UNIPROT:P00750 - FACTA Search

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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we identify the principal splice variant of human cytosolic phospholipase A(2)beta (cPLA(2)beta) (also known as Group IVB cPLA(2)) present in cells. In human lung, spleen, and ovary and in a lung epithelial cell line (BEAS-2B), cPLA(2)beta is expressed as a 100-kDa protein, not the 114-kDa form originally predicted. Using RNA interference, the 100-kDa protein in BEAS-2B cells was confirmed to be cPLA(2)beta. BEAS-2B cells contain three different RNA splice variants of cPLA(2)beta (beta1, beta2, and beta3). cPLA(2)beta1 is identical to the previously cloned cPLA(2)beta, predicted to encode a 114-kDa protein. However, cPLA(2)beta2 and cPLA(2)beta3 splice variants are smaller and contain internal deletions in the catalytic domain. The 100-kDa cPLA(2)beta in BEAS-2B cells is the translated product of cPLA(2)beta3. cPLA(2)beta3 exhibits calcium-dependent PLA(2) activity against palmitoyl-arachidonyl-phosphatidylethanolamine and low level lysophospholipase activity but no activity against phosphatidylcholine. Unlike Group IVA cPLA(2)alpha, cPLA(2)beta3 is constitutively bound to membrane in unstimulated cells, localizing to mitochondria and early endosomes. cPLA(2)beta3 is widely expressed in tissues, suggesting that it has a generalized function at these unique sites.
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PMID:Identification of the expressed form of human cytosolic phospholipase A2beta (cPLA2beta): cPLA2beta3 is a novel variant localized to mitochondria and early endosomes. 1661 59

We examined the mechanism by which secretory group V phospholipase A(2) (gVPLA(2)) secreted from stimulated epithelial cells activates eosinophil adhesion to ICAM-1 surrogate protein and secretion of leukotriene (LT)C(4). Exogenous human group V PLA(2) (hVPLA(2)) caused an increase in surface CD11b expression and focal clustering of this integrin, which corresponded to increased beta(2) integrin-mediated adhesion. Human IIaPLA(2), a close homolog of hVPLA(2), or W31A, an inactive mutant of hVPLA(2), did not affect these responses. Exogenous lysophosphatidylcholine but not arachidonic acid mimicked the beta(2) integrin-mediated adhesion caused by hVPLA(2) activation. Inhibition of hVPLA(2) with MCL-3G1, a mAb against gVPLA(2), or with LY311727, a global secretory phospholipase A(2) (PLA(2)) inhibitor, attenuated the activity of hVPLA(2); trifluoromethylketone, an inhibitor of cytosolic group IVA PLA(2) (gIVA-PLA(2)), had no inhibitory effect on hVPLA(2)-mediated adhesion. Activation of beta(2) integrin-dependent adhesion by hVPLA(2) did not cause ERK1/2 activation and was independent of gIVA-PLA(2) phosphorylation. In other studies, eosinophils cocultured with epithelial cells were stimulated with FMLP/cytochalasin B (FMLP/B) and/or endothelin-1 (ET-1) before LTC(4) assay. FMLP/B alone caused release of LTC(4) from eosinophils, which was augmented by coculture with epithelial cells activated with ET-1. Addition of MCL-3G1 to cocultured cells caused approximately 50% inhibition of LTC(4) secretion elicited by ET-1, which was blocked further by trifluoromethylketone. Our data indicate that hVPLA(2) causes focal clustering of CD11b and beta(2) integrin adhesion by a novel mechanism that is independent of arachidonic acid synthesis and gIVA-PLA(2) activation. We also demonstrate that gVPLA(2), endogenously secreted from activated epithelial cells, promotes secretion of LTC(4) in cocultured eosinophils.
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PMID:Transcellular secretion of group V phospholipase A2 from epithelium induces beta 2-integrin-mediated adhesion and synthesis of leukotriene C4 in eosinophils. 1678 55

