Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complement in the human respiratory tract protects the host from invading microorganisms and from other inhaled insults. However, complement may also lyse the host's respiratory tract cells, leading to tissue injury. In many extrapulmonic tissues, cells express cell-membrane complement regulatory glycoproteins that protect the cells from complement-induced lysis. To determine whether these glycoproteins are expressed in human respiratory tract tissue, we studied tissue biopsies of healthy and diseased human respiratory tract from nose to alveoli for the presence of four cell-membrane complement regulatory glycoproteins (membrane cofactor protein [MCP], decay-accelerating factor [DAF], CD59, and complement receptor type 1 [CR1]) using an immunoperoxidase technique. In addition, to establish a model for in vitro studies of these glycoproteins in respiratory cells, we studied whether they are expressed in cultured nasal epithelial cells, using the same technique. Altogether, 26 tissue specimens from 22 patients were studied. We found that normal human respiratory tract from nose to alveoli express MCP, DAF, and CD59, but not CR1, and that this expression increases in inflammation and in lung cancer. In addition, expression in nasal epithelial cells is retained under cell culture conditions. These findings suggest that human respiratory tract tissue may regulate complement activation on its surface in order to avoid self-injury. We propose that imbalances in the mechanism that regulates cell-membrane complement may predispose the respiratory tract to tissue injury and disease, and that iatrogenic modulation of such imbalances may help to prevent these adverse consequences.
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PMID:Expression and distribution of cell-membrane complement regulatory glycoproteins along the human respiratory tract. 754 58

Human cells express cell surface complement regulatory molecules that inhibit the activity of the C3/C5 convertases (DAF, MCP, CR1) or inhibit the membrane attack complex (CD59). A single molecule that inhibits both the convertase activity and formation of the membrane attack complex has never been characterized. To this end, we have developed two reciprocal chimeric complement inhibitors (CD, NH2-CD59-DAF-GPI; and DC, NH2-DAF-CD59-GPI) that contain the functional domains of decay accelerating factor (DAF; CD55) and CD59. Cell surface expression of the CD and DC chimeric proteins was detected with DAF- and CD59-specific antisera. Cell surface C3d deposition was inhibited on cells expressing the chimeric molecules, thereby indicating that the DAF moiety was functional in both molecules. Conversely, Ab-blocking experiments demonstrated that only the DC molecule retained CD59 function. Therefore, the DC molecule represents a novel potent chimeric bifunctional complement inhibitor that retains the functional domains of two distinct complement regulatory molecules.
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PMID:A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex. 759 66

A membrane-associated receptor for the C1q subcomponent of complement is widely distributed among different cell types. While a number of possible physiological functions of the C1q receptor (C1qR) on different cell types have been described, the way in which C1qR regulates complement activity remains unclear. This report describes the mechanism by which C1qR regulates activation of the first component of complement, C1. Using purified components of complement, we were able to show that membrane-associated C1qR as well as detergent-solubilized C1qR, purified from polymorphonuclear leukocytes, human umbilical vein endothelial cells or an endothelial cell line, EA.hy 926, are able to inhibit complement-mediated lysis of C1q-sensitized erythrocytes. Using hemolytic assays, we were able to demonstrate that C1qR prevents the association of C1q with C1r and C1s to form macromolecular C1. In addition, incubation of C1qR with the collagen-like stalks, but not with the globular heads of C1q, inhibits the effect of C1qR. This demonstrates that C1qR exerts its complement inhibitory effect by binding to the collagen-like stalk of C1q. No complement regulatory effect of C1qR was observed on preformed macromolecular C1. These data suggest that besides such-well-known complement regulatory molecules as CD55 (DAF), CD46 (MCP), CD35 (CR1) and CD59 (HRF), C1qR too is able to regulate complement activity.
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PMID:Regulation of the function of the first component of complement by human C1q receptor. 766 83

Recent studies have suggested that the complement (C) system is involved in the development of tissue injury of myocardial infarction. As it is not known why the strictly controlled C system starts to react against autologous heart tissue, we have analyzed the expression of various membrane regulators of C (CR1, DAF, MCP, CD59, C8 binding protein) and the pattern of deposition of C components and plasma C regulators (C4b binding protein and vitronectin) in normal (n = 7) and infarcted (n = 13) human myocardium. In the infarcted myocardium deposits of the C membrane attack complex (MAC) were observed by immunofluorescence microscopy, and lesions resembling the transmembrane channels of MAC were detected by transmission electron microscopy. CD59 and C8 binding protein were strongly expressed by muscle cells of normal myocardial tissue. Little or no CR1, MCP, and DAF was observed on these cells. The assembly of MAC was accompanied by the deposition of vitronectin (S-protein) and C4b binding protein in the infarcted areas of myocardium. In accordance with our earlier results the expression of CD59 but not of C8 binding protein was clearly diminished in the lesions. The results show that C8 binding protein, vitronectin, and C4b binding protein do not prevent complement attack against the infarcted myocardium but rather become codeposited with the MAC. Ischemia-induced transformation of nonviable cells into complement activators, acquired loss of resistance to the MAC by shedding of CD59, and recruitment of multifunctional serum proteins by MAC could thus constitute a general process aimed at the clearance of injured tissue.
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PMID:Regulation of complement membrane attack complex formation in myocardial infarction. 768 45

