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)

In an effort to elucidate the activation status of neutrophils (PMN) in inflammatory joint disease the expression of relevant cell surface proteins was examined using immunofluorescence and flow cytometry. Paired samples of SF and peripheral blood were obtained from 18 patients with RA and PMN purified using methods designed to minimize activation in vitro. We then used flow cytometry to measure expression of the four membrane complement regulatory molecules, decay accelerating factor (DAF; CD55), complement receptor 1 (CR1; CD35), membrane cofactor protein (MCP; CD46) and CD59; two adhesion molecules of the integrin family LFA1 (alpha chain, CD11a), complement receptor 3 (CR3; alpha chain, CD11b), and their common beta chain (CD18); the major receptor for immune complexes Fc gamma RIII (CD16), and the leucocyte common antigen tyrosine phosphatase (L-CA; CD45). Expression of these molecules was also measured on peripheral blood PMN from 18 age- and sex-matched normal controls. In RA, SF PMN expressed significantly higher levels of the complement regulators CD55 and CD35, the adhesion molecule CR3 (CD11b/CD18) and of CD45 but significantly lower levels of CD46 and CD11a in comparison with blood PMN from the same patient. Expression of CD59 and CD16 did not differ between the two groups. These changes may increase adhesiveness and complement resistance of PMN in SF compared with blood. PMN from RA expressed significantly less of all the complement C3 convertase regulators (CD55, CD46, CD35), all the adhesion molecules (CD11a, CD11b, CD18) and the phosphatase CD45 than did blood PMN from age and sex-matched control individuals.
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PMID:Expression of complement regulatory molecules and other surface markers on neutrophils from synovial fluid and blood of patients with rheumatoid arthritis. 805 95

Membrane cofactor protein (MCP, CD46), a widely distributed regulatory protein, inhibits complement activation on host cells and serves as a measles virus receptor. Most cells express four isoforms (with one of two cytoplasmic tails, CYT-1 or CYT-2). Previously, we noted that MCP precursors had variable intracellular processing. Therefore, we characterized the intracellular transport of individual MCP isoforms. Transfectants were used for pulse-chase analyses. MCP isoforms bearing CYT-1 chased into their mature, surface forms with a half-life (t1/2) of 10-13 min while those with CYT-2 required 35-40 min. The precursor of a tail-less mutant possessed a t1/2 of 160-165 min. Chimeras were constructed that added both tails in opposite orientation onto the isoform (i.e. CYT 1 + 2 or CYT 2 + 1). Chimera 1 + 2 precursor processed with a t1/2 of 35-37 min, similar to CYT-2. Chimera 2 + 1 had a t1/2 of 15-19 min, more closely resembling CYT-1. Thus, in both cases the carboxyl-terminal tail controlled the processing rate. Deletions were made in the beginning, middle, and carboxyl terminus of CYT-1. Deletion of the first or middle six amino acids had no effect on the processing rate. However, deletion of the terminal tetrapeptide (FTSL) slowed the rate to 30-32 min, suggesting that this sequence facilitates exit from the endoplasmic reticulum.
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PMID:Membrane cofactor protein (CD46) of complement. Processing differences related to alternatively spliced cytoplasmic domains. 814 66

Previous studies have shown that human sperm that have undergone the acrosome reaction express a unique tissue-specific variant of the complement component 3 (C3)-binding molecule membrane cofactor protein (MCP, CD46) and that damaged or dead sperm activate the alternative pathway of complement and bind C3 catabolites. In this study we provide evidence that MCP on sperm that have undergone the acrosome reaction specifically binds dimeric C3b and that human sperm acrosomal proteases released during the acrosome reaction directly cleave C3, facilitating its binding to MCP. Furthermore, human and hamster oocytes can activate the alternative pathway of complement and also bind human C3 fragments. Monoclonal antibodies specific for complement receptors type 1 (CD35) and type 3 (CD11b/CD18) bind to the human oocyte plasma membrane, indicating that specific complement-binding molecules may play a role in the attachment of C3 catabolites to oocytes. Subsaturating concentrations of dimeric C3b (0.01-1 microM) promoted penetration of hamster oocytes by human sperm, whereas saturating doses (> 10 microM) inhibited this process. In addition, antibodies to both MCP and C3 significantly inhibited penetration of hamster oocytes by human sperm. These data provide evidence that regulated gamete-induced generation of C3 fragments and the binding of these fragments by selectively expressed receptors on sperm and oocytes may be an initial step in gamete interaction, leading to membrane fusion and fertilization.
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PMID:The role of complement component C3b and its receptors in sperm-oocyte interaction. 823 55

The immunohistochemically stained membrane cofactor protein of complement (MCP/CD46), one of the complement regulatory proteins, was up-regulated in some diseased kidney tissues. MCP in diseased kidneys was strongly concentrated along the glomerular capillary walls as well as in the mesangial regions, while MCP in normal kidneys was weakly detected in all glomerular structural cells and in the epithelial cells of tubules. Since the enhanced staining was noted in those areas where depositions of C3b/C3c occurred, ongoing complement reaction might be responsible for the up-regulation of MCP expression. MCP expression may be up-regulated by complement fragments generated during complement activation in glomerulonephritis. Furthermore, anti-MCP staining was stronger in intensity in patients with moderate to massive proteinuria, indicating that up-regulation of MCP expression could be directly correlated to the kidney damage.
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PMID:Immunohistochemical demonstration of membrane cofactor protein (MCP) of complement in normal and diseased kidney tissues. 840 4

