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)

Semliki Forest virus inhibits phosphatidylethanolamine biosynthesis in baby hamster kidney-21 cells 6 h after infection. Viral infection reduced the incorporation of [1,2-14C]-ethanolamine into intact cells by approximately 50%. A similar reduction in the activity of the ethanolaminephosphotransferase (EC 2.7.8.1) was also observed. The apparent Km for CDPethanolamine was 60 muM for the microsomal enzymes from infected or mock-infected cells. In addition, exogenous diglyceride only stimulated by 1.5-fold the ethanolaminephosphotransferase from virus- or mock-infected cells, whereas the same diglyceride preparations stimulated the cholinephosphotransferase (EC 2.7.8.2) from baby hamster kidney cells by sixfold. Generation of endogenous diglyceride by pretreatment of the microsomes with phospholipase C (EC 3.1.4.3) stimulated the activity of the cholinephosphotransferase but not the ethanolaminephosphotranferase. Semliki Forest virus does not inhibit all microsomal enzymes, since the activities of NADH- K3Fe(CN)6 reductase and NADH dehydrogenase (EC 1.6.99.3) were not affected. The ethanolaminephosphotransferase from virus- and mock-infected cells showed similar profiles of activity as a function of temperature; this result and other studies suggest that that membranous environment of the ethanolaminephosphotransferase was not significantly modified by the virus.
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PMID:Inhibition of phosphatidylethanolamine biosynthesis in baby hamster kidney-21 cells infected with Semliki Forest virus. 17 Oct 43

Recent studies indicate that viruses may influence polyphosphoinositide levels. This study has examined the effects of vaccinia virus infection on phospholipase C activity. Infection of BS-C-1 cells, an African Green Monkey kidney cell line, or A431 cells, a human carcinoma cell line, with vaccinia virus inhibits receptor-mediated phospholipase C activation. As a consequence, agonist-mediated Ca2+ mobilization in BS-C-1 cells also was inhibited by vaccinia virus infection. Alleviation of the inhibition of phospholipase C activation was observed in vaccinia virus-infected cells treated with cycloheximide without influencing uninfected cells. Treatment of infected cells with alpha-amanitin, an inhibitor of host mRNA synthesis but not virus mRNA synthesis, failed to alleviate the inhibition of phospholipase C activation. Together these results suggest that a virus-encoded gene product mediates the inhibition of phospholipase C activation without the need of a virus-induced host factor. Analysis of the processes involved in the formation of inositol (1,4,5)-trisphosphate and mobilization of intracellular Ca2+ indicate that the vaccinia virus gene product exerts its inhibitory effects at the level of phospholipase C activity. This may occur by either directly reducing the amount of phospholipase C, reducing the specific activity of phospholipase C, or by inhibiting the association of phospholipase C with its substrate, phosphatidylinositol 4,5-bisphosphate.
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PMID:Inhibition of agonist-induced activation of phospholipase C following poxvirus infection. 146 12

Neutrophil dysfunction consequent to influenza A virus infection has been described in vivo and in vitro and may contribute to the serious bacterial sequelae which occur in influenza-infected hosts. On the premise that such dysfunction may represent a form of "deactivation," we sought to characterize neutrophil activation by the virus in comparison with other agonists. The virus induces a respiratory burst in which H2O2 (but not O2-) are formed. Preceding the respiratory burst, a rise in intracellular calcium (Ca2+i) is noted, but both responses are nearly independent of extracellular Ca2+, unlike those elicited by the other well-characterized Ca2+-dependent agonists, formyl-methyl-leucyl-phenylalanine (FMLP), or Concanavalin-A (Con-A). The Ca2+ increase is paralleled by IP3 generation, implying that it is the result of phospholipase C (PLC) activation. The virus also elicits neutrophil membrane depolarization, which is independently mediated from the Ca2+ increase and respiratory burst and may reflect protein kinase C (PK-C) activation. Virus-induced responses are insensitive to pertussis toxin (PT); cholera toxin does inhibit these responses but in a nonspecific manner. Thus, although influenza virus activates PLC in neutrophils, it does so in a PT-insensitive manner and does not elicit or require a discernible Ca2+ influx to generate a respiratory burst response. In aggregate, the data indicate that influenza A virus activates neutrophils in a manner distinct from that of other well-described neutrophil agonists. These results illustrate the diversity of neutrophil activation mechanisms and support the notion that further characterization of this pathway may facilitate understanding of neutrophil dysfunction induced by the virus.
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PMID:Characterization of influenza A virus activation of the human neutrophil. 215 30

