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)

Although the human immunodeficiency virus can induce cytopathic changes in human lymphocytes in vitro, the mechanism(s) underlying progressive lymphopenia in patients with AIDS and AIDS-related complex has not been elucidated. To investigate this issue, peripheral blood lymphocytes of AIDS and AIDS-related complex patients and healthy control subjects were examined for their ability to resist homologous complement-mediated lysis. Upon sensitization with monoclonal antibodies to major histocompatibility complex class I antigen, as much as 48% lysis of patients' cells was observed in as little as a 1:32 dilution of human serum compared to 18 +/- 8% (mean +/- SD) lysis of controls' cells even in a 1:8 dilution of human serum. To investigate the mechanism of the abnormal complement sensitivity, AIDS and AIDS-related complex cells were analyzed for expression of decay-accelerating factor (DAF), a complement regulatory protein that functions intrinsically in blood cell membranes to prevent complement activation on their surfaces. Flow cytometric assays using anti-DAF monoclonal antibodies demonstrated that patients' lymphocytes and monocytes were DAF-deficient, in contrast to their polymorphonuclear leukocytes, which showed normal DAF levels. Expression of DAF was diminished on CD4+ as well as CD8+ T-lymphocyte subpopulations as opposed to expression of CD3, which was comparable in patients and controls. Incubation of normal lymphocytes with anti-DAF monoclonal antibodies or phosphatidylinositol-specific phospholipase C, an enzyme that cleaves DAF, enhanced lysis. Conversely, reconstitution of patients' cells with exogenous DAF reduced their lysis. The findings of heightened complement sensitivity and DAF deficiency of patients' lymphocytes in vitro suggest the possibility that the DAF deficit may contribute to the progressive lymphopenia of AIDS in vivo.
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PMID:Heightened complement sensitivity of acquired immunodeficiency syndrome lymphocytes related to diminished expression of decay-accelerating factor. 247 Nov 98

A membrane protein of MW 60,000 was purified from mouse erythrocytes. This protein inhibits generation of mouse complement C3/C5 convertases on antibody-sensitized rabbit erythrocytes, in a haemolytic assay system using guinea-pig serum diluted in EDTA as the source of C3 to C9. This protein also has the capacity to accelerate the decay of human C3 convertase of the classical complement pathway. Antibody to this membrane protein also reacted with peripheral blood mononuclear cells and spleen cells, as observed by fluorescent flow cytometry analysis. Since the reactivity of these cells to the antibody was reduced by treatment with phosphatidyl inositol-specific phospholipase C (PIPLC), it is suggested that the protein is attached to the membrane via a glycophospholipid anchor. Based on these results, we conclude that this membrane protein is a murine homologue of human decay-accelerating factor (DAF).
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PMID:Murine membrane inhibitor of complement which accelerates decay of human C3 convertase. 248 41

Lymphocyte function-associated antigen 3 (LFA-3) is a widely distributed cell surface glycoprotein that binds to the T lymphocyte CD2 surface glycoprotein. This interaction mediates CTL-target cell conjugate formation and adhesion of thymocytes to thymic epithelial cells. CD2 is also the E rosette receptor of T lymphocytes and mediates rosetting with autologous E by binding to LFA-3. We describe deficient expression of LFA-3 on E from paroxysmal nocturnal hemoglobinuria (PNH) patients. PNH is an acquired defect affecting phosphatidylinositol-anchored membrane proteins, of which decay-accelerating factor (DAF) is most important in the clinical symptoms of PNH. LFA-3-negative, weakly positive, and positive populations were found among PNH E. There was a good correlation with DAF deficiency. PNH E exhibited decreased binding of 125I-CD2 and rosetting with a human T lymphoma cell line. PNH E readily incorporated purified LFA-3, restoring LFA-3 expression and the CD2 binding and rosetting activity to normal levels. The expression of DAF was not restored after the incorporation of purified LFA-3 into PNH E, showing that LFA-3 and DAF are different molecules. Phosphatidylinositol-specific phospholipase C (PIPLC) treatment of a B lymphoma cell line released 35% of the cell surface LFA-3 and 62% of DAF. LFA-3 on E was resistant to PIPLC. However, when LFA-3 purified from human E was reconstituted in sheep E or human E and subjected to PIPLC treatment, 40-50% of LFA-3 was released from the cell membrane. The results show that LFA-3 is attached to the cell membrane by a phosphatidylinositol glycolipid moiety, and confirm previous findings (37-41) that LFA-3 is a cell adhesion molecule that mediates adhesion by interacting with CD2 antigen.
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PMID:Deficiency of lymphocyte function-associated antigen 3 (LFA-3) in paroxysmal nocturnal hemoglobinuria. Functional correlates and evidence for a phosphatidylinositol membrane anchor. 330 23