The levels of complement-regulatory molecules (complement receptor type one [CR1], decay-accelerating factor [DAF], membrane cofactor protein [MCP], and an inhibitor of membrane attack complex [CD59]) in lung cancer cells were analyzed to investigate the relation between their expression and histological subtypes, and the possibility of homologous complement deposition on cancer cells. In 25 cell lines (10 adenocarcinoma, 3 large-cell carcinoma, 7 small-cell lung cancer [SCLC], and 5 squamous cell carcinoma), flow cytometric analysis revealed that MCP was expressed in all cell lines, whereas none of the cell lines was CR1-positive. CD59 was detected in all cells. The DAF epitope defined by IA10 was expressed in all cells except one large cell carcinoma cell line. However, another epitope for anti-DAF monoclonal antibody, D17, was not detected in 5 (71.4%) SCLC and in 4 (22.2%) non-small-cell lung cancer. This disparity was seen in most cell lines, irrespective of histological subtypes. The loss of D17 reactivity seemed to be pertinent to malignant phenotype, because most of the normal pulmonary cells possessed the D17 epitope. Furthermore, a cell line lacking DAF (IA10-/D17-) allowed alternative pathway-mediated homologous complement (C3) deposition after pretreatment with anti-MCP antibody. This raises a new possibility for immunotargeting of cancer. These cell lines should be useful in studying the biology of lung cancer.
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PMID:Levels of complement regulatory molecules in lung cancer: disappearance of the D17 epitope of CD55 in small-cell carcinoma. 769 Mar 55

In this report, we have shown the expression of the complement regulatory proteins decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and CD59 on human D54-MG astroglioma cells by several methods, including immunofluorescence, flow cytometry and Western blotting and Northern blot analysis. These studies demonstrate that all three proteins are structurally and antigenically similar to their counterparts expressed on HepG2 and SW480 cells (hepatocyte and epithelial cell lines, respectively). D54-MG cells express mRNA for all three proteins of the appropriate size(s). The phosphatidylinositol-specific enzyme, PIPLC, cleaved DAF from the surface of D54-MG cells, demonstrating that DAF is linked by a glycophospholipid anchor as has been shown for other cell types. Flow cytometry demonstrates that primary rat astrocytes also constitutively express all three regulatory proteins. These data are the first to demonstrate the expression of CD59 on astrocytes, and the presence of all three regulatory proteins on astrocytes suggests that regulation of complement activation in the central nervous system is important in neural host defense mechanisms.
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PMID:Expression of decay-accelerating factor (CD55), membrane cofactor protein (CD46) and CD59 in the human astroglioma cell line, D54-MG, and primary rat astrocytes. 769 Mar 70

Research on membrane complement inhibitors (DAF, MCP, and CD59) has led to understanding of the regulation of complement system; however, their precise role and distribution remain speculative. In this study, we used an indirect fluorescent immunostaining to investigate the distribution of complements, MCP, DAF, and CD59, in the villi before the 10th week of pregnancy in 18 women. DAF and MCP were observed at the surface of syncytiotrophoblasts (ST) and extravillous trophoblast (EVT) in all subjects. They were observed in villous cytotrophoblast (VCT) in the subjects before the 8th week of pregnancy but were not observed in any subject after the 9th week. However, CD59 appeared in ST but never in VCT. MCP, DAF, and CD59 were observed in EVT. These findings indicated that these complement inhibitors played an important role in early pregnancy, and that CD59 continued to appear in early pregnancy, whereas the expression of MCP and DAF depended on the stage of pregnancy.
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PMID:The change of membrane complement regulatory protein in chorion of early pregnancy. 769 57