To study the growth control of human thyroid cells in different stages of differentiation, we established two human thyroid cell lines of adenomatous goiter and papillary carcinoma. A 59-year-old female patient with adenomatous goiter was operated in September 1991, and a 27-year-old female patient with papillary carcinoma in May 1990. The thyroid cell lines were established by successive passage without cellular or genetic manipulations such as fusing other cell lines or oncogenic viral infection. These cell lines, human adenomatous goiter cells (hAG) and human papillary thyroid carcinoma cells (hPTC), exhibited a flattened polygonal shape and proliferated as a monolayer in cell culture. The doubling time of the hAG cells was 60 h in Ham's F12 medium supplemented with 10% fetal bovine serum, and that of the hPTC cells, 18 h in the same medium. Both cell lines expressed mRNA for TSH receptor and secreted cAMP into the medium during incubation with thyrotropin (TSH) at concentrations as low as 0.01 mU/mL. The effects of activators of protein kinase A (PKA), protein kinase C (PKC), tyrosine kinase (TK), and estradiol (E2) on proliferation of the hAG cells and the hPTC cells were assessed by measuring cellular DNA content in 24-well plates with diaminobenzoic acid. TSH stimulated proliferation of the hAG cells, but it inhibited proliferation of the hPTC cells. Since TSH activates two signaling pathways, the adenyl cyclase-PKA system and phospholipase C-PKC system, we tested effects of dibutylyl cAMP (dBC) and phorbol myristate 13-acetate (PMA), separately. dBC stimulated proliferation of the hAG cells, but it inhibited that of the hPTC cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Different growth control of the two human thyroid cell lines of adenomatous goiter and papillary carcinoma. 778 32

The entry process of alphaherpesviruses consists of two steps, initial virus attachment and subsequent virus penetration involving membrane fusion. Glycoprotein D (gD) of the alphaherpesvirus bovine herpesvirus 1 (BHV 1) is an essential envelope protein, and it has been previously documented that gD plays a significant part in both of the virus entry steps. In order to gain further insight into the virus entry process, we attempted to define the essential function of BHV 1 gD. We replaced the gD transmembrane and cytoplasmic domains with a lipid-addition signal sequence from human decay accelerating factor and produced a stably transfected Madin Darby bovine kidney (MDBK) cell line that expresses a nonfusogenic, glycosylphosphatidylinositol (GPI)-anchored gD. We found that this cell line was able to support the growth of a gD gene-deletion mutant; the resultant gD mutant progeny contained the GPI-anchored gD on its virions and was able to enter into and produce a production infection in MDBK cells. This result suggests that fusion activity does not constitute the essential function of gD. In addition, we found that a gD-null virus (a virus containing no gD on its virion) could infect gD-expressing cells, but not normal MDBK cells. The ability of the gD-null virus to infect gD-expressing cells was dependent on the gD present on the cell surface, since either treating cells with phosphatidylinositol-specific phospholipase C to remove the GPI-anchored gD or incubating cells with gD monoclonal antibodies could block gD-null virus infection. This demonstrates that gD present on the cell surface can act in trans to facilitate the entry of virion lacking gD. This indicates that essential gD function can take place in the absence of gD-mediated virus attachment and membrane fusion. We also found that the gD monoclonal antibodies that block gD-null virus entry into gD-expressing cells are strictly restricted to the monoclonal antibodies that show postadsorption neutralization activity, indicating that the trans-acting function exhibited by the gD present on the cell surface represents the same function as defined by postadsorption antibody neurtralization. The results from this study suggest that the essential function of gD in virus entry is to modulate other virus-cell interaction(s) involved in productive virus penetration.
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PMID:Delineation of the essential function of bovine herpesvirus 1 gD: an indication for the modulatory role of gD in virus entry. 788 47

Dengue virus nonstructural protein 1 (NS1) is expressed on the surface of infected cells and is a target of human antibody responses to dengue virus infection. We show here that dengue virus uses the cellular glycosyl-phosphatidylinositol (GPI) linkage pathway to express a GPI-anchored form of NS1 and that GPI anchoring imparts a capacity for signal transduction in response to binding of NS1-specific antibody. This study is the first to identify GPI linkage of a virus-encoded protein. The GPI anchor addition signal for NS1 was identified, by transfection of HeLa cells with dengue cDNA constructs, as a downstream hydrophobic domain in NS2A. GPI linkage of NS1 in both transfected and infected cells was demonstrated by cleavage of NS1 from the surface by PI-specific phospholipase C and by metabolic incorporation of the GPI-specific components ethanolamine and inositol. In common with other GPI-anchored proteins, addition of specific antibody resulted in signal transduction, as evidenced by tyrosine phosphorylation of cellular proteins. Antibody-induced signal transduction by GPI-linked NS1 suggests a mechanism of cellular activation that may contribute to the pathogenesis of human dengue disease. Signal transduction by a GPI-anchored viral antigen interacting with a specific antibody that it induces is a new concept in the pathogenesis of viral disease.
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PMID:Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. 1092 95

