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)

Three of the proteins protecting cells from autologous lysis by complement are: membrane cofactor protein (MCP; CD46), an inhibitor of the membrane attack complex formation (CD59), and decay accelerating factor (DAF; CD55). We have investigated the expression of these proteins in breast and colorectal carcinoma by immunohistochemistry and immunoblotting of breast tissue for CD46. CD46 was consistently and strongly expressed in the epithelial compartment in 26/28 ductal carcinomas of the breast, 9/9 fibroadenomas, and 9/11 cases of control non-neoplastic breast tissue. CD59 showed a similar degree of expression in the fibroadenomas (9/9), but was less strongly expressed in carcinomatous (22/28) and control (5/11) tissues. In marked contrast, no CD55 expression was detected in tissue from 15 ductal carcinomas. Immunoblotting of breast tissue for CD46 showed the same size of the molecule as for lymphocytes. It had however considerably stronger expression in tumour tissue than in non-neoplastic tissue. CD46 and CD59 were either lacking or only weakly expressed in the epithelial component of control colorectal mucosa: 2/15 and 5/15, respectively. In contrast, tissue samples from colorectal adenocarcinomas showed clear staining for both CD59 (10/18) and, more markedly, CD46 (15/18). There was no association between the pattern or intensity of CD46 and CD59 expression and tumour differentiation. As the complement regulatory proteins CD46 and CD59 are also strongly expressed by trophoblast at the feto-maternal tissue interface, these results support the concept that similar mechanisms are employed both by the genetically dissimilar fetus and certain tumours to evade immune attack by their host.
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PMID:The complement regulatory proteins CD46 and CD59, but not CD55, are highly expressed by glandular epithelium of human breast and colorectal tumour tissues. 980 13

We designed a cDNA construct encoding an artificial membrane molecule consisting of all 8 short consensus repeats (SCRs) of human monomeric C4b-binding protein (C4bp) followed by DAF's GPI anchor, named mC4bp, and expressed the protein on swine endothelial cells (SEC). At the same level of expression, mC4bp protected host cells as effectively as DAF, the most potent complement (C) regulator on the membrane. This result was unexpected from the reported functional properties of natural multimeric C4bp. Here, we investigated the mechanism whereby mC4bp has potent cell-protective activity. Our results were as follows: (1) mC4bp serves more efficiently as a methylamine-treated C3 (C3ma)-inactivating factor I-cofactor than natural C4bp and as efficiently as MCP as a methylamine-treated (C4ma)-inactivating cofactor by fluid-phase cofactor assay: (2) the potency of C3ma inactivation by mC4bp and factor I is quite high compared to those of other cofactors: (3)blocking studies using mAbs against C4bp suggested that both the 48 kDa N-terminal fragment and the C-terminal domain near the portion responsible for bundle formation participate in the high C3ma-inactivating capacity of mC4bp. Thus, acquiring high C3ma-inactivating capacity secondary to monomeric alteration leads to high C regulatory activity of mC4bp. These results infer that mC4bp differs from C4bp in its potent factor I-cofactor activity and is a good candidate as a safeguard against hyperacute rejection of xenografts.
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PMID:A monomeric human C4b-binding protein (C4bp) more efficiently inactivates C3b than natural C4bp: participation of C-terminal domains in factor I-cofactor activity. 980 81

The aetiopathogenesis of chronic otitis media with effusion (OME) in children is not yet fully understood. OME is characterized by metaplasia of the epithelium and accumulation of sticky, glue-like effusion in the middle ear containing different mediators of inflammation, including activation fragments of the complement system. Here we examined whether the fluid phase complement activation is reflected in the middle ear mucosa and how the mucosa is protected against the cytolytic activity of complement. Mucosal biopsies from 18 middle ears of children with a history of chronic OME were taken. The biopsies were analysed by immunofluorescence microscopy after staining for complement fragments iC3b/C3c, C3d and C9, and regulators membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55) and protectin (CD59). There was a strong staining for iC3b/C3c, and a weaker one for C3d and C9 on the surface of the middle ear epithelial cells of OME patients but not in controls without OME. MCP was expressed on the hyperplastic three to four outer cell layers of the epithelium, while CD59 was expressed throughout the middle ear mucosa. The results suggest a strong ongoing complement activation and consequent inflammation in the middle ear cavity. Unrestricted complement damage of the epithelial lining is prevented by the strong expression of MCP and CD59.
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PMID:Complement activation and expression of membrane regulators in the middle ear mucosa in otitis media with effusion. 1036 Dec 26

