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)

The virulence of Pseudomonas aeruginosa is multifactorial and caused by several extracellular enzymes and other substances. The importance of these virulence factors for the pathogenesis of human P. aeruginosa infections is dependent on the type of infection. For acute, systemic infections in immunocompromised patients, exotoxin A, alkaline protease and elastase are essential virulence factors. In localized infections (e.g., cystic fibrosis) they seem to be of minor importance, since they are neutralized by specific antibodies in immune complexes, and in the case of exotoxin A cleavage by proteinases from polymorphonuclear leukocytes occurs. The rhamnolipid of P. aeruginosa which has been detected in sputa of patients with cystic fibrosis evades the host's immune response and has to be regarded as a potential virulence factor together with the phenazine pigments, also in chronic P. aeruginosa infections.
Infection
PMID:[Significance of Pseudomonas aeruginosa virulence factors in acute and chronic Pseudomonas aeruginosa infections]. 310 28

The virulence of Pseudomonas aeruginosa is multifactorial and caused by several extracellular enzymes and other substances. The importance of these virulence factors for the pathogenesis of human P. aeruginosa infections is dependent on the type of infection. For acute, systemic infections in immunocompromised patients, exotoxin A, alkaline protease and elastase are essential virulence factors. In localized infections (e. g., cystic fibrosis) they seem to be of minor importance, since they are neutralized by specific antibodies in immune complexes, and in the case of exotoxin A cleavage by proteinases from polymorphonuclear leukocytes occurs. The rhamnolipid of P. aeruginosa which has been detected in sputa of patients with cystic fibrosis evades the host's immune response and has to be regarded as a potential virulence factor together with the phenazine pigments, also in chronic P. aeruginosa infections.
Infection 1987
PMID:[Significance of Pseudomonas aeruginosa virulence factors for acute and chronic Pseudomonas aeruginosa infections]. 311 18

Pseudomonas aeruginosa elastase, but not alkaline protease, degraded pooled, normal, human IgG in vitro and this degraded IgG lost its protective effect when used to treat burned, P. aeruginosa infected mice. Plasma IgG levels in burned, uninfected mice declined immediately postburning, but remained relatively constant thereafter; the levels in burned, P. aeruginosa infected mice continued to decline until death ensued. Infection of burned mice with an elastase+ strain caused the IgG decline, while infection with an elastase- strain did not, suggesting that elastase production caused the in vivo decline in plasma IgG. Local treatment with the protease inhibitor alpha 2-macroglobulin, of burned mice infected with an elastase+ organism, reduced the IgG decline observed in control mice. These data support the hypothesis that P. aeruginosa elastase acts as an IgG protease both in vitro and in vivo and gives insight into how this enzyme may act as a virulence factor in P. aeruginosa.
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PMID:Experimental studies of the pathogenesis of infections owing to Pseudomonas aeruginosa: elastase, an IgG protease. 643 5

Infection of target cells with cytopathic viruses inhibits IFN induction of cytolytic resistance to NK cell-mediated cytolysis [IFN-mediated cytoprotection (IFN-MCP)]. It has been thought that the virally induced inhibition of IFN-MCP is secondary to the shutdown of cellular macromolecular synthesis that accompanies cytopathic virus infections. Group C, adenovirus serotype 5 (Ad5) infection inhibits both IFN-MCP and cellular protein synthesis. This study determined if the Ad5-induced inhibition of IFN-MCP was independent of adenovirus (Ad) infection and secondary only to the expression of the Ad early region 1A gene (E1A). To test this hypothesis, 4-h NK cytolysis assays were performed on IFN-gamma-treated human cells infected with an Ad5 E1A deletion mutant, dl343, or transfected with the Ad5 E1A gene. IFN-MCP was not inhibited by infection with dl343, despite the production of large amounts of both early (E1B, p55) and late (hexon) Ad proteins. In contrast to E1A-negative, parental cell lines, IFN-MCP was blocked in Ad5 E1A-transfected epithelial and fibroblastic cell lines. Genetic mapping studies within the E1A gene demonstrated that expression of only the first exon of E1A was sufficient to inhibit IFN-MCP. DNA sequence homology of E1A genes between different Ad groups (group A, Ad12; group C, Ad5) is limited almost entirely to three conserved regions located within the first exon of E1A. Because IFN-MCP was also blocked in Ad12 E1A-transfected cell lines, expression of one or more of the E1A-conserved regions may be necessary to inhibit IFN-MCP. In summary, the expression of E1A gene products inhibited IFN-MCP independently of virus infection. E1A's inhibition of IFN-MCP has the net effect of promoting the selective NK cell-mediated clearance of Ad-infected or Ad-transformed human cells.
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PMID:Adenovirus E1A inhibits IFN-induced resistance to cytolysis by natural killer cells. 768 16