Phosphodiesterase (PDE)4 inhibition attenuates neutrophilic inflammation in chronic obstructive pulmonary disease. The objective of the present study was to examine the efficacy and mechanism by which PDE4 inhibition blocks adhesion of beta(2)-integrin to an endothelial counterligand. Neutrophils (polymorphonuclear leukocytes (PMNs)) were isolated from humans receiving no medication. Adhesion was analysed by myeloperoxidase activity. The effects of cilomilast+/-salmeterol on the following were determined: 1) surface CD11b expression; 2) adhesion; 3) intracellular cyclic adenosine monophosphate (cAMP) concentration; and 4) extracellular signal-regulated kinase (ERK)-1/2-mediated group IVA-phospholipase A(2) (gIVA-PLA(2)) phosphorylation caused by leukotriene (LT)B(4) or tumour necrosis factor (TNF)-alpha activation. Either cilomilast or rolipram+/-salmeterol caused concentration-related blockade of LTB(4)-induced adhesion to counterligand, but had no effect on TNF-alpha-activated PMNs. A comparable increase in intracellular cAMP concentration for PMNs activated with LTB(4) and TNF-alpha was caused by 1 muM cilomilast and 0.1 microM salmeterol. Upregulation of surface CD11b expression and ERK-1/2 phosphorylation were blocked by cilomilast or rolipram+/-salmeterol for PMNs activated by LTB(4), but not for cells stimulated by TNF-alpha. Cilomilast+/-salmeterol also blocked gIVA-PLA(2) phosphorylation caused by LTB(4) but not TNF-alpha. In conclusion, the current study demonstrates that both leukotriene B(4) and tumour necrosis factor-alpha upregulate cyclic adenosine monophosphate. However, cyclic adenosine monophosphate does not block beta(2)-integrin adhesion caused by tumour necrosis factor-alpha. It was concluded that tumour necrosis factor-alpha prevents inhibition of extracellular signal-regulated kinase-1/2-mediated group IVA-phospholipase A(2) activation, which is essential for beta(2)-integrin adhesion in polymorphonuclear leukocytes.
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PMID:Phosphodiesterase 4 inhibition of beta2-integrin adhesion caused by leukotriene B4 and TNF-alpha in human neutrophils. 1680 66

The deposition of atherogenic lipoproteins such as oxidized low-density lipoprotein (oxLDL) within the mesangium is involved in the overproduction of extracellular matrix proteins, a key event in the progression of glomerular diseases including glomerulosclerosis. To clarify the mechanisms underlying the oxLDL-induced production of extracellular matrix proteins, we examined the possible involvement of group IVA phospholipase A(2) (PLA(2)) using human mesangial cells and group IVA PLA(2)-deficient mouse mesangial cells. oxLDL accelerated the production of fibronectin and collagen (type IV), components of extracellular matrix proteins, with the preceding release of arachidonic acid. Methyl arachidonyl fluorophosphonate (MAFP), known as an inhibitor of group IVA PLA(2), markedly suppressed the oxLDL-induced production of fibronectin as well as the release of arachidonic acid, whereas it did not inhibit the production of collagen. The inhibitory effect of MAFP on the production of fibronectin was reversed by adding arachidonic acid and 12-hydroxyeicosatetraenoic acid. Furthermore, we found that in group IVA PLA(2)-deficient mouse mesangial cells, the production of fibronectin in response to oxLDL was weak as compared with that in wild-type cells. However, the production by oxLDL of collagen was not suppressed in the group IVA PLA(2)-deficient cells. These findings suggest that group IVA PLA(2) is involved in the production of fibronectin in oxLDL-stimulated mesangial cells.
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PMID:Group IVA phospholipase A2-mediated production of fibronectin by oxidized LDL in mesangial cells. 1683 27

Osmotic swelling of NIH3T3 mouse fibroblasts activates a bromoenol lactone (BEL)-sensitive taurine efflux, pointing to the involvement of a Ca(2+)-independent phospholipase A(2) (iPLA(2)) (Lambert IH. J Membr Biol 192: 19-32, 2003). We report that taurine efflux from NIH3T3 cells was not only increased by cell swelling but also decreased by cell shrinkage. Arachidonic acid release to the cell exterior was similarly decreased by shrinkage yet not detectably increased by swelling. NIH3T3 cells were found to express cytosolic calcium-dependent cPLA(2)-IVA, cPLA(2)-IVB, cPLA(2)-IVC, iPLA(2)-VIA, iPLA(2)-VIB, and secretory sPLA(2)-V. Arachidonic acid release from swollen cells was partially inhibited by BEL and by the sPLA(2)-inhibitor manoalide. Cell swelling elicited BEL-sensitive arachidonic acid release from the nucleus, to which iPLA(2)-VIA localized. Exposure to the bee venom peptide melittin, to increase PLA(2) substrate availability, potentiated arachidonic acid release and osmolyte efflux in a volume-sensitive, 5-lipoxygenase-dependent, cyclooxygenase-independent manner. Melittin-induced arachidonic acid release was inhibited by manoalide and slightly but significantly by BEL. A BEL-sensitive, melittin-induced PLA(2) activity was also detected in lysates devoid of sPLA(2), indicating that both sPLA(2) and iPLA(2) contribute to arachidonic acid release in vivo. Swelling-induced taurine efflux was inhibited potently by BEL and partially by manoalide, whereas the reverse was true for melittin-induced taurine efflux. It is suggested that in NIH3T3 cells, swelling-induced taurine efflux is dependent at least in part on arachidonic acid release by iPLA(2) and possibly also by sPLA(2), whereas melittin-induced taurine efflux is dependent on arachidonic acid release by sPLA(2) and, to a lesser extent, iPLA(2).
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PMID:Roles of phospholipase A2 isoforms in swelling- and melittin-induced arachidonic acid release and taurine efflux in NIH3T3 fibroblasts. 1685 15

