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:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One hundred kidney graft recipients were analysed retrospectively with regard to the presence of Fc gamma RII (EAI) blocking or cytotoxic HLA antibody induced by pretransplant transfusion. Previous studies suggested that transfusion induces the production of EAI blocking antibody which may have specificity to TLX/CD46/MCP alloantigens. A superior graft survival (65%/9 yr) was found in the presence of EAI alloantibody compared to graft survival in the absence of this antibody (40%/9 yr). Further analysis showed the following survival rates in relation to the combined appearance of HLA cytotoxic and EAI antibody (EAI positive, HLA negative 67%/9 yr; EAI positive, HLA positive 60%/9 yr; EAI negative, HLA positive 0%/9 yr; EAI negative, HLA negative 40%/9 yr). There was striking low graft failure in the first 6 months in patients with EAI antibody. Taking into consideration that the HLA B/DR mismatching grade in all various groups were the same and no considerable difference was found in association to graft survival, the presence or absence of alpha EAI (anti-TLX) antibody solely seems to have superior or additional effect on graft survival as compared to HLA matching.
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PMID:Association between long-term kidney graft survival and the presence of pre-transplant cytotoxic anti-HLA and/or non-MHC 'Fc gamma RII blocking' (anti-TLX) alloantibody. 893 Apr 62

Rat oligodendrocytes spontaneously activate complement (C) and lack the C inhibitor CD59. As a consequence, rat oligodendrocytes are susceptible to lysis by autologous C in vitro. Expression of C inhibitors on human oligodendrocytes in vitro and other human glia has yet to be well characterized. We have previously shown expression at the mRNA level of the membrane inhibitors CD59, decay-accelerating factor (DAF; CD55) and membrane cofactor protein (MCP; CD46) in human astrocytes. We here examine the expression of membrane and secreted C inhibitors by the oligodendrocyte cell line, HOG. HOG cells abundantly expressed CD59, assessed at protein and mRNA level, and expressed DAF and MCP, albeit at a lower level. Expression of all three inhibitors was enhanced by incubation with interferon-gamma or with phorbol ester (PMA). Complement receptor type 1 (CR1; CD35) was neither expressed constitutively nor induced by cytokines. HOG also constitutively secreted C1-inhibitor, S-protein and clusterin. Factor H was secreted only after stimulation with cytokines. C4b binding protein was expressed at a very low level and was detected only at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). For comparison, astrocyte expression of CD59, DAF, MCP and CR1 was confirmed at the mRNA and protein levels. HOG did not activate C spontaneously, as judged by the lack of deposition of C fragments, and were not lysed by C even after inhibition of CD59 and DAF using specific monoclonal antibodies.
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PMID:Complement regulatory protein expression by a human oligodendrocyte cell line: cytokine regulation and comparison with astrocytes. 895 45

Complement in the respiratory tract protects the host from invading micoorganisms and other inhaled insults, but may damage normal tissue. Recently we reported that human respiratory epithelium from the nose to the alveoli expresses three cell-membrane regulators of complement activation: membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF; CD55), and CD59. In this study we investigated whether two of these complement-regulatory proteins, DAF and CD59, protect human nasal epithelial cells from complement-mediated lysis. Treatment of nasal epithelial cells in suspension with 50% or 100% normal human serum (NHS) lysed small percentages of cells (8% and 16%, respectively). Addition of complement activators, rabbit serum antinasal epithelial cells (anti-NEC), or lipopolysaccharide (LPS) increased cell lysis in the presence of 50% NHS in a dose-dependent manner up to 50% and 35% lysis, respectively. Human serum deficient in C3 or C7 did not lyse nasal epithelial cells even in the presence of anti-NEC. To assay the contribution of DAF and CD59 to cell protection against lysis, nasal epithelial cells in suspension were treated with appropriate blocking antibodies. Both anti-DAF and anti-CD59 markedly increased the susceptibility of human nasal epithelial cells to lysis by complement. At 50% NHS, anti-DAF and anti-CD59 antibodies increased epithelial cell lysis from 8% to 24% and 67%, respectively. A similar pattern of response to complement was demonstrated by monolayers of substrate-anchored cultured cells. These results indicate that DAF and CD59 protect human nasal epithelial cells from complement-mediated lysis; however, intense activation of complement may overcome this protection, leading to cell death and tissue injury. We speculate that imbalance between complement regulation and complement activation in the human respiratory tract in disease may result in tissue injury and impaired tissue function.
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PMID:Protection of human nasal respiratory epithelium from complement-mediated lysis by cell-membrane regulators of complement activation. 896 67