Proteasomes are the major source for the generation of peptides bound by MHC class I molecules. To study the functional relevance of the IFN-gamma-inducible proteasome subunits low molecular mass protein 2 (LMP2), LMP7, and mouse embryonal cell (MEC) ligand 1 in Ag processing and concomitantly that of immunoproteasomes, we established the tetracycline-regulated mouse cell line MEC217, allowing the titrable formation of immunoproteasomes. Infection of MEC217 cells with Adenovirus type 5 (Ad5) and analysis of Ag presentation with Ad5-specific CTL showed that cells containing immunoproteasomes processed the viral early 1B protein (E1B)-derived epitope E1B192-200 with increased efficiency, thus allowing a faster detection of viral entry in induced cells. Importantly, optimal CTL activation was already achieved at submaximal immunosubunit expression. In contrast, digestion of E1B-polypeptide with purified proteasomes in vitro yielded E1B192-200 at quantities that were proportional to the relative contents of immunosubunits. Our data provide evidence that the IFN-gamma-inducible proteasome subunits, when present at relatively low levels as at initial stages of infection, already increase the efficiency of antigenic peptide generation and thereby enhance MHC class I Ag processing in infected cells.
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PMID:MHC class I antigen processing of an adenovirus CTL epitope is linked to the levels of immunoproteasomes in infected cells. 1077 50

Type I interferon (IFN) induces antiviral responses through the activation of the ISGF3 transcription factor complex that contains the subunit proteins STAT1, STAT2, and p48/ISGF3 gamma/IRF9. The ability of some human paramyxoviruses to overcome IFN actions by specific proteolysis of STAT proteins has been examined. Infection of cells with type 2, but not type 1 or type 3 human parainfluenza virus (HPIV) leads to a loss of cellular STAT2 protein. Expression of a single HPIV2 protein derived from the V open reading frame blocks IFN-dependent transcriptional responses in the absence of other viral proteins. The loss of IFN response is due to V-protein-induced proteolytic degradation of STAT2. Expression of HPIV2 V causes the normally stable STAT2 protein to be rapidly degraded, and this proteolytic activity can be partially alleviated by proteasome inhibition. No V-protein-specific effects on STAT2 mRNA levels were observed. The results indicate that the V protein of HPIV2 is sufficient to recognize and target a specific cellular transcription factor for destruction by cellular machinery.
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PMID:The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2. 1133 48

Coxsackievirus group B3 (CVB3) replication is influenced by host cell cycle status. However, the effect of CVB3 infection on cell cycle regulation and the mechanisms involved are not precisely defined. In this study, we examined cell cycle progression and regulation when the infection was initiated in late G(1) phase of the cell cycle. Analysis of cellular DNA synthesis in infected cells by thymidine incorporation assays showed a significant reduction in [(3)H]thymidine uptake compared to that of sham-infected cells. To further clarify the effects of CVB3 on the host cell cycle, we examined the cell cycle regulatory proteins involved in G(1) progression and G(1)/S transition. Infection resulted in dephosphorylation of retinoblastoma protein and reduced G(1) cyclin-dependent kinase activities, accompanied by decreased levels of G(1) cyclin protein expression (cyclin D1 and cyclin E). We further investigated the mechanisms by which CVB3 infection down-regulates cyclin D1 expression. Northern blotting showed that cyclin D1 mRNA levels were modestly increased following CVB3 infection, suggesting that cyclin D1 regulation occurs by a posttranscriptional mechanism. Viral infection resulted in only a 20 to 30% inhibition of cyclin D1 protein synthesis 3 h postinfection. However, the proteasome inhibitors MG132 and lactacystin prevent CVB3-induced cyclin D1 reduction, indicating that CVB3-induced down-regulation of cyclin D1 is facilitated by ubiquitin-proteasome proteolysis. Finally, using GSK3beta pathway inhibitors, we showed that the reduction of cyclin D1 is GSK3beta independent. Taken together, our results demonstrate that CVB3 infection disrupts host cell homeostasis by blocking the cell cycle at the G(1)/S boundary and induces cell cycle arrest in part through an increase in ubiquitin-dependent proteolysis of cyclin D1.
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PMID:Ubiquitin-dependent proteolysis of cyclin D1 is associated with coxsackievirus-induced cell growth arrest. 1247 5