Phospholipase A(2) (PLA(2)) is a superfamily of enzymes that may play a major role in airways inflammation. We investigated the effect of interferon-gamma (IFN-gamma) on the gene expression of 19 different PLA(2) types in human monocyte-derived macrophages and nasal epithelial cells (RPMI 2650). The cells were stimulated with IFN-gamma for different lengths of time (up to 48 h), and the mRNA levels of the different PLA(2) types were determined by reverse transcriptase-PCR (RT-PCR) and normalized to those of the house-keeping gene, GAPDH. It appeared that IFN-gamma clearly increased the expression of secretory PLA(2) IID (but not IIA) in macrophages, while both PLA(2) IID and IIA were upregulated in RPMI 2650 cells. Moreover, after 18 h, the mRNA levels of cytosolic PLA(2) IVA were 2-3 times higher in IFN-gamma-stimulated macrophages than controls, while there was no such effect of IFN-gamma in RPMI 2650 cells. Lipopolysaccharide (LPS) augmented the increased gene expression of PLA(2) IVA but decreased both the basal and the IFN-gamma-induced PLA(2) IID mRNA expression in macrophages (but not in RPMI 2650 cells). The NF-kappaB inhibitor Pyrrolidine dithiocarbamate (PDTC) and the phoshatidylinositol 3-kinase (PI3K) inhibitor wortmannin were employed to get an insight into the mechanism behind these observations. Incubation of macrophages with PDTC had no effect on the LPS impairment of PLA(2) IID gene expression, but inhibited the LPS mediated activation of PLA(2) IVA. No significant effect was noted of PDTC on IFN-gamma stimulation, while PI3K had no effect at all on any of the stimuli used. Furthermore, LPS (but not IFN-gamma) increased the mRNA levels of the nuclear factor (NF)-kappaB inhibitors alpha and xi in macrophages, but not in RPMI 2650 cells. These findings indicate that (a) the gene expression of secretory types PLA(2) IID and IIA in response to IFN-gamma is much dependent on cell type, and (b) the regulation of PLA(2) type IID in human macrophages is clearly different from that of PLA(2) type IVA. (c) PLA(2) IVA is probably under control of both NF-kappaB and IFN-gamma-responsive elements (GRE) or IFN-gamma-activating sites (GAS). The possibility that PLA(2) IID is involved in cytokine-mediated inflammation in the nasal mucosa is inferred, as is the potential role of PLA(2) IID in the host defense against LPS-containing bacteria.
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PMID:Interferon gamma-induced gene expression of the novel secretory phospholipase A2 type IID in human monocyte-derived macrophages is inhibited by lipopolysaccharide. 1689 54

Arachidonic acid (AA) and its metabolites mediate many physiological processes including reproduction and endocrinology. The current study investigated effects of several inhibitors of AA cascade on steroidogenesis by rat corpus luteum cells in vitro. Dispersed luteal cells prepared from rat corpus luteum on day 6 of pseudopregnancy secreted progesterone (P4) in time-dependent and human chorinonic gonadotropin (hCG)-dependent fashion. Arachidonyl trifluoromethyl ketone, a preferential inhibitor of the type IVA phospholipase A(2) (PLA(2)-IVA), stimulated basal P4 secretion and had no influence on hCG-stimulated steroidogenesis. A novel and more specific inhibitor pyrrophenone inhibited hCG-induced P4 secretion. A cyclooxygenase inhibitor indomethacin did not affect basal secretion but inhibited hCG-stimulated secretion. Nordihydroguaiaretic acid tended to decrease basal P4 secretion and completely inhibited hCG-stimulated secretion. Obtained results suggest that AA metabolic cascade, which is triggered at least in part by PLA(2)-IVA activity, is potentially implicated in hCG-stimulated P4 secretory response in the rat corpus luteum.
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PMID:Effects of arachidonate metabolism inhibitors on basal and human chorionic gonadotropin-stimulated progesterone secretion by rat corpus luteum cells in vitro. 1725 80