CD59 (protectin) and CD46 (membrane cofactor protein, MCP) are membrane-bound complement regulator proteins which inhibit complement-mediated cytolysis of autologous cells. CD59, a phosphatidyl-inositol-anchored glycoprotein, inhibits the formation of the terminal membrane attack complex (MAC) of complement and was found to be a second ligand for CD2 contributing to T-cell activation. In 20 colorectal normal mucosa samples, in ten adenomas, 71 carcinomas and in ten liver metastases derived thereof, CD59 was inconsistently expressed in the epithelial compartment. In carcinomas CD59 expression in the whole neoplastic compartment was more often found in well- and moderately differentiated tumours. By contrast, focal expression or even complete lack of CD59 was more often found in poorly differentiated tumours (P = 0.021). In addition, carcinomas without metastases at the time of operation (Dukes A/B) more often expressed CD59 in the entire neoplastic population compared to those carcinomas which had already metastasised (P = 0.018). There was no correlation between the mode of CD59 expression in colorectal carcinomas and the tumour type or location. CD46 has C3b/C4b binding and factor-I dependent cofactor activity and is broadly expressed in various cells and tissues. In the epithelial compartment of normal colorectal mucosa, of all adenomas, carcinomas and their liver metastases, CD46 was expressed throughout the epithelial compartment. Since CD46 was consistently expressed in colorectal carcinomas the low expression or even lack of CD59 in a subset of tumours might not lead to critical complement-mediated attack of CD59-negative tumour cells. Regarding CD59 as a natural T-cell ligand involved in cognate T-cell-target-cell interaction, however, loss of CD59 might well be a selection advantage, provided that tumour antigen-mediated T-cell toxicity in colorectal carcinoma exists.
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PMID:Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium. 769 19

Human seminal plasma contains 0.55 microgram/ml of membrane cofactor protein (MCP; CD46) of 60,000 MW. By ultracentrifugation, gel filtration and immunoelectron microscope methods, we found that the MCP in seminal plasma was associated with prostasomes. The functional properties of the prostasome-bound MCP were assessed in comparison with a recombinant soluble form, gamma MCP1, which is composed of four short consensus repeats (SCR), type C of the serine/threonine-rich domain (STC), and unknown significance (UK). The MCP in seminal plasma, although demonstrably bound to prostasomes, behaved more like the soluble form of MCP. In the absence of detergent it, together with factor I, degraded the fluid-phase ligand, methylamine-treated C3 [C3(MA)], which is insensitive under no-detergent conditions to the membrane form of MCP and factor I. Moreover, C3dg fragment was generated as a final product instead of C3bi during the incubation, indicating that the prostasomal MCP and proteases may be responsible for the C3dg generation. The prostasomes neutralized measles virus (MV) infectivity, while gamma MCP1, for the most part, did not. These results, taken together with the CD59 concentration on the prostasomes, suggest that the prostasomes are potential immunomodulators for complement activation, providing the C3- and C9-step inhibitors. The present report also reinforces the idea that there are two different forms of MCP in semen. One is located in the inner acrosomal membrane of spermatozoa, which appears through acrosomal reaction and spermatoon-egg interaction. The other is a prostasome-bound form maintaining activities sufficient to regulate complement activation and, probably, MV infection.
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PMID:Membrane cofactor protein (CD46) in seminal plasma is a prostasome-bound form with complement regulatory activity and measles virus neutralizing activity. 779 37

Membrane cofactor protein (MCP, CD46) is an integral protein that serves as a cofactor for factor I in inactivating C3b/C4b deposited on the same cell membrane as C3bi/C4c+C4d. This C3b/C4b inactivation is closely associated with self-protection of host cells from autologous complement attack. We have studied the distribution and properties of MCP in the normal human kidney by immunohistochemical and immunoblotting methods using monoclonal antibodies against MCP. MCP was predominantly expressed on the juxtaglomerular apparatus. Glomerular capillary walls, mesangial areas, and tubulus were also MCP positive. Glomerulus MCP was composed of two major bands of 45-65 kDa, which were similar to those of lymphocyte MCP. The proportion of the high and low molecular weight components in glomerulus MCP, however, was considerably different from that of lymphocyte MCP among the individual samples tested. Glomerular epithelial cells and mesangial cells from an individual having equal amounts of high and low molecular weight components in the lymphocytes were cultured separately and the properties of their MCP investigated. MCP in the mesangial cells and glomerular epithelial cells showed profiles in which the upper band was predominant. The results may explain the unique distribution of the high and low molecular weight forms in the glomerulus. These forms of MCP together with factor I were all capable of inactivating C3b to C3bi. Message analysis suggested that glomerular epithelial cells and mesangial cells synthesized a single species of mRNA of 4.2 kb from which the polymorphic MCP species were generated. Flow cytometric analysis suggested that MCP was minimal in mesangial cells. These results, taken together with the previous reports on the distribution of other complement regulatory proteins, infer that the distribution profile of MCP is rather similar to that of DAF but differs from those of CD59 and CR1 in the normal human kidney; this may reflect the differences between their roles or functional properties in renal tissue.
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PMID:Identification and characterization of membrane cofactor protein (CD46) in the human kidneys. 802 16


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