Intracerebral infection with Theiler's virus induces a demyelinating disease that resembles human MS. In order to delineate the early events in virus-induced inflammatory disease, we have analyzed chemokine gene activation following Theiler's murine encephalomyelitis virus (TMEV) infection. Infection of primary astrocyte cultures results in activation of various chemokine genes (GRO-1, MCP-1, MCP-5, MIP-1alpha, MIP-1beta, MIP-2, RANTES, IP-10 and MCP-3) that are important in the initiation of an inflammatory response. As early as 1-3 h after TMEV infection, chemokine gene expression is strongly activated. In addition, proinflammatory cytokines do not interfere with TMEV-induced chemokine gene expression and some cytokines may function synergistically for virus-induced upregulation of chemokine gene expression. Chemokine gene activation by TMEV appears to be largely independent of the IFNalphabeta pathway and partly dependent on dsRNA-dependent protein kinase (PKR) and MAP kinase pathways. However, TMEV-induced chemokine gene expression is completely dependent on the NFkappaB pathway. These results strongly suggest that the expression of select chemokine genes upon TMEV infection is activated via the NFkappaB pathway, similar to that of proinflammatory cytokine genes, and these cellular gene products appear to synergistically promote inflammatory responses in the CNS.
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PMID:The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler's virus. 1502 72

Inhibitors of the proteasome, a multicatalytic proteinase complex responsible for intracellular proteolysis, activate programmed cell death in part through the c-Jun-N-terminal kinase (JNK). Proteasome inhibitors also induce mitogen-activated protein kinase phosphatase-1 (MKP-1), however, which can inactivate JNK, and we therefore considered the hypothesis that MKP-1 induction may be antiapoptotic. Over-expression of MKP-1 in A1N4-myc human mammary epithelial and BT-474 breast carcinoma cells decreased proteasome inhibitor-mediated apoptosis. On the other hand, BT-474 cells stably expressing an MKP-1 small interfering RNA (siMKP-1) and MKP-1 knockout mouse embryo fibroblasts underwent enhanced apoptosis compared with their respective controls. MKP-1-mediated inhibition of apoptosis was associated with decreased phospho-JNK levels, whereas MKP-1 suppression or inactivation enhanced phospho-JNK. Anthracyclines repress MKP-1 transcription, suggesting that they could enhance proteasome inhibitor-mediated apoptosis. Such combinations induced increased cell death in association with enhanced phospho-JNK and decreased MKP-1 levels. Inhibition of JNK signaling decreased the proapoptotic activity of the anthracycline/proteasome inhibitor regimen. Xenograft studies showed the combination was more effective at inducing tumor growth delay, associated with suppression of MKP-1 and enhancement of apoptosis and phospho-JNK. Infection of anthracycline/proteasome inhibitor-treated A1N4-myc cells with Adenoviral-MKP-1 suppressed apoptosis and phospho-JNK. Finally, the anthracycline/proteasome inhibitor regimen activated apoptosis and phospho-JNK to a greater extent in BT-474/siMKP-1 cells than controls. These findings for the first time demonstrate that proteasome inhibitor-mediated induction of MKP-1 is antiapoptotic through inhibition of JNK. Furthermore, they suggest that a proteasome inhibitor/anthracycline regimen holds potential for enhanced antitumor activity in part through repression of MKP-1, supporting clinical evaluation of such combinations.
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PMID:Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. 1544 90

Natural killer (NK) cells are an important early mediator of host immunity to murine cytomegalovirus (MCMV) infection. However, MCMV has evolved mechanisms to elude recognition and clearance by NK cells. We have identified an MCMV immune evasion protein that impairs NKG2D-mediated NK cell antiviral activity. Infection of BALB/c 3T3 cells with the Smith strain of MCMV resulted in strong down-regulation of H60, a high affinity ligand for NKG2D, from the surface of virus-infected cells. The MCMV m155 protein specifically down-regulated H60 without affecting expression of the other known NKG2D ligands, RAE-1 and MULT-1. Treatment with the proteasome inhibitors lactacystin or epoxomicin reversed m155 down-regulation of H60. An MCMV mutant virus lacking m155 was severely attenuated in BALB/c mice; however, treatment with neutralizing anti-NKG2D monoclonal antibody or with NK-depleting anti-asialo GM1 antisera restored virulence of the mutant virus. Thus, down-regulation of H60 by m155 is a powerful mechanism of inhibiting NKG2D-mediated antiviral function.
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PMID:The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions. 1547 45


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