Disease relevance of PLA2G4A

• PLA2G4A is located on Chromosome 1q, where a number of groups have reported linkage to type 2 diabetes mellitus [1].
• Secretory phospholipase A2 activates the cascade of mitogen-activated protein kinases and cytosolic phospholipase A2 in the human astrocytoma cell line 1321N1 [2].
• Induction of cytosolic phospholipase A2 by oncogenic Ras in human non-small cell lung cancer [3].
• Cytosolic phospholipase A2 participates with TNF-alpha in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra [4].
• Differential role of cytosolic phospholipase A2 in the invasion of brain microvascular endothelial cells by Escherichia coli and Listeria monocytogenes [5].

Psychiatry related information on PLA2G4A

• BanI polymorphism of the cytosolic phospholipase A2 gene and mood disorders in the Korean population [6].

High impact information on PLA2G4A

• Cytosolic phospholipase A2 initiates the biosynthesis of prostaglandins, leukotrienes, and platelet-activating factor (PAF), mediators of the pathophysiology of asthma and arthritis [7].
• Treatment of cells with agents that stimulate the release of arachidonic acid causes increased serine phosphorylation and activation of cytosolic phospholipase A2 (cPLA2) [8].
• We report the cloning and expression of a cDNA encoding a high molecular weight (85.2 kd) cytosolic phospholipase A2 (cPLA2) that has no detectable sequence homology with the secreted forms of PLA2 [9].
• Cytosolic phospholipase A2 and the distinct transcriptional programs of astrocytoma cells [10].
• Since inhibition of iPLA2, but not cPLA2, attenuated IgM binding to apoptotic cells, these results strongly suggest that the endogenous calcium independent PLA(2), iPLA(2), is involved in the hydrolysis of plasma membrane phospholipids and exposure of the epitope(s) recognized by IgM [11].

Chemical compound and disease context of PLA2G4A

• Signaling mechanisms involved in the activation of arachidonic acid metabolism in human astrocytoma cells by tumor necrosis factor-alpha: phosphorylation of cytosolic phospholipase A2 and transactivation of cyclooxygenase-2 [12].
• Inhibition of cytosolic phospholipase A2 mRNA expression: a novel mechanism for acetylsalicylic acid-mediated growth inhibition and apoptosis in colon cancer cells [13].
• Enhancement of prostaglandin E2 production by epidermal growth factor requires the coordinate activation of cytosolic phospholipase A2 and cyclooxygenase 2 in human squamous carcinoma A431 cells [14].
• Thromboxane synthesis is increased by upregulation of cytosolic phospholipase A2 and cyclooxygenase-2 in peripheral polymorphonuclear leukocytes during bacterial infection in childhood [15].
• Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells [16].

Biological context of PLA2G4A

• Six single nucleotide polymorphisms (SNPs) present in the PTGS2/PLA2G4A locus were detected among 118 British family trios of schizophrenia patients [17].
• The conditioning on genotype test, but not on allele test, revealed a strong association for the combination of the CLDN5 gene with the PLA2G4A gene (chi(2) = 10.17, df = 2, P = 0.006) [18].
• The transmission disequilibrium test showed that SNP4 located in the 5'-flanking region of the PLA2G4A gene was associated with schizophrenia and that the haplotype analysis also showed a genetic association between the PTGS2 gene and schizophrenia [17].
• The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727 [19].
• We have shown previously that cytosolic phospholipase A2 (cPLA2) is able to activate gene expression through PPAR-gamma response elements (Pawliczak, R., Han, C., Huang, X. L., Demetris, A. J., Shelhamer, J. H., and Wu, T. (2002) J. Biol. Chem. 277, 33153-33163) [20].

Anatomical context of PLA2G4A

• Involvement of cytosolic phospholipase A2 and secretory phospholipase A2 in arachidonic acid release from human neutrophils [21].
• Cytosolic phospholipase A2 activation is essential for beta 1 and beta 2 integrin-dependent adhesion of human eosinophils [22].
• Interleukin-1 beta induces cytosolic phospholipase A2 and prostaglandin H synthase in rheumatoid synovial fibroblasts. Evidence for their roles in the production of prostaglandin E2 [23].
• Although prostaglandin release has been studied in various epithelial cell models, the subcellular location of cPLA2-alpha in these cells is unknown [24].
• Furthermore, treatment of cells with the Golgi-disrupting agent brefeldin A caused a redistribution of cPLA2-alpha, confirming that cPLA2-alpha associates with Golgi-derived membranes [24].

