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)

Mouse cells ubiquitously express CRRY, which is a functional orthologue of human decay-accelerating factor (DAF; CD55) and membrane cofactor protein (MCP; CD46), and thus protects cells from homologous complement. NIH3T3 cells expressed minute levels of mouse CD46 (mCD46) mRNA but barely produced mCD46 protein. mCD46 message and protein levels were markedly increased during mouse cytomegalovirus (mCMV) infection. Consistently, mCD46-expressing cells became resistant to mouse complement; primary-cultured fibroblasts from mCD46 gene-disrupted mice showed no increase in protection, resulting in complement-dependent cytolysis. Thus, the marked up-regulation of mCD46 in mouse fibroblast cells/cell lines by mCMV infection participates in host cell protection from complement. By mCD46 promoter deletion assay, the region necessary for induction of the promoter activity by mCMV infection was shown to be restricted to a sequence of 19 bp, which was homologous to the corresponding portion in human CD46, and the promoter regions of early-inducible human CMV UL36 and human herpesvirus 6 UL29. The results were confirmed by mutation analysis of this 19-bp region. We designated this sequence as the CMV-responsive element (CMVRE). Electrophoretic mobility shift assay demonstrated the existence of a CMVRE-binding factor, expression of which was significantly increased after mCMV infection. Thus, mCMV up-regulates the gene expression of mCD46 via CMVRE and CMVRE-binding factor, resulting in mCD46 protein expression on mCMV-infected cells. Since both the membrane and soluble mCD46retained complement regulatory activity, mCD46 induced by mCMV infection may act as a regulator of systemic complement activation. This represents a unique strategy of mCMV survival in host cells with sufficient replication by circumventing host complement attack.
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PMID:Mechanism of host cell protection from complement in murine cytomegalovirus (CMV) infection: identification of a CMV-responsive element in the CD46 promoter region. 1235 49

In xenotransplantation the use of donors transgenic for recipient-type complement regulatory protein decay-accelerating factor (DAF/CD55) or membrane co-factor protein (MCP/CD46) protects grafts against hyperacute rejection (HAR), which is primarily mediated by xenoreactive natural antibodies and complement. In the Langendorff model, we previously demonstrated that rat hearts transgenic for human CD55 (hCD55), perfused with human serum, were protected against HAR. However, ex vivo, these hearts were found to be destroyed by a process occurring after the period of HAR. The question arose as to whether hearts transgenic for hCD55 are also protected against adhesion and infiltration by cells implicated in the early phases of xenograft rejection. The aim of the present study was to analyze this process in the ex vivo heart perfusion model. hCD55-transgenic rat hearts and their controls were perfused with either heat-inactivated or normal human blood solutions for 60 min. Although most of the hearts had stopped beating within the 60-min perfusion period, the perfusion was not stopped to enable adhesion of cells during a fixed period identical for all groups. Independent of the presence of complement, H&E-stained tissues of hCD55-transgenic hearts revealed fewer PMN leukocytes adhering to the endothelium than the controls (mean: 31% vs 60%). Standard histology and immunohistochemistry showed that hCD55-transgenic hearts exhibited less interstitial edema, hemorrhage, microthrombosis, fibrin deposition, and leukocyte infiltration than did the controls. All hearts showed mild to moderate levels of P-selectin and similar levels of ICAM-1, C3c, C9, IgA, IgG, and IgM deposition. hCD55 expressed on rat hearts not only inhibits complement activation, but also human leukocyte adhesion and apparently functions as an anti-adhesion molecule. hCD55 is an efficient factor in protecting grafts against HAR and protects the graft against adhesion of leukocytes as well.
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PMID:Human decay-accelerating factor expressed on rat hearts inhibits leukocyte adhesion. 1266 11

Complement control proteins (CCPs) contain repeated protein domains, short consensus repeats (SCRs), which must be relevant to diverse functions such as complement activation, coagulation, viral binding, fetal implantation, and self-nonself recognition. Although SCRs share some discontinuous and imperfect motifs, there are many variable positions and indels making classification in subfamilies extremely difficult. Using domain-by-domain phylogenetic analysis, we have found that most domains can be classified into only 11 subfamilies, designated a, b, c, d, e, f, g, h, i, j, or k and identified by critical residues. Each particular CCP is characterized by the order of representatives of the subfamilies. Human complement receptor 1 (CR1) has ajefbkd repeated four times and followed by ch. The classification crosses CCPs and indicates that a particular CCP is a function of the mix of SCRs. The aje set is a feature of several CCPs including human CR1 and DAF and murine Crry and appears to be associated with the success or failure of implantation inter alia. This approach facilitates genomic analysis of available sequences and suggests a framework for the evolution of CCPs. Units of duplication range from single SCRs, to septamers such as efbkdaj, to extensive segments such as MCP-CR1L. Imperfections of duplication with subsequent deletion have contributed to diversification.
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PMID:Amino acid patterns within short consensus repeats define conserved duplicons shared by genes of the RCA complex. 1548 90