Ovarian cancer has features that makes it well-suited for MAb adjuvant immunotherapy. Several of the MAbs used in clinical trials mediate cancer cell destruction by activation of complement (C). In this study, therefore, we examined the ability of ovarian-tumor cells to resist C attack. We found that the C regulators membrane cofactor protein (MCP, CD46) and protectin (CD59) were strongly expressed in the tumor cells in all 28 benign and malignant tumors examined. Decay-accelerating factor (DAF; CD55) was more heterogeneously expressed, and only 75% of the tumors exhibited a moderate amount of DAF in the tumor cells. In adenoma cells, CD59 and DAF were preferentially located apically, while in adenocarcinoma cells they were expressed also at the basolateral cell surface. The ovarian-carcinoma cell lines SK-OV-3, Caov-3, SW626 and PA-1 expressed both the 58- and the 68-kDa isoforms of MCP. DAF was present as a glycosyl-phosphatidylinositol(GPI)-anchored 70-kDa glycoprotein. The surface-expression level of DAF varied, and correlated with the vulnerability of the cells to C-mediated lysis. CD59 was expressed as a GPI-linked 19- to 25-kDa protein exhibiting multiple glycosylation variants. The surface expression of CD59 correlated with the amount of the main 1.9 + 2.1-kb CD59 mRNA transcripts. Neutralization of CD59 with an anti-CD59 MAb significantly enhanced C-mediated killing of the cell lines. Low expression of C regulators on the PA-1 teratocarcinoma cell line was associated with high sensitivity to C lysis. Thus, the expression of C regulators on malignant ovarian cells may constitute a tumor escape mechanism, and is a critical parameter to be examined when MAb therapy is being considered.
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PMID:Complement-regulatory proteins in ovarian malignancies. 898 85

We isolated a 1257-bp cDNA encoding a membrane cofactor protein (MCP, CD46)/measles virus (MV) receptor-like protein from a cDNA library of Vero cells, in which wild MV strains were established. Vero cells contain MCP mRNA splice products encoding different cytoplasmic tails like human cells. The deduced amino acid sequence of the cDNA was 86% identical to that of human MCP. Vero cell MCP expressed on CHO cells was recognized by monoclonal antibodies against human MCP, and served as a potent MV receptor. In addition, Vero MCP was as effective as human MCP in human factor I-mediated C3b cleavage. Thus, the high MV susceptibility of Vero cells can in part be attributed to an MCP-like molecule that is structurally and functionally similar to human MCP.
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PMID:Molecular cloning of a complementary DNA for a membrane cofactor protein (MCP, CD46)/measles virus receptor on Vero cells and its functional characterization. 899 35

A panel of mAbs were raised against pig lymphocytes. Seven mAbs immunoprecipitated a 50- to 60-kDa membrane-bound protein. This protein, termed JM4C8-Ag, was expressed on a wide variety of cells, including all circulating cells and cells of fibroblast, epithelial, and endothelial origin. The JM4C8-Ag was transmembrane-anchored and glycosylated. One of the Abs was used in immunoaffinity chromatography to isolate JM4C8-Ag from erythrocyte membranes. N-terminal amino acid analysis through the first 28 residues showed a 43% homology with the human complement regulatory molecule membrane cofactor protein (MCP; CD46). The purified protein had cofactor activity for factor I-mediated cleavage of human and pig C3b, confirming its identity as the pig analogue of human MCP. The purified protein also strongly inhibited lysis of rabbit erythrocytes by human and pig complement after activation of the classical or alternative pathway. This is the first report of a nonprimate analogue of MCP. The presence of a resident MCP on pig cells capable of acting as a cofactor in the control of human complement activation has consequences for the use of pig organs in xenotransplantation.
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PMID:Purification and characterization of the pig analogue of human membrane cofactor protein (CD46/MCP). 902 6

Two phosphatidylinositol (PI)-anchored versions of a measles virus (MV) receptor membrane cofactor protein (MCP; CD46) were generated by fusing the extracellular domain of MCP to the decay-accelerating factor (DAF; CD55) or its PI anchor. The PI-anchored forms of MCP expressed on Chinese hamster ovary cells, otherwise non-permissive to MV, conferred a smaller MV cytopathic effect than a wild-type MCP, a Ser/Thr-rich domain-deletion mutant and a cytoplasmic tail-deletion mutant of MCP. Therefore the differences in MV receptor properties between the two PI-anchored and three transmembrane forms were investigated. The PI-anchored forms were predominantly expressed on microvilli as in DAF, whereas the other transmembrane forms were found on intracellular membranes. The PI-anchored forms conferred high MV-binding capacity compared with the transmembrane versions. MV replication was, however, severely suppressed in cells expressing the PI-anchored forms, resulting in ineffective syncytium formation. In contrast, cell-to-cell fusion occurred efficiently after co-transfection of cDNA species encoding MV-H. MV-F and any version of MCP. Thus the PI-anchored forms, despite showing sufficient MV binding and cell-to-cell fusion competence together with MV-H and MV-F, mediate inefficient MV entry or replication, which causes severe suppression of the MV cytopathic effect. A biased receptor distribution on microvilli might participate in the selection of a low MV uptake pathway in the PI-anchored forms of MCP. Taken together, the transmembrane portion of MCP is a critical factor for effective virus-cell fusion and the subsequent MV replication.
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PMID:The CD46 transmembrane domain is required for efficient formation of measles-virus-mediated syncytium. 907 53