Associations of PLA2G4A with chemical compounds

• Phospholipase A2, Group IVA (PLA2G4A) belongs to the class of cytosolic calcium-dependent phospholipases (cPLA2s) that preferentially cleave arachidonic acid (AA) from membrane glycerophospholipids [1].
• We have screened the PLA2G4A gene and identified a C-->G variant, which predicts a phenylalanine to leucine substitution [1].
• CRE activation occurred by BK inducing cytosolic phospholipase A2-mediated arachidonic acid release and rapid prostaglandin E2 (PGE2) production, thereby increasing cAMP [25].
• Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases [19].
• By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells [19].

Physical interactions of PLA2G4A

• The role of TFIID, the initiator element and a novel 5' TFIID binding site in the transcriptional control of the TATA-less human cytosolic phospholipase A2-alpha promoter [26].

Enzymatic interactions of PLA2G4A

• We have previously reported that in thrombin-stimulated human platelets, cytosolic phospholipase A(2) (cPLA2) is phosphorylated on Ser-505 by p38 protein kinase and on Ser-727 by an unknown kinase [19].
• Cytosolic phospholipase A2 is phosphorylated in collagen- and thrombin-stimulated human platelets independent of protein kinase C and mitogen-activated protein kinase [27].

Regulatory relationships of PLA2G4A

• Whereas Smad activation inhibited tumor cell growth, phosphorylation of cPLA2 alpha promoted growth and counteracted Smad-mediated mitoinhibition [28].
• Interleukin-4 inhibits the gene expression and biosyntheis of cytosolic phospholipase A2 in lipopolysaccharide stimulated U937 macrophage cell line and freshly prepared adherent rheumatoid synovial cells [29].
• We report that IFN-gamma induces the synthesis and prolonged activation of cytosolic phospholipase A2 (cPLA2) in a human bronchial epithelial cell line (BEAS 2B) [30].
• We show that TNF-induced activation of NF-kappaB was inhibited by the well-known selective inhibitors of cytosolic phospholipase A2 (cPLA2): the trifluoromethyl ketone analogue of arachidonic acid (AACOCF3) and methyl arachidonyl fluorophosphate [31].
• This was associated with both a significant increase in cyclo-oxygenase-2 (COX-2) mRNA levels (approximately fourfold compared with control) and translocation of cytoplasmic phospholipase A2 (cPLA2) from the cytosol to the membrane fraction [32].

Other interactions of PLA2G4A

• Enhancement of TNF-alpha-stimulated PGE2 production in synovial cells was accompanied by increased expression of cyclooxygenase (COX)-2 and cytosolic phospholipase A2 (cPLA2)-alpha [33].
• Moreover, this effect was selective in that the protein expression of two other important enzymes involved in the metabolism of arachidonic acid, cytosolic phospholipase A2 and 5-lipoxygenase, was not affected [34].
• We have isolated a cDNA encoding a 1012-amino acid polypeptide cPLA2-beta, that has significant homology with cPLA2-alpha in both the calcium-dependent lipid binding domain as well as in the catalytic domain [35].
• However, differences were observed in the ability of the hPGHS isoforms to utilize endogenous arachidonic acid released intracellularly following calcium ionophore stimulation or released by human cytosolic phospholipase A2 transiently expressed in the cells [36].
• Interleukin-4, transforming growth factor beta 1, and dexamethasone inhibit superantigen-induced prostaglandin E2-dependent collagenase gene expression through their action on cyclooxygenase-2 and cytosolic phospholipase A2 [37].

Analytical, diagnostic and therapeutic context of PLA2G4A

• Molecular cloning and expression of human Ca(2+)-sensitive cytosolic phospholipase A2 [38].
• Cytosolic PLA2 (cPLA2) and COX-2 messenger RNA (mRNA) were determined using semiquantitative reverse transcriptase-polymerase chain reaction [39].
• We evaluated cPLA2 and cyclooxygenase-2 (COX-2) protein expression in 65 colon carcinomas by immunohistochemistry, and in eight colorectal cancer cell lines by Western Blot [40].
• Furthermore, immunofluorescence microscopy studies revealed that cells stimulated for periods of greater than 10 min showed a high proportion of calcium-independent membrane-associated cPLA2-alpha [41].
• Both secretory and cytosolic phospholipase A2 enzymes have been implicated in the pathogenesis of arthritis in animal models, but the exact expression patterns of the enzymes in diseased human joint tissue are uncertain [42].

References