Glycosylphosphatidylinositol (GPI)-modified variants of murine B7-1 and B7-2 cell surface costimulators were produced via chimerization with alternative GPI-modification signal sequences from decay-accelerating factor (DAF). GPI anchorage was verified by demonstrating phosphatidylinositol-specific phospholipase C (PI-PLC) sensitivity of the chimeric polypeptides in both immunofluorescence/flow-cytometric and immunoprecipitation analyses. The various GPI-modified chimeric B7-1:DAF and B7-2:DAF polypeptides were shown to retain costimulator function, in both an in vitro proliferation assay and an in vivo triggering of cytotoxicity assay. The findings indicate that costimulator function for both B7-1 and B7-2 is not dependent upon native hydrophobic transmembrane anchorage. Moreover, the functionality of the GPI-modified variants in enhancing the immunogenicity of the murine T lymphoma line EL-4 suggests a novel route for generating APC-centered immunotherapeutics, including cellular cancer vaccines, that is based upon protein transfer of GPI-modified costimulators.
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PMID:Glycosylphosphatidylinositol-modified murine B7-1 and B7-2 retain costimulator function. 749 30

Human E express two surface forms of decay-accelerating factor (DAF; CD55). On SDS-PAGE under reducing conditions the major form, DAF-1, migrates as a 70-kDa protein and the minor form, DAF-2, present at < 10% the amount of DAF-1, migrates as a 140-kDa protein (Kinoshita, T., S. I. Rosenfeld, and V. Nussenzweig. 1987. J. Immunol. 138:2994). Both forms possess decay-accelerating activity and, after purification from solubilized E, reinsert into sheep E, indicating a glycosylphosphatidylinositol anchor. In contrast to human cells, these two forms of DAF from orangutan E are expressed in approximately equal amounts (Nickells, M. W., and J. P. Atkinson. 1990. J. Immunol. 144:4262). An orangutan B lymphocyte cell line, CP81, also expresses similar quantities of both forms. These sources of orangutan DAF were utilized for further characterization of DAF-2. Orangutan and human DAF-1 were 98% and 95% homologous at the nucleotide and amino acid levels, respectively. Northern and Southern analyses of orangutan DAF were also similar to those for human DAF. Tryptic peptide maps of DAF-1 and DAF-2 were identical. After treatment with phosphatidylinositol-specific phospholipase C and glycosidases, the change in M(r) of DAF-2 was consistent with it possessing two glycosylphosphatidylinositol anchors and twice as much oligosaccharide as DAF-1. Biosynthetic analysis demonstrated a single 46-kDa precursor for both forms. Taken together, these data indicate that DAF-2 is a covalently cross-linked dimer of DAF-1. Analysis of a series of human DAF deletion mutants localized the cross-link(s) within the short consensus repeat domains.
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PMID:Characterization of DAF-2, a high molecular weight form of decay-accelerating factor (DAF; CD55), as a covalently cross-linked dimer of DAF-1. 750 31

Decay-accelerating factor (DAF) is a membrane protein that protects host cells from attack by its own complement. Although DAF expression on endothelial cells is thought to increase pathophysiologically, little is known about the natural mediators that modulate DAF expression on endothelial cells. In this study, we evaluated the effect of histamine on DAF expression on human umbilical vein cells (HUVEC). HUVEC were cultured with histamine, and DAF expression on HUVEC was determined by flow cytometry after immunostaining with a mAb to DAF. DAF expression on HUVEC was increased at 10 microM histamine, and the final level was increased time-dependently by 150% to 200% after a 24-h incubation with 100 microM histamine. The histamine-induced DAF expression was inhibited by actinomycin D and cycloheximide and accompanied by an increase in the DAF mRNA level, indicating that both transcription and translation are required. In addition, the histamine-induced DAF expression was inhibited by pyrilamine, an H1 blocker, but not by cimetidine, an H2 blocker, indicating that histamine induces the DAF expression through H1 receptors. We also demonstrated that the turnover of DAF is faster than that of MCP and CD59, and DAF is released into the culture supernatant. DAF is a glycosylphosphatidylinositol-linked protein that is released from HUVEC by a phosphatidylinositol-specific phospholipase C. Although HUVEC also contain the glycosylphosphatidylinositol-anchored complement inhibitor CD59, this was not released during a 24-h incubation, suggesting that the shedding of DAF from HUVEC is not caused by PI-PLC but by other enzymes, possibly proteinases. These results suggest that histamine, which is released from mast cells and basophils by complement-derived anaphylatoxins, increases the complement defense ability of endothelial cells by increasing their levels of DAF expression.
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PMID:Decay-accelerating factor on human umbilical vein endothelial cells. Its histamine-induced expression and spontaneous rapid shedding from the cell surface. 750 66