A sperm protein of molecular mass 43 kDa (the spermatozoa membrane cofactor protein, smMCP) and a seminal plasma protein of 60 kDa (ssMCP) were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting with four monoclonal antibodies (mAb) against membrane cofactor protein (MCP, CD46). These proteins served as factor I cofactors for the cleavage of methylamine-treated C3 (C3ma), the activity of which was blocked by M75, an MCP cofactor-activity-blocking mAb. Thus, these semen proteins are antigenic and functional homologous of MCP. On SDS-PAGE analysis these MCP migrated as single-band proteins which differed from the two-band forms of MCP expressed on other cells. smMCP was N-glycosylated but not O-glycosylated, while ssMCP was O-glycosylated: after deglycosylation of these proteins bands were detected at 38-40 kDa and 43 kDa on SDS-PAGE, respectively. These semen MCP are therefore, structurally different from the conventional MCP. ssMCP in both normal and "sterile" subject groups was determined by sandwich enzyme-linked immunosorbent assay. Seminal plasma in the two groups contained 250-700 ng/ml ssMCP. The difference between the two groups was marginal, although samples from normal subjects tended to show higher concentrations of ssMCP than samples from "sterile" subjects. No molecular difference was observed with ssMCP and smMCP in the two groups by SDS-PAGE/immunoblotting analysis. Immunohistochemical analysis suggested that MCP was positive in glandular epithelial cells and the lumen of the prostate, and in most intra-lumen cells of the testis. Using antibody M177, solubilized prostate and testis were analyzed by immunoblotting and compared with other cell MCP. The major band of MCP in the testis, but not in the prostate, was of 60 kDa, which aligned with ssMCP. No band of testis or prostate MCP, however, aligned with smMCP. ssMCP may be produced in the testis, while the origin of smMCP remains unknown. We hypothesize that ssMCP is important in the survival of spermatozoa, protecting them against local secretion of immunoglobulin and complement in the female genital tract, and that smMCP, which is expressed on acrosome-reacted spermatozoa, plays an essential role in the interaction of spermatozoa with oocytes.
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PMID:Membrane cofactor protein (MCP, CD46) in seminal plasma and on spermatozoa in normal and "sterile" subjects. 850 May 28

Human adult cells are protected from complement-induced damage in part by membrane cofactor protein (MCP, CD46). To examine fetal characteristics which might influence autoantibody-mediated diseases acquired in utero, such as heart block in neonatal lupus, the tissue expression of MCP was studied. Using a high ratio of acrylamide:bisacrylamide, immunoblots of tissues from six fetuses (aged 19-24 weeks) probed with rabbit anti-MCP antibodies revealed a band at 60 KD in addition to the known 65 KD and 55 KD isoforms which comprise the codominant allelic system of MCP. Five fetuses expressed the most common MCP polymorphism (predominance of the 65 KD isoform, upper band alpha-phenotype) in the kidney, spleen, liver and lung. In contrast, all hearts from these five fetuses demonstrated a different pattern in which there was a marked decrease in the intensity of the 65 KD band and accentuation of the lower molecular weight bands. In a sixth fetus, which expressed the second most common polymorphism (equal expression of the 65 KD and 55 KD MCP isoforms, alpha beta-phenotype), the heart was similar to the other tissues. These studies confirm the expression of MCP in early gestational life. Preferential expression of the MCP beta-isoform in the majority of fetal hearts irrespective of the phenotype of other organs, suggests tissue-specific RNA splicing or post-translational modification which may relate to autoantibody-mediated injury in diseases such as neonatal lupus.
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PMID:Ontogeny of membrane cofactor protein: phenotypic divergence in the fetal heart. 852 26

Human membrane cofactor protein (MCP, CD46) is a receptor for the measles virus and serves as a complement regulator which protects host cells from autologous complement attack. MCP is highly polymorphic due to a variety of mRNA splice products. The levels of MCP expression on T and myeloid cell lines are usually two-eightfold higher than those on their normal counterparts, whereas Burkitt's lymphoma B cell lines express less MCP than B cell lineages carrying no EB virus. The molecule has a Ser/Thr-rich (ST) domain adjacent to the functional domain, namely short consensus repeats (SCR). The ST domain and a cytoplasmic tail (CYT) contribute to the MCP polymorphism. The ST domain is encoded by three exons (A, B and C) and major ST isoforms are STABC, STBC and STC. The authors investigated the relationship between the expression levels and isoform usage of MCP by flow cytometry using specific antibodies against STA and STC, by reverse transcriptase-polymerase chain reaction (RT-PCR) with size markers for each splice variant, and by RT-PCR/Southern blotting using a specific probe for STA. The results were (1) the profiles of mean shifts of myeloid and T cell lines were STC < STA on flow cytometry while those of B cell lines and normal blood cells were STA < STC; (2) all cell lines tested by RT-PCR expressed the messages for the isoforms STBC/CYT1, STC/CYT1, STBC/CYT2, and STC/CYT2. The band for STABC/CYT2 overlapped that for STC/CYT1, and the band for STABC/CYT1 was marginal in all cell lines examined; (3) semi-quantitative analysis of the STABC isoforms by Southern blotting indicated the presence of high levels of the STABC messages in myeloid and T-cell lines in comparison with B lymphoid cells and normal leucocytes. Thus, the quantity of MCP expressed parallels the STABC message level, which is up-regulated in T and myeloid leukaemia cell lines.
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PMID:High expression of membrane cofactor protein of complement (CD46) in human leukaemia cell lines: implication of an alternatively spliced form containing the STA domain in CD46 up-regulation. 855 81

