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)

Interaction of many infectious agents with eukaryotic host cells is known to cause activation of the ubiquitous transcription factor nuclear factor kappaB (NF-kappaB) (U. Siebenlist, G. Franzoso, and K. Brown, Annu. Rev. Cell Biol. 10:405-455, 1994). Recently, we reported a biphasic pattern of NF-kappaB activation in cultured human umbilical vein endothelial cells consequent to infection with Rickettsia rickettsii, an obligate intracellular gram-negative bacterium and the etiologic agent of Rocky Mountain spotted fever (L. A. Sporn, S. K. Sahni, N. B. Lerner, V. J. Marder, D. J. Silverman, L. C. Turpin, and A. L. Schwab, Infect. Immun. 65:2786-2791, 1997). In the present study, we describe activation of NF-kappaB in a cell-free system, accomplished by addition of partially purified R. rickettsii to endothelial cell cytoplasmic extracts. This activation was rapid, reaching maximal levels at 60 min, and was dependent on the number of R. rickettsii organisms added. Antibody supershift assays using monospecific antisera against NF-kappaB subunits (p50 and p65) confirmed the authenticity of the gel-shifted complexes and identified both p50-p50 homodimers and p50-p65 heterodimers as constituents of the activated NF-kappaB pool. Activation occurred independently of the presence of endothelial cell membranes and was not inhibited by removal of the endothelial cell proteasome. Lack of involvement of the proteasome was further confirmed in assays using the peptide-aldehyde proteasome inhibitor MG 132. Activation was not ATP dependent since no change in activation resulted from addition of an excess of the unhydrolyzable ATP analog ATPgammaS, supplementation with exogenous ATP, or hydrolysis of endogenous ATP with ATPase. Furthermore, Western blot analysis before and after in vitro activation failed to demonstrate phosphorylation of serine 32 or degradation of the cytoplasmic pool of IkappaB alpha. This lack of IkappaB alpha involvement was supported by the finding that R. rickettsii can induce NF-kappaB activation in cytoplasmic extracts prepared from T24 bladder carcinoma cells and human embryo fibroblasts stably transfected with a superrepressor phosphorylation mutant of IkappaB alpha, rendering NF-kappaB inactivatable by many known signals. Thus, evidence is provided for a potentially novel NF-kappaB activation pathway wherein R. rickettsii may interact with and activate host cell transcriptional machinery independently of the involvement of the proteasome or known signal transduction pathways.
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PMID:Proteasome-independent activation of nuclear factor kappaB in cytoplasmic extracts from human endothelial cells by Rickettsia rickettsii. 957 57

The proteasome is a recently identified intracellular protease whose catalytic active site is a threonine residue and has been shown to play key roles in a variety of important intracellular events, including cell cycle progression, the antigen-presenting pathway, and apoptosis. However, its biological significance in multicellular organisms is still largely unknown because of lack of experimental systems for its study. Here we verified potential involvement of the proteasome in angiogenesis using lactacystin, a specific proteasome inhibitor. Lactacystin treatment resulted in almost complete prevention of in vivo neovascularization in the developing chick embryo chorioallantoic membrane. It also inhibited vascular endothelial tube formation on Matrigel, a model for in vitro angiogenesis, in a concentration-dependent fashion. Moreover, it prevented production of plasminogen activator, an important protease responsible for induction of angiogenesis, by endothelial cells, which correlated well with its suppression of intracellular proteasome activity. Our studies suggest that the proteasome operates in the process of angiogenesis, a phenomenon essential in important physiological and pathological settings.
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PMID:The proteasome is involved in angiogenesis. 960 Jan

gamma-Tocotrienol (gamma-T3), a HMG CoA reductase inhibitor, was previously shown to stimulate the intracellular degradation of apolipoprotein B (apoB) in HepG2 cells. The aim of this study was to explore the effects of gamma-T3 on the proteasome dependent co-translational degradation and the proteasome independent post-translational degradation of apoB. Previous studies have shown that apoB translocation across the endoplasmic reticulum (ER) membrane governs the co-translational degradative pathway of apoB. Therefore, we first examined the effects of gamma-T3 on this pathway using a specific translocation assay derived from HepG2 cells. Our results indicated that gamma-T3 reduced the efficiency of apoB translocation across the ER membrane, suggesting that co-translational degradation may be partially involved. Evidence of an ER associated post-translational degradation was also provided upon pre-treating digitonin-permeabilized HepG2 cells with a proteasome inhibitor, lactacystin. When chased for 2h, ER degradation of apoB was observed and was further enhanced in the presence of gamma-T3 versus untreated control, in spite of proteasome inhibition. Combined with the ability of ALLN, a proteasome and cysteine protease inhibitor, to block the post-translational degradation of apoB, the data suggest that gamma-T3 diverted more apoB to a cytosolic proteasomal dependent and possibly an ER-associated proteasomal independent degradation pathways.
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PMID:Effects of tocotrienol on the intracellular translocation and degradation of apolipoprotein B: possible involvement of a proteasome independent pathway. 961 65