Group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) initiates eicosanoid production; however, this pathway is not completely ablated in cPLA(2)alpha(-/-) lung fibroblasts stimulated with A23187 or serum. cPLA(2)alpha(+/+) fibroblasts preferentially released arachidonic acid, but A23187-stimulated cPLA(2)alpha(-/-) fibroblasts nonspecifically released multiple fatty acids. Arachidonic acid release from cPLA(2) alpha(-/-) fibroblasts was inhibited by the cPLA(2)alpha inhibitors pyrrolidine-2 (IC(50), 0.03 microM) and Wyeth-1 (IC(50), 0.1 microM), implicating another C2 domain-containing group IV PLA(2). cPLA(2) alpha(-/-) fibroblasts contain cPLA(2)beta and cPLA(2)zeta but not cPLA(2)epsilon or cPLA(2)delta. Purified cPLA(2)zeta exhibited much higher lysophospholipase and PLA(2) activity than cPLA(2)beta and was potently inhibited by pyrrolidine-2 and Wyeth-1, which did not inhibit cPLA(2)beta. In contrast to cPLA(2)beta, cPLA(2)zeta expressed in Sf9 cells mediated A23187-induced arachidonic acid release, which was inhibited by pyrrolidine-2 and Wyeth-1. cPLA(2)zeta exhibits specific activity, inhibitor sensitivity, and low micromolar calcium dependence similar to cPLA(2)alpha and has been identified as the PLA(2) responsible for calcium-induced fatty acid release and prostaglandin E(2) production from cPLA(2) alpha(-/-) lung fibroblasts. In response to ionomycin, EGFP-cPLA(2)zeta translocated to ruffles and dynamic vesicular structures, whereas EGFP-cPLA(2)alpha translocated to the Golgi and endoplasmic reticulum, suggesting distinct mechanisms of regulation for the two enzymes.
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PMID:Function, activity, and membrane targeting of cytosolic phospholipase A(2)zeta in mouse lung fibroblasts. 1729 13

Group IIA secretory phospholipase A(2) (sPLA(2)-IIA) is a prototypic sPLA(2) enzyme that may play roles in modification of eicosanoid biosynthesis as well as antibacterial defense. In several cell types, inducible expression of sPLA(2) by pro-inflammatory stimuli is attenuated by group IVA cytosolic PLA(2) (cPLA(2)alpha) inhibitors such as arachidonyl trifluoromethyl ketone, leading to the proposal that prior activation of cPLA(2)alpha is required for de novo induction of sPLA(2). However, because of the broad specificity of several cPLA(2)alpha inhibitors used so far, a more comprehensive approach is needed to evaluate the relevance of this ambiguous pathway. Here, we provide evidence that the induction of sPLA(2)-IIA by pro-inflammatory stimuli requires group VIB calcium-independent PLA(2) (iPLA(2)gamma), rather than cPLA(2)alpha, in rat fibroblastic 3Y1 cells. Results with small interfering RNA unexpectedly showed that the cytokine induction of sPLA(2)-IIA in cPLA(2)alpha knockdown cells, in which cPLA(2)alpha protein was undetectable, was similar to that in replicate control cells. By contrast, knockdown of iPLA(2)gamma, another arachidonyl trifluoromethyl ketone-sensitive intracellular PLA(2), markedly reduced the cytokine-induced expression of sPLA(2)-IIA. Supporting this finding, the R-enantiomer of bromoenol lactone, an iPLA(2)gamma inhibitor, suppressed the cytokine-induced sPLA(2)-IIA expression, whereas (S)-bromoenol lactone, an iPLA(2)beta inhibitor, failed to do so. Moreover, lipopolysaccharide-stimulated sPLA(2)-IIA expression was also abolished by knockdown of iPLA(2)gamma. These findings open new insight into a novel regulatory role of iPLA(2)gamma in stimulus-coupled sPLA(2)-IIA expression.
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PMID:A novel role of group VIB calcium-independent phospholipase A2 (iPLA2gamma) in the inducible expression of group IIA secretory PLA2 in rat fibroblastic cells. 1747 22

Prostaglandin (PG) E(2) is considered to participate in the storage of fat in adipocytes and hepatocytes, but roles of group IVA phospholipase A(2) (PLA(2)), a key PLA(2) isozyme in the arachidonic acid cascade, remain unclear. The present study examined the possible involvement of the enzyme using group IVA PLA(2)-deficient mice (C57BL/6 background, 22 weeks of age) fed a normal diet (5.3% fat). The ratio of epididymal fat pad weight to body weight was significantly reduced in group IVA PLA(2)-deficient mice compared to wild-type mice. Histological analysis revealed that in group IVA PLA(2)-deficient mice, the adipocytes were smaller, and hepatocytes bearing cytoplasmic vacuolation were scarce. Hepatic triglyceride content and the serum levels of PGE(2) in the deficient mice were also lower. However, there was no difference in the serum levels of insulin, glucose, non-esterified free fatty acid, or total cholesterol between the deficient and wild-type mice. Our findings suggest that group IVA PLA(2) is involved in the storage of lipids in the adipose tissue and liver and in determining circulating PGE(2) levels.
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PMID:Group IVA phospholipase A2 is associated with the storage of lipids in adipose tissue and liver. 1828 78

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