We have shown previously that it is possible to target complement-mediated killing against cultured ovarian tumour cells in vitro. As malignant ovarian cells usually grow in solid nodules in vivo, we have in the present study examined the effectiveness of complement killing against ovarian teratocarcinoma cells (PA-1) growing in three-dimensional tumour microspheroids (TMSs). Our study shows that PA-1 cells growing in TMSs are less susceptible to complement-mediated killing than cells growing in monolayer cultures, even after neutralization of protectin (CD59), the main inhibitor of complement lysis. Cells in suspension and cells growing in TMSs showed a similar expression of membrane co-factor protein (MCP, CD46) and CD59. Decay-accelerating factor (DAF, CD55) was not detected on the surface of cells in suspension, but appeared focally on the outermost cell layers of the TMSs. Complement-activating antibodies bound to all PA-1 cells in suspension but only to the most peripherally located cells in TMSs, even though the target antigens were similarly expressed in the two systems. Antibody-induced complement activation on PA-1 cells in suspension led to C3 and C5b-9 deposition on most cells, while C3 and C5b-9 were only found on the outermost layers of the TMSs. The increased complement resistance of tumour cells growing in three-dimensional spheroids is partly because of an insufficient penetration of antibodies and complement into the TMSs. TMSs are a useful model for the development of more efficient ways to kill malignant cells in micrometastases with monoclonal antibodies and complement.
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PMID:Resistance of ovarian teratocarcinoma cell spheroids to complement-mediated lysis. 915 42

Regulation of the membrane cofactor protein (MCP: CD46) was examined. While the expression of MCP in mice carrying MCP(BC2) cDNA with 125 bp of 3' untranslated region (3'UT) was minimal, that in mice carrying MCP cDNA without total 3' UT was evident in many organs. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis clearly showed the presence of mRNA even in transgenic mice with 3' UT, suggesting that the expression was regulated at the post-transcriptional stage. The in vitro expression data of MCP molecules on the stable Chinese hamster ovary (CHO) cell clone corresponded to that in transgenic mice. The first 125 bp downregulated the expression of MCP molecules in combination with not only beta-actin, but also SR alpha, promoter. Also, this region inhibited expression of decay accelerating factor (DAF: CD55) molecules when it was inserted into cDNA of DAF. Furthermore, the first 32 bp of the 3' UT revealed the same downregulation effect as 125 bp on MCP molecules. These findings indicated that the first 125 bp (and the first 32 bp in particular) of 3' UT regulate the expression of MCP molecules in transgenic mice.
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PMID:The regulation of membrane cofactor protein (CD46) expression by the 3' untranslated region in transgenic mice. 916 42

Organs of transgenic pigs that express human complement regulatory proteins are under assessment as an alternative to transplantation. A major barrier to the transplantation of pig organs is the hyperacute rejection caused by pre-existing antibodies and complement. Pig cells are very susceptible to human complement, presumably because pig cell-surface complement regulatory proteins are inefficient against it. Expression of human complement regulatory proteins, such as decay-accelerating factor and membrane cofactor proteins (MCP or CD46), by means of transgenes would confer resistance to human complement upon pig cells, thereby preventing hyperacute rejection. To express sufficient levels of human complement regulatory proteins at appropriate sites, regulatory elements of genes of pig membrane-bound complement regulatory proteins would be useful. To obtain their cDNAs, we transfected human cells with a pig cDNA library, selected cells by incubation with pig complement and rescued the plasmids. We cloned a cDNA for the pig homologue of MCP, pMCP. The cDNA encoded a predicted protein of 363 amino acids with 42% amino acid identity with human MCP. The pMCP consisted of four short consensus repeats, a Ser/Thr/Pro-rich domain, and transmembrane and cytoplasmic domains. Recombinant soluble pMCP that lacked transmembrane and cytoplasmic domains had factor I cofactor activity in C3b cleavage, indicating that it is functionally, as well as structurally homologous to MCP. FACS analysis with anti-pMCP mAb demonstrated that pMCP is expressed on all blood leukocytes, erythrocytes, and on endothelial and epithelial cell lines.
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PMID:Molecular cloning of a pig homologue of membrane cofactor protein (CD46). 919 70


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