapping the catalytic pocket of phospholipases A2 and C using a novel set of phosphatidylcholines. 1069 94

Synthetic melittin mediated the release of [3H]-oleic acid ([3H]-OA) or its acylated lipids from [3H]-OA-labeled E. coli cells exposed to human serum. This phenomenon was not observed in the absence of serum and was calcium independent. The addition of serum was not required for melittin-mediated lysis of erythrocytes, although lysis was greater in the presence of serum than in its absence (P<0.001). Trypsin treatment of human serum reduced the melittin-mediated release of [3H]-OA/acylated lipids, and this effect was more pronounced upon boiling the serum (P<0.01). A kinetic study showed that maximum release of [3H]-OA/acylated lipids occurred within 3-6 min. Thin layer chromatography (TLC) analysis showed the lipids to be phosphatidyl ethanolamine (PE), phosphatidylethanol (PEt) and phosphatidic acid (PA). There was no detectable level of oleic acid (OA), diacylglycerol (DAG), phosphatidyl choline (PC) or phosphatidyl serine (PS). These findings suggested that a trypsin and heat-sensitive enzyme/factor present in the serum had a role in melittin-mediated action. These findings further showed that melittin activated phospholipase D (PLD), without affecting phospholipase A(2) (PLA(2)) or phospholipase C (PLC) activity.
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PMID:Melittin-mediated release of [3H]-oleic acid from E. coli cells is dependent upon heat- and trypsin-sensitive factor(s) in human serum. 1070 99

The signal transduction involved in the purinergic stimuli-induced activation of protein kinase C (PKC) in CHO-K1 cells was investigated. Purinergic stimuli such as adenosine triphosphate and uridine triphosphate induced a transient translocation of PKC epsilon, gamma, and delta from the cytoplasm to the plasma membrane. These translocations were blocked by an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), but not by an inhibitor of phosphatidylcholine-specific PLC. A diacylglycerol (DAG) analogue also induced reversible translocations of PKC gamma, epsilon, and delta from the cytoplasm to the plasma membrane, while the calcium ionophore A23187 caused a similar translocation of only the gamma subtype. These results confirm that the hydrolysis of phosphatidylinositol-2-phosphate by PLC and the subsequent generation of DAG and increase in Ca(2+ )are involved in the purinergic stimuli-induced translocation of PKC. A DAG antagonist, 1-o-hexadecyl-2-o-acetyl-glycerol, blocked the DAG analogue-induced translocations of all PKC subtypes tested but failed to inhibit the purinergic stimuli-induced translocations of PKC epsilon and gamma. The DAG antagonist could not block the ATP- and UTP-induced translocation of PKC epsilon even in the absence of extracellular Ca(2+). Co-application of the DAG antagonist and a phospholipase A(2) (PLA(2)) inhibitor such as aristolochic acid, arachidonyltrifluoromethyl ketone, or bromoenol lactone inhibited the purinergic receptor-mediated translocation of PKC epsilon although each PLA(2) inhibitor alone did not block the translocation. In contrast to the epsilon subtype, ATP-induced translocation of PKC gamma was observed in the presence of both the PLA(2) inhibitor and the DAG antagonist. However, it is noteworthy that re-translocation of PKC gamma was hastened by the PLA(2) inhibitor. Furthermore products of PLA(2), such as lysophospholipids and fatty acids, induced the translocation of PKC gamma and epsilon in a dose dependent manner, but not delta. These results indicate that, in addition to PLC and DAG, PLA(2) and its products are involved in the purinergic stimuli-induced translocation of PKC epsilon and gamma in CHO-K1 cells. Each subtype of PKC in CHO-K1 cell is individually activated in response to a purinergic stimulation.
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PMID:Phospholipase A(2) and its products are involved in the purinergic receptor-mediated translocation of protein kinase C in CHO-K1 cells. 1072 17

Treatment of human natural killer (NK) cells with phospholipase A(2) (PLA(2)) inhibitors, mepacrine and 4-bromophenacyl bromide (BPB), diminished their ability to lyse K562 target cells by as much as 100%. The ability of NK cells to bind to K562 cells was significantly affected by BPB above 2 microM, but not by mepacrine at any concentration tested. This indicates that BPB is having effects on NK cells unrelated to its inhibition of PLA(2) activity at concentrations above 2 microM. The activation of phospholipase C in response to K562 cell binding (as measured by inositol phosphate turnover) was unaffected by inhibition of the PLA(2) activity. The products of PLA(2) catabolism are a fatty acid (often arachidonic acid) and a lysophospholipid. Inhibition of NK cytotoxicity by mepacrine or BPB is reversed significantly when lysophosphatidylcholine, but no other lysolipid, is added back to the NK cells before assaying for cytotoxicity. Arachidonic acid, but not linoleic acid, also significantly reverses inhibition of NK cytotoxicity. Finally, the 15-lipoxygenase product, 15S-hydroperoxyeicosatetraenoic acid (15S-HPETE), is also able to reverse mepacrine-induced inhibition of NK cytotoxicity. The 5-lipoxygenase product 5S-HPETE was not effective. These data indicate that PLA(2) activation is a necessary signal in human NK cytotoxicity and that it is not involved in protein tyrosine kinase and subsequent phospholipase C activation; these latter two enzymes are also required in the cytotoxic response. Thus PLA(2) activation is either a more distal signal, dependent on activation of some earlier signal, or an independent cosignal stimulated by tumor-target binding which generates lysophosphatidylcholine, arachidonic acid, and/or a lipoxygenase product(s).
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PMID:Lysophosphatidylcholine and arachidonic acid are required in the cytotoxic response of human natural killer cells to tumor target cells. 1074 96