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) encodes a chemokine-like G protein-coupled receptor (KSHV-GPCR) that is implicated in the pathogenesis of Kaposi's sarcoma (KS). Since endothelial cells appear to be targets for the virus, we developed an in vitro mouse lung endothelial cell model in which KSHV-GPCR is stably expressed and KSHV-GPCR signaling was studied. In mouse lung endothelial cells: 1) KSHV-GPCR does not exhibit basal signaling through the phosphoinositide-specific phospholipase C pathway but inositol phosphate production is stimulated by growth-related oncogene alpha (Gro-alpha) via a pertussis toxin (PTX)-insensitive pathway; 2) KSHV-GPCR signals basally through a PTX-sensitive pathway leading to a lowering of intracellular cAMP level that can be lowered further by Gro alpha and increased by interferon gamma-inducible protein 10; 3) KSHV-GPCR stimulates phosphatidylinositol 3-kinase via a PTX-insensitive mechanism; and 4) KSHV-GPCR activates nuclear factor-kappa B (NF-kappa B) by a PTX-sensitive G beta gamma subunit-mediated pathway. These data show that KSHV-GPCR couples to at least two G proteins and initiates signaling via at least three cascades in endothelial cells thereby increasing the complexity of regulation of endothelial cell function by KSHV-GPCR that may occur during viral infection.
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PMID:Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells. 1144 67

Cellular infection by cytomegalovirus (CMV) is associated with very early G-protein-mediated signal transduction and reprogramming of gene expression. Here we investigated the involvement of human CMV (HCMV)-encoded US27, US28, and UL33 receptors as well as murine CMV-encoded M33 transmembrane (7TM) receptors in host cell signaling mechanisms. HCMV-encoded US27 did not show any constitutive activity in any of the studied signaling pathways; in contrast, US28 and M33 displayed ligand-independent, constitutive signaling through the G protein q (Gq)/phospholipase C pathway. In addition, M33 and US28 also activated the transcription factor NF-kappaB as well as the cyclic AMP response element binding protein (CREB) in a ligand-independent, constitutive manner. The use of specific inhibitors indicated that the p38 mitogen-activated protein (MAP) kinase but not the extracellular signal-regulated kinase 1/2-MAP kinase pathway is involved in M33- and US28-mediated CREB activation but not NF-kappaB activation. Interestingly, UL33-the HCMV-encoded structural homologue of M33-was only marginally constitutively active in the Gq/phospholipase C turnover and CREB activation assays and did not show any constitutive activity in the NF-kappaB pathway, where M33 and US28 were highly active. Hence, CMVs appear to have conserved mechanisms for regulating host gene transcription, i.e., constitutive activation of certain kinases and transcription factors through the constitutive activities of 7TM proteins. These data, together with the previous identification of the incorporation of such proteins in the viral envelope, suggest that these proteins could be involved in the very early reprogramming of the host cell during viral infection.
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PMID:Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. 1213 21

Itk and Rlk are members of the Tec kinase family of nonreceptor protein tyrosine kinases that are expressed in T cells, NK cells, and mast cells. These proteins are involved in the regulation of signaling processes downstream of the TCR in CD4(+) T cells, particularly in the phosphorylation of phospholipase C-gamma1 after TCR activation; furthermore, both Itk and Rlk are important in CD4(+) T cell development, differentiation, function, and homeostasis. However, few studies have addressed the roles of these kinases in CD8(+) T cell signaling and function. Using Itk(-/-) and Itk(-/-)Rlk(-/-) mice, we examined the roles of these Tec family kinases in CD8(+) T cells, both in vitro and in vivo. These studies demonstrate that the loss of Itk and Rlk impairs TCR-dependent signaling, causing defects in phospholipase C-gamma1, p38, and ERK activation as well as defects in calcium flux and cytokine production in vitro and expansion and effector cytokine production by CD8(+) T cells in response to viral infection. These defects cannot be rescued by providing virus-specific CD4(+) T cell help, thereby substantiating the important role of Tec kinases in CD8(+) T cell signaling.
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PMID:Tec kinases Itk and Rlk are required for CD8+ T cell responses to virus infection independent of their role in CD4+ T cell help. 1642 86

CCL2 (MCP-1) has been shown to enhance HIV-1 replication. The expression of this chemokine by macrophages is up-modulated as a consequence of viral infection or gp120 exposure. In this study, we show for the first time that the phosphatidylcholine-specific phospholipase C (PC-PLC) is required for the production of CCL2 triggered by gp120 in human monocyte-derived macrophages (MDMs). Using a combination of pharmacologic inhibition, confocal laser-scanner microscopy, and enzymatic activity assay, we demonstrate that R5 gp120 interaction with CCR5 activates PC-PLC, as assessed by a time-dependent modification of its subcellular distribution and a concentration-dependent increase of its enzymatic activity. Furthermore, PC-PLC is required for NF-kB-mediated CCL2 production triggered by R5 gp120. Notably, PC-PLC activation through CCR5 is specifically induced by gp120, since triggering CCR5 through its natural ligand CCL4 (MIP-1beta) does not affect PC-PLC cellular distribution and enzymatic activity, as well as CCL2 secretion, thus suggesting that different signaling pathways can be activated through CCR5 interaction with HIV-1 or chemokine ligands. The identification of PC-PLC as a critical mediator of well-defined gp120-mediated effects in MDMs unravels a novel mechanism involved in bystander activation and may contribute to define potential therapeutic targets to block Env-triggered pathologic responses.
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PMID:Phosphatidylcholine-specific phospholipase C activation is required for CCR5-dependent, NF-kB-driven CCL2 secretion elicited in response to HIV-1 gp120 in human primary macrophages. 1820 56


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