Of human malignantly transformed cell lines, xeroderma pigmentosum (XP) cell lines were found to be highly susceptible to homologous complement (C): cells were opsonized by C3 fragments on incubation with diluted normal human serum. C3 fragment deposition on XP cells was Ca2+-dependent and occurred on live cells but not UV-irradiated apoptotic cells. (Ca2+ is required for activation of the classical C pathway via C1q and the lactin pathway via mannose binding lectin (MBL), and the surface of apoptotic cells usually activates the alternative C pathway.) In this study we tested which of the pathways participates in XP cell C3 deposition. In seven cell lines that allowed C3 deposition (i), Clq was shown to be essential but MBL played no role in C activation, (ii) Cls but not MASP bound XP cells for activation, (iii) no antibodies recognizing XP cells were required for homologous C3 deposition, and (iv) the alternative pathway barely participated in C3 deposition. Furthermore, the levels of C-regulatory proteins for host cell protection against C, decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), were found to be relatively low in almost all XP cell lines compared with normal cells. These results indicate that XP cells activate the classical C pathway in an antibody-independent manner through the expression of a molecule which directly attracts C1q in a C-activating form, and that relatively low levels of DAF and MCP on XP cells facilitate effective C3 deposition. The possible relationship between the pathogenesis of XP and our findings is discussed.
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PMID:Antibody-independent classical complement pathway activation and homologous C3 deposition in xeroderma pigmentosum cell lines. 1036 Dec 49

The shortage of human organs has prompted scientists to seek xenogeneic sources of donors. To date, DAF, MCP, and CD59 transgenic pigs have been generated to inhibit hyperacute rejection. However, besides hyperacute rejection, acute and chronic rejection must also be considered in the use of porcine organs for xenotransplantation. The role of HLA-II in transgenic xeno-organ transplantation remains to be elucidated. By microinjecting 1655 embryos, we have generated one stillborn HLA-DR and two live HLA-DP transgenic pigs: P113-7 (male, carrying one copy of exogene) and P113-8 (female, carrying 2-3 copies of exogenes). The gene status of the live transgenic pigs was confirmed by PCR, Southern blot, and PCR product sequencing analysis. The expression of transgenes in these transgenic pigs were confirmed by RT-PCR analysis and immunohistochemical staining of frozen sections of ear tissue.
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PMID:Generation of HLA-DP transgenic pigs for the study of xenotransplantation. 1040 93

In humans, host cells are protected from homologous complement by membrane proteins encoded in the regulators of complement activation (RCA) gene cluster. These include complement receptor 1 (CR1), decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46). In mouse and rat a single membrane inhibitor, Crry, appeared to perform the functions of both DAF and MCP and was proposed to be the functional analogue of both. Recently, however, murine homologues of DAF and MCP have been identified, prompting a search for the rat counterparts. We have described the identification of rat DAF and here describe the cloning of rat MCP from cDNA and genomic libraries, using a probe based on the mouse MCP cDNA sequence. The domain structure for rat MCP was identical to that of mouse MCP with four short consensus repeats (SCRs) followed by a STP domain, transmembrane segment and cytoplasmic tail. Overall identity of rat and mouse MCP was 77% at the amino acid level and 88% at the nucleotide level. Northern blot analysis from a range of tissues indicated that high-level expression was limited to the testis, although expression in other tissues was detected using reverse transcription-polymerase chain reaction. Rat MCP mRNA localized to Sertoli cells and spermatogonia in seminiferous tubules by in situ hybridization, but was absent in mature sperm. In cofactor assays utilizing human factor I, a recombinant soluble form of rat MCP catalysed cleavage of human C3ma.
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PMID:Molecular cloning, expression and characterization of the rat analogue of human membrane cofactor protein (MCP/CD46). 1046 44