Previous studies have shown that transforming growth factor-beta1 (TGF-beta1) stimulates protein kinase C (PKC) via a mechanism that is independent of phospholipase C or tyrosine kinase, but involves a pertussis toxin-sensitive G-protein. Maximal activation occurs at 12 h and requires new gene expression. To understand the signaling pathways involved, resting zone chondrocytes were incubated with TGF-beta1 and PKC activity was inhibited with chelerythrine, staurosporine or H-7. [(35)S]Sulfate incorporation was inhibited, indicating that PKC mediates the effects of TGF-beta1 on matrix production. However, there was little, if any, effect on TGF-beta1-dependent increases in [(3)H]thymidine incorporation, and TGF-beta1-stimulated alkaline phosphatase was unaffected, indicating that these responses to the growth factor are not regulated via PKC. TGF-beta1 caused a dose-dependent increase in prostaglandin E(2) (PGE(2)) production which was further increased by PKC inhibition. The increase was regulated by TGF-beta1-dependent effects on phospholipase A(2) (PLA(2)). Activation of PLA(2) inhibited TGF-beta1 effects on PKC, and inhibition of PLA(2) activated TGF-beta1-dependent PKC. Exogenous arachidonic acid also inhibited TGF-beta1-dependent increases in PKC. The effects of TGF-beta1 on PKC involve genomic mechanisms, but not regulation of existing membrane-associated enzyme, since no direct effect of the growth factor on plasma membrane or matrix vesicle PKC was observed. These results support the hypothesis that TGF-beta1 modulates its effects on matrix production through PKC, but its effects on alkaline phosphatase are mediated by production of PGE(2) and protein kinase A (PKA). Inhibition of PKA also decreases TGF-beta1-dependent proliferation. We have previously shown that PGE(2) stimulates alkaline phosphatase through its EP2 receptor, whereas EP1 signaling causes a decrease in PKC. Thus, there is cross-talk between the two pathways.
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PMID:Transforming growth factor-beta1 regulation of resting zone chondrocytes is mediated by two separate but interacting pathways. 1077 Oct 99

A short term exposure of PC12 cells to a concentration of tert-butylhydroperoxide (tB-OOH) causing peroxynitrite-dependent DNA damage and cytotoxiticity promoted a release of arachidonic acid (AA) that was sensitive to phospholipase A(2) (PLA(2)) inhibitors and insensitive to phospholipase C or diacylglycerol lipase inhibitors. The extent of AA release was also mitigated by nitric oxide synthase (NOS) inhibitors and peroxynitrite scavengers. Low levels (10 microM) of authentic peroxynitrite restored the release of AA mediated by tB-OOH in NOS-inhibited cells whereas concentrations of peroxynitrite of 20 microM, or higher, effectively stimulated a PLA(2) inhibitor-sensitive release of AA also in the absence of additional treatments. These results are consistent with the possibility that endogenous as well as exogenous peroxynitrite promotes activation of PLA(2).
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PMID:Peroxynitrite-mediated release of arachidonic acid from PC12 cells. 1078 Sep 56

We have previously demonstrated that Ca(2+)/calmodulin-dependent protein kinase (CaMK) mediates pyrimidinoceptor potentiation of LPS-elicited inducible nitric oxide synthase (iNOS) induction in murine J774 macrophages. In the present paper, we have explored the role of cyclo-oxygenase (COX)-dependent prostaglandin E(2) (PGE(2)) formation in this event. In J774 macrophages predominantly expressing P2Y(6) receptors, the simultaneous addition of UTP and lipopolysaccharide (LPS) resulted in potentiated increase in PGE(2) release. UTP-induced increased PGE(2) release was demonstrated by a concomitant increase in COX-2 protein expression, and was decreased by inhibitors specific for phosphatidylinositide-phospholipase C (PI-PLC), CaMK, protein kinase C (PKC), nuclear factor-kappa B (NF-kappaB) or COX-2. NS-398 (a selective COX-2 inhibitor) reduced LPS plus UTP-elicited iNOS induction and nitrite accumulation, supporting for the positive regulation of iNOS gene expression by endogenous PGE(2). Moreover, the cyclic AMP/PKA-dependent up-regulation of iNOS expression mediated by PGE(2) was drawn from the inhibitory effects of 2',5'-dideoxyadenosine, KT5720 and H-89. Exogenous PGE(2) induced NF-kappaB activation and potentiated nitrite accumulation in response to LPS. In addition to COX-2 induction, arachidonic acid (AA) release and steady-state mRNA levels of type V secretory phospholipase A(2) (sPLA(2)) and Ca(2+)-independent PLA(2) (iPLA(2)) were also increased in the presence of LPS and UTP; the LPS-induced increase in iPLA(2) activity was also potentiated by UTP. Taken together, we conclude that UTP-mediated COX-2 and iPLA(2) potentiation and PGE(2) formation contribute to the iNOS induction, and that CaMK activation is the primary step in the UTP enhancement of COX-2 induction.
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PMID:Pyrimidinoceptor potentiation of macrophage PGE(2) release involved in the induction of nitric oxide synthase. 1086 83


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