Sulfasalazine (SASP) has been reported to depress the fertility in men and experimental male animals, but the fundamental mechanisms of infertility caused by SASP are still unknown. This study was designed to investigate the mechanisms of infertility in rats treated with SASP at a dose of 600 mg/kg for 28 days, including monitoring of sperm motility using computer associated sperm analysis system and acrosome reaction by FITC-concanavalin A lectin staining. The sperm motility and acrosome reaction, which are important for fertilization, were significantly reduced by SASP. Furthermore, to investigate the molecular mechanisms of infertility induced by SASP, mRNA expression analysis in the testes was performed using cDNA microarray as a first screening. It was revealed that CD59, which is located on the acrosomal membrane and is known to be important for the reproductive function of sperm, was affected in the testes; this was also confirmed by real-time PCR analysis, but the spermatogenesis-related genes examined in this study were not affected. Therefore, we focused on CD59 and two other acrosome membrane related-genes: MCP and DAF. CD59, MCP, and DAF in the epididymides of SASP-treated rats were significantly decreased as assessed by real-time RT-PCR analysis and additionally, the expression of CD59 protein was found to be decreased by Western blotting. These results allowed us to hypothesize that the suppression of epididymal acrosomal membrane proteins synthesis with their consequent reduced incorporation to the sperm membrane leads to a depressed sperm motility and acrosome reaction, and thereby leads to infertility in SASP treated male rats.
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PMID:Effects of sulfasalazine on sperm acrosome reaction and gene expression in the male reproductive organs of rats. 1562 86

The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.
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PMID:Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. 1566 53

The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.
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PMID:Complement activation in very early Alzheimer disease. 1594 22

A fully active complement system deriving from the maternal circulation as well as from local production by various cell source is present in the placenta. The role of this system at the placental level, as in any other tissue in the body, is to protect both the fetus and the mother against infectious and other toxic agents. As fetal tissues are semi-allogeneic and alloantibodies commonly develop in the mother, the placenta is potentially subject to complement-mediated immune attack at the feto-maternal interface with the potential risk of fetal loss. Uncontrolled complement activation is prevented in successful pregnancy by the three regulatory proteins DAF, MCP and CD59 positioned on the surface of trophoblasts. The critical role played by these complement regulators is supported by the embryonic lethality observed in mice deficient in the complement regulator Crry. Excessive complement activation in the placenta places the fetus at risk for growth restriction or death. The role played by the complement system in the fetal damage induced by anti-phospholipid antibodies in a mouse model will be examined.
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PMID:The complement system in the pathophysiology of pregnancy. 1602 27

A number of proteins anchored on the cell surface function to protect host tissues from bystander injury when complement is activated. In humans, they include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and CD59. Although disease conditions directly attributable to abnormal function of these proteins are relatively rare, it has become evident from recent studies using animal models that membrane complement regulatory proteins are important modulators of tissue injury in many autoimmune and inflammatory disease settings. Evidence is also emerging to support a role of these proteins in regulating cellular immunity. In this article, we highlight recent advances on the in vivo biology of membrane complement regulatory proteins and discuss their relevance in human disease pathogenesis and therapeutics.
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PMID:Membrane complement regulatory proteins. 1633 72

Complement is not only part of the innate immune system, but has also been implicated in adaptive immunity. The role of complement and its regulatory proteins in modulating T cell activity has been the focus of several recent studies. These, which have included work on the membrane co-factor protein (MCP or CD46), decay accelerating factor (DAF or CD55) and CD59, indicate that complement regulators can influence the proliferative capacity of T cells and their ability to produce cytokines, influencing the outcome of a T cell response to a given antigen. Here we review these studies, which reveal another important link between the innate and the adaptive immune system.
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PMID:Holding T cells in check--a new role for complement regulators? 1640

Complement (C) activation is thought to contribute to the initiation and progression of atherosclerosis. Proliferation of smooth muscle cells plays an important role in atherosclerotic plaque formation. Our aim was to investigate the suitability of the rat aortic smooth muscle cell line A7r5 as an in vitro model to study C-induced events in smooth muscle cells. A7r5 cells abundantly expressed membrane bound C-regulators (CReg) Crry and CD59 as assessed by flow-cytometry, but no DAF or MCP was detected. Using RT-PCR in addition to Crry and CD59, also mRNA for rat DAF but not for MCP was detected. Flow-cytometry of cells removed by EDTA instead of trypsin demonstrated that A7r5 did express cell surface DAF. Upon prolonged culturing under either logarithmic growing conditions or under conditions where cells were kept over-confluent, two different sub cell lines were obtained, one which had lost the expression of CD59, while the other showed increased expression of DAF and Crry. The change in expression of these CReg resulted in a change in C-susceptibility. Incubation of the A7r5 cells with human serum induced membrane attack complex dependent proliferation. Transfection with human CD59 efficiently protected the cells from C-mediated killing and C-induced cell proliferation. Our results show that A7r5 cells can be used as an in vitro model for C-induced events, but care has to be taken to use the cells at an early stage of passaging as they readily change their phenotype.
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PMID:Characterisation of the complement susceptibility of the rat aortic smooth muscle cell line A7r5. 1651 69


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