In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individuals. In HD striatum, neurons, myelin and astrocytes were strongly stained with antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contrast, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and the internal capsule samples but not in normal brain. RT-PCR analysis and in-situ hybridisation were carried out to determine whether complement was synthesised locally by activated glial cells. By RT-PCR, we found that complement activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compared to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor and C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confirmed that C3 mRNA and C9 mRNA were expressed by reactive microglia in HD internal capsule. We propose that complement produced locally by reactive microglia is activated on the membranes of neurons, contributing to neuronal necrosis but also to proinflammatory activities. Complement opsonins (iC3b) and anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimulation of glial cells and phagocytes bearing specific complement receptors.
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PMID:Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease. 1050 8

Clinical and experimental studies have suggested that complement may play a role in tumor cytotoxicity. However, the efficiency of complement-mediated tumor cell lysis is hampered by various protective mechanisms, which may be divided into two categories: basal and induced mechanisms. The basal mechanisms are spontaneously expressed in cells without a need for prior activation, whereas the induced mechanisms develop in cells subjected to stimulation with cytokines, hormones, drugs or with sublytic doses of complement and other pore-formers. Membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein), CD35 (CR1, Complement Receptor type 1) and CD59, which serve as an important mechanism of self protection and render autologous cells insensitive to the action of complement. appear to be over-expressed on certain tumors. Furthermore, tumor cells secrete several soluble complement inhibitors. Tumor cells may also express proteases that degrade complement proteins, such as C3, or ecto-protein kinases which can phosphorylate complement components, such as C9. Besides this basal resistance, nucleated cells resist, to some extent, complement damage by removing the membrane attack complexes (MAC) from their surface. Several biochemical pathways, including protein phosphorylation, activation of G-proteins and turnover of phosphoinositides have been implicated in resistance to complement. Calcium ion influx and activation of protein kinase C (PKC) and of mitogen-activated protein kinase (MAPK) have also been demonstrated to be associated with the complement-induced enhanced resistance to lysis. The complete elucidation of the molecular mechanisms involved in basal and induced tumor cell resistance will enable the development of strategies for interfering with these evasion mechanisms and the use of the cytotoxic complement system against tumor cells.
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PMID:Complement resistance of tumor cells: basal and induced mechanisms. 1069 47

The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitor (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.
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PMID:[The complement system: an old story or target of new therapeutic approaches?]. 1083 72

Rituximab (IDEC-C2B8, Mabthera(R)) is a chimeric (human-mouse) monoclonal antibody (MoAb) against the B-cell specific CD20-antigen. It has been used for the clinical treatment of non-Hodgkin's lymphomas, but variable clinical results suggest that some lymphoma cells remain resistant. In the present study we have evaluated the relative efficiencies of humoral and cell-mediated effector mechanisms complement-dependent cytotoxicity (CDC), antibody-(ADCC), complement-(CDCC) dependent cellular cytotoxicity and apoptosis on lymphoma cell killing by rituximab. Rituximab activated the cytolytic complement (C) cascade and induced a strong CDC, but the rituximab-triggered ADCC and CDCC were relatively ineffective. The CDC was strongly enhanced by antibodies against the C inhibitor CD59 (protectin). Neutralization of CD55 (DAF) and CD46 (MCP) had a similar but weaker effect. Rituximab also induced apoptosis but in a cell line-dependent fashion. The results strongly emphasize the role of direct CDC as the major, fast and efficient effector mechanism of rituximab. In the immunotherapeutic treatment of B-cell lymphomas, it is important to consider the role of C-regulatory proteins as an escape mechanism of the malignant cells. Our results suggest that the effect of rituximab therapy could be enhanced by combining it with neutralization of CD59.
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PMID:Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. 1084 76


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