Recent evidence suggests that complement is activated in human nasal airways in inflammatory states. Activated complement protects the nasal mucosa against microorganisms, but also has the potential to lyse the host's normal cells. Complement-mediated cell lysis depends on adsorption of complement to the cell membrane and on uninterrupted activation of the complement cascade upon the same cell membrane. In the present study, the authors investigated first whether key complement components, C3-related fragments, are adsorbed to nasal epithelial cell membrane. Second, we investigated whether nasal epithelium expresses cell membrane complement regulatory proteins that are known as interruptors of complement activation. Studies were done using fresh nasal mucosa obtained at turbinectomies from allergic rhinitis and vasomotor rhinitis patients. In addition, in order to establish an in vitro model, studies were also done using primary cell cultures of nasal epithelium. We have found that complement C3-related fragments are present on cell membranes of fresh nasal epithelium and that C3-related fragments are adsorbed to the epithelial cell membrane in nasal mucosa tissue segments and in cell cultures that were incubated with autologous serum. Adsorption of C3-related fragments to the cell membrane of cultured nasal epithelial cells was found by flow cytometry analysis to be concentration-dependent. In addition, we found that nasal epithelium in fresh tissue and in cell culture express three cell membrane complement regulatory proteins: membrane cofactor protein (MCP, CD46), decay-accelerating factor (DAF, CD55), and CD59. Our findings in fresh nasal epithelium suggest that complement activation may occur upon the nasal epithelial cell membrane during inflammation in vivo and that nasal epithelium might regulate this complement activation. Our in vitro cell culture model will allow further investigations of complement activation and regulation upon the human nasal epithelial cell membrane.
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PMID:Human nasal epithelium adsorbs complement C3-related fragments and expresses cell membrane complement regulatory proteins. 862 88

To avoid destruction by complement, normal and malignant cells express membrane glycoproteins that restrict complement activity. These include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and protectin (CD59), which are all expressed on colonic adenocarcinoma cells in situ. In this study we have characterised the C3/C5 convertase regulators DAF and MCP on the human colonic adenocarcinoma cell line HT29. DAF was found to be a glycosyl-phosphatidylinositol-anchored 70-kDa glycoprotein. Blocking experiments with F(ab')2 fragments of the anti-DAF monoclonal antibody BRIC 216 showed that DAF modulates the degree of C3 deposition and mediates resistance to complement-mediated killing of the cells. The expression and function of DAF were enhanced by tumour necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). Cells incubated with interferon gamma (IFN gamma) did not alter their DAF expression. Two MCP forms were expressed, with molecular masses of approximately 58 kDa and 68 kDa, the lower form predominating. MCP expression was up-regulated by IL-1 beta, but not by TNF alpha or INF gamma. Expression of DAF and MCP promotes resistance of colonic adenocarcinoma cells to complement-mediated damage, and represents a possible mechanism of tumour escape.
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PMID:Characterisation of the complement-regulatory proteins decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46) on a human colonic adenocarcinoma cell line. 864 Aug 47

Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding glycoprotein that inhibits complement activation on host cells. MCP is expressed primarily as four isoforms that arise by alternative splicing of a single gene. The differences reside in the domains for O-glycosylation and cytoplasmic tails. Tissue-specific expression of isoforms and the differential processing of precursors mediated by the cytoplasmic tails suggest that isoform variations are biologically significant. The goal of these experiments was to characterize the complement inhibitory profile of the four commonly expressed isoforms. The MCP isoforms (BC) with a larger O-glycosylation domain bound C4b more efficiently than the C isoforms, which are smaller and less glycosylated in this region. Additionally, cytoprotection assays of individual clones of transfected isoforms bearing equivalent copy numbers demonstrated that the BC isoforms also provided enhanced protection in a classical pathway-mediated system and cleaved cell-bound C4b more efficiently than the C isoforms. Taken together, these data demonstrate that BC isoforms preferentially protect against the classical pathway of complement. Such findings indicate a physiologic role for isoform variation and have therapeutic implications for use of MCP isoforms as complement inhibitors in such areas as xenotransplantation.
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PMID:Membrane cofactor protein (MCP; CD46). Isoforms differ in protection against the classical pathway of complement. 866 15


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