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)

Human gametes and pre-implantation embryos express selectively several complement regulatory proteins. Membrane cofactor protein (MCP, CD46) and decay accelerating factor (DAF, CD55) are regulators for C3 convertases and protectin (CD59) is an inhibitor of the membrane attack complex. These three proteins were identified on human sperm and found to be functional. CD55 and CD59 were both expressed by the plasmic membrane of unfertilized oocytes and pre-implantation embryos. CD46 was not present on unfertilized oocytes but appeared at the 6/8 cell-stage embryo when human gene expression first occurs. Complement receptor 1 (CR1, CD35) and MHC class I antigens were not found on oocytes neither on embryos. Such a selective expression of complement regulatory proteins associated with the lack of MHC class I antigens may represent an immune protective mechanism by which human gametes and pre-implantation embryos escape from complement-mediated damage during their travel through the female genital tract. Indeed uterine, tubal and follicular fluids contain all the components of the complement cascade, including classical and alternative pathways. Nevertheless participation of CD46 and CD59 in cell to cell interaction during fertilization and/or implantation cannot be excluded. CD59 is an adhesive molecule involved in the rosette phenomena and CD46 has been described as the human receptor for measles virus, which binds through a fusion protein. Monoclonal antibodies raised against these two proteins (CD46 and CD59) are able to inhibit heterospecific fertilization between zona-free hamster oocytes and human spermatozoa suggesting the role of these proteins during fertilization.
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PMID:[Expression and role of complement regulatory proteins on human gametes and pre-implantation embryos]. 749 32

Human decay-accelerating factor (DAF, CD55) is a phosphatidyl inositol-anchored glycoprotein consisting, from the N-terminus, of 4 short consensus repeats (SCR), a Ser/Thr (ST)-rich region providing O-glycosylation sites, and the membrane-anchoring unit. A mAb, named D17, was raised against purified erythrocyte-DAF. This mAb recognized DAF on blood cells and most cell lines as determined by flow cytometry and immunoblotting. Its reactivity was similar to but weaker than that of two other well-characterized mAbs to DAF, IA10 (seeing an epitope within SCR1) and 1C6 (seeing an epitope within SCR3). The reactivity of D17 with erythrocyte DAF became increased by treatment with sialidase/O-glycanase, suggesting that its epitope is located close to the O-glycosylation sites, probably within the ST-rich region or SCR4. D17 barely blocked the decay-accelerating activity of DAF. Using the three mAbs, tissue-associated and soluble forms of DAF were identified by SDS-PAGE/immunoblotting and immunohistochemical staining. IA10 and 1C6 recognized a 50 kDa protein in spermatozoa lysate and two proteins of Mr 70 and 55 kDa, respectively, in seminal fluid. These represented membrane-associated and soluble forms of DAF, which were neither recognized by mAb against membrane cofactor protein (MCP, CD46) and C3b/C4b receptor (CR1, CD35) nor by non-immune IgG. In contrast to IA10 and 1C6, D17 did not recognize either spermatozoa-DAF or seminal plasma-DAF, or the deglycosylated or untreated forms of them. Immunohistochemical analysis showed that testis was stained with IA10 but not with D17.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A monoclonal antibody against human decay-accelerating factor (DAF, CD55), D17, which lacks reactivity with semen-DAF. 750 2

U937 cells are known to be relatively sensitive to C-mediated killing and have been reported to show variable expression of CD59. We have obtained stable CD59+ and CD59- sublines of the U937 cell line. Expression of other C-regulatory proteins, decay-accelerating factor (DAF), MCP and CR1, was similar on both cell lines. Although the sublines were morphologically similar and expressed similar amounts of most surface antigens, qualitative difference in expression of CD13 and CD64 and a quantitative difference in CD15 expression was observed. Sensitivity to C-mediated killing of the cell lines was measured using classical pathway activation. Both cell lines appeared to be equally sensitive to C-mediated killing. Monoclonal antibodies against CD59, which neutralize CD59 and enhance killing of most cell lines (including K562, HL60 and Molt4), did not enhance the killing of the CD59- cells but, surprisingly, also did not enhance killing of the CD59+ U937 subline. CD59 was expressed on the U937 subline at similar levels to that on HL60 and K562 cells, was glycosylphosphatidylinositol (GPI) anchored and could be immunoprecipitated from cell extracts. However, unlike these other cell lines, U937 cell extracts were negative in a Western blot using a variety of anti-CD59 antibodies even when ultrasensitive detection methods were used. These results indicate that the CD59+ U937 cell expresses a form of CD59 which is dysfunctional and structurally abnormal.
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PMID:Presence of a dysfunctional form of CD59 on a CD59+ subclone of the U937 cell line. 751 99

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

The restriction of alternative complement pathway activation in fluid phase or on nonactivator surfaces has been described as the major physiologic function of the complement regulatory protein factor H. In this study, we provide evidence that factor H is also a restriction factor of classical pathway activation on the surface of nucleated cells. We found that C3b was rapidly converted to inactivated C3b (iC3b) on human SK-MEL-93-2 melanoma cells after classical pathway activation with the murine monoclonal IgG3 Ab R24 directed against the disialoganglioside surface Ag GD3. The SK-MEL-93-2 cells are nonactivators of the alternative pathway and express neither CR1 (CD35) nor the C3b-cleaving protease p65. The cells are further characterized by the expression of only moderate amounts of DAF (CD55) and approximately 5 x 10(3) MCP (CD46) molecules/cell. FACS analysis and direct quantitation using [125I]factor H revealed high level binding of factor H to the melanoma cells (5.6 x 10(6) molecules/cell) during classical pathway activation. The binding of factor H could be inhibited under conditions that inactivate the classical complement pathway (EGTA and heat treatment), but not by factor B depletion of the serum, demonstrating that classical pathway activation was responsible for factor H binding. Treatment of factor B-depleted serum with neutralizing concentrations of polyclonal anti-factor H resulted in the prolonged presence of intact C3b on the cells and a significantly reduced generation of iC3b. The increased amount of C3b on these cells correlated with a 2.65-fold greater rate of cell death. In contrast, the increase in cell death effected by neutralizing concentrations of anti-CD46 or anti-CD55 Ab was only 0.13- or 0.35-fold, respectively. In addition, the supplementation of serum with purified factor H decreased the extent of lysis of the cells. Collectively, these data provide experimental evidence that factor H, through its cofactor activity for C3b degradation, is involved in the restriction of the classical pathway of complement on the surface of nucleated cells, a function that to date has been exclusively attributed to the membrane regulatory proteins CD35 and CD46.
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PMID:Classical complement pathway activation on nucleated cells. Role of factor H in the control of deposited C3b. 759 1

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

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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