Approximately one-fifth of first trimester losses can be characterized by the onset of hypocomplementemia prior to ultrasonographic loss of embryonic viability. Monoclonal antibodies to the membrane complement regulatory protein, decay-accelerating factor (DAF), were bound to the surface of trophoblastic tissues, with the estimated number of DAF molecules in tissues obtained from hypocomplementemic women less than those from normocomplementemic women (approximately 10%). While trophoblastic tissue obtained from normocomplementemic women did not decomplement normal human sera, pretreatment of this tissue with anti-DAF antibodies resulted in activation of the complement (C') system via the alternate C' pathway (ACP). If trophoblastic tissue from normocomplementemic women was pretreated with phospholipase C, decomplementation of human serum occurred. These data strongly suggest that trophoblasts evade the ACP with functional DAF, possibly through absorption of the molecule's lipophilic diacylglycerol membrane-anchored moiety into the outer lipid bilayer of the trophoblast and may be a rational means for the utilization of immunotherapy in recurrent spontaneous aborters.
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PMID:Decay-accelerating factor protects human trophoblast from complement-mediated attack. 753 Jan 76

The survival of transfused red cells (RBCs) diminishes with time of in vitro storage in blood banks, but the molecular mechanisms underlying the slow but incessant deterioration are incompletely understood. To investigate the possibility that impaired resistance to autologous complement attack could play a role in this phenomenon, packed RBCs stored for variable periods were assayed for decay-accelerating factor (DAF) and CD59, two glycoinositol-phospholipid (GPI)-anchored, membrane-associated complement regulatory proteins that function physiologically to protect blood cells from autologous complement activation on their surfaces. Immunoradiometric and flow cytometric assays employing DAF and CD59 monoclonal antibodies showed that levels of both surface proteins gradually declined over 6 weeks. Digestion analyses with phosphatidylinositol-specific phospholipase C, an enzyme that releases GPI-anchored proteins from cell surfaces, showed that DAF and CD59 molecules with GPI anchors containing unacylated inositol were preferentially lost. These findings suggest: 1) that DAF and CD59 molecules with acylated GPI anchors are more stable in RBC membranes than are molecules with unacylated GPI anchors, and 2) that DAF and CD59 loss may participate with other membrane alterations that occur during in vitro storage in compromising the survival of transfused cells.
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PMID:Time-dependent loss of surface complement regulatory activity during storage of donor blood. 848 Mar 47

Mutants of bovine herpesvirus 1 that express a truncated envelope glycoprotein gIII or a gIII-human decay-accelerating factor (hDAF) chimeric protein (gIII.hDAF) were employed to evaluate the function of the transmembrane and cytoplasmic domains of the gIII molecule. Truncated gIII (i.e., lacking the transmembrane and cytoplasmic region) was readily released from infected cells and was not detected on mature virus particles. In contrast, replacement of the transmembrane and cytoplasmic domains with the carboxyl-terminal portion of hDAF restored the expression of gIII on the membranes of infected cells as well as on virion surfaces. The presence of the gIII.hDAF chimera on virus particles was also associated with normal gIII function, i.e., the mediation of virus attachment and penetration. The gIII-hDAF chimera, which is present on both infected cell surfaces and virions, could be cleaved by a phosphatidylinositol-specific phospholipase C, indicating that it was anchored in the membrane via glycosyl phosphatidylinositol. Our results from this study suggest that the transmembrane and cytoplasmic regions of the gIII molecule serve as a general membrane anchor, but they do not contain structural signals required for the specific assembly of envelope proteins into mature virions.
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PMID:Expression of glycoprotein gIII-human decay-accelerating factor chimera on the bovine herpesvirus 1 virion via a glycosyl phosphatidylinositol-based membrane anchor. 768 5

In previous studies we have demonstrated that mouse Crry/p65 regulates complement component C3 deposition on self membranes, a functional property that both human decay-accelerating factor (DAF) and membrane cofactor protein (MCP) exhibit. We have proposed that Crry/p65 has a similar biologic role in mouse as MCP and perhaps DAF and is the mouse analogue of one or both of these proteins. In order to address this hypothesis and further study Crry/p65, we have prepared rat mAb and a rabbit polyclonal Ab to this protein. Using these reagents we demonstrate that, like human MCP and DAF, the tissue distribution of Crry/p65 is very broad. Most if not all cells of nonneuronal origin express this protein. In addition, by immunohistochemical analysis, Crry/p65 is shown to be more highly expressed in some tissues at potential sites of immune complex deposition and damage, such as the mesangium of the renal glomerulus and the arterial vessel endothelium. By Western blot analysis, protein isoforms can be demonstrated. Unlike human DAF, however, no phosphatidylinositol-specific phospholipase C-sensitive Crry/p65 protein form can be demonstrated on lymphocytes or erythrocytes. Five of six anti-Crry/p65 mAb can partially or completely reverse the capacity of Crry/p65 to block C3 deposition on cell membranes. Analysis of four IgG rat anti-Crry/p65 mAb demonstrates that two major independent epitopes can be detected. Overall, Crry/p65 retains many of the major features of human MCP and DAF, and the use of these reagents should further the understanding of the biologic roles of this class of complement regulatory proteins.
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PMID:Mouse Crry/p65. Characterization of monoclonal antibodies and the tissue distribution of a functional homologue of human MCP and DAF. 769 44


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