Different established cell lines (SK-v human keratinocytes, B16F10 mouse melanoma, Muntjac fibroblasts, 3T3 mouse fibroblasts, CLV human fibroblasts) as well as primary cultures of mouse fibroblasts and giant cells were treated with N-benzyloxycarbonyl-Ile-Glu(O-t-butyl)-Ala-leucinal (proteasome inhibitor, PSI), a specific inhibitor of the chymotrypsin-like activity of the proteasome. PSI induced well characterized morphological changes in all cell lines studied, including vacuolization and accumulation of perinuclear aggregates, as detected by amido black staining. Together with previous reports on HeLa cells, the present findings support the hypothesis that ubiquitin- and proteasome-dependent proteolysis does not occur randomly in the entire cell, but it is concentrated in a well defined perinuclear region, the proteolytic center.
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PMID:An inhibitor of the chymotrypsin-like activity of the proteasome (PSI) induces similar morphological changes in various cell lines. 961 20

Human monocyte chemoattractant protein-1 (MCP-1) is expressed by a variety of cell types in response to various stimuli. MCP-1 expressed by the endothelium plays an important role in cell migration and activation. MCP-1 is a major chemoattractant for monocytes, T lymphocytes, and basophils. In the present study, we present evidence that the proteasome complex is involved in mediating the interleukin (IL)-1beta induction of MCP-1 in endothelial cells. We present evidence that a proteasome inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal (norLeu), and the protease inhibitor tosyl-Phe-chloromethylketone (TPCK) block IL-1beta induction of MCP-1 protein expression. norLeu and TPCK also blocked IL-1beta-induced MCP-1 promoter-driven reporter gene expression as well as nuclear factor (NF)-kappaB-mediated reporter gene expression. The effects of norLeu were due to its inhibition of the proteasome rather than calpain, because other calpain inhibitors had no effect on MCP-1 expression. In contrast to TPCK, which blocked NF-kappaB translocation to the nucleus, norLeu had no effect on NF-kappaB nuclear translocation or IL-1beta-induced phosphorylation of p65. This study demonstrates that the proteasome pathway is involved in IL-1beta-induced MCP-1 gene expression in human endothelial cells.
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PMID:IL-1beta-induced monocyte chemoattractant protein-1 gene expression in endothelial cells is blocked by proteasome inhibitors. 963 34

Myeloperoxidase (MPO) deficiency is a common inherited disorder linked to increased susceptibility to infection and malignancy. We identified a novel missense mutation in the MPO gene at codon 173 whereby tyrosine is replaced with cysteine (Y173C) that is associated with MPO deficiency and assessed its impact on MPO processing and targeting in transfectants expressing normal or mutant proteins. Although the precursor synthesized by cells expressing the Y173C mutation (MPOY173C) was glycosylated, associated with the molecular chaperones calreticulin and calnexin, and acquired heme, it was neither proteolytically processed to mature MPO subunits nor secreted. After prolonged association with calreticulin and calnexin in the endoplasmic reticulum, MPOY173C was degraded. Furthermore, the 20S proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinyl inhibited its degradation, suggesting that the proteasome mediates proteolysis of MPOY173C and, thus, participates in quality control in this novel form of hereditary MPO deficiency.
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PMID:A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. 963 25

The majority of cases of early-onset familial Alzheimer disease are caused by mutations in the recently identified presenilin 1 (PS 1) gene, located on chromosome 14. PS1, a 467 amino acid protein, is predicted to be an integral membrane protein containing seven putative transmembrane domains and a large hydrophilic loop between the sixth and seventh membrane-spanning domain. We produced 7 monoclonal antibodies that react with 3 non-overlapping epitopes on the N-terminal hydrophilic tail of PS1. The monoclonal antibodies can detect the full size PS1 at M(r) 47,000 (47K) and a more abundant M(r) 28,000 (28K) product in membrane from human brain and human cell lines. We examined the sub-cellular localization by using these antibodies. Immuno-electronmicroscopic and biochemical analysis indicated that PS1 is localized on cellular membrane (plasma, endoplasmic reticulum, and perinuclear) in COS-7 cells overexpressing PS1. Interestingly, the PS1 immunoreactivity in the plasma membrane was concentrated in the regions with cell-cell contact. This observation suggests a possible role of PS1 on the cell membrane as a cell adhesion molecule. To determine the protease cleaving the full length PS1 to two fragments, we treated cells with various protease inhibitors. Only proteasome inhibitor affected the PS1 processing, indicating that proteasome is a candidate protease for PS1 proteolytic cleavage. PC12 cells transiently transfected with PS1 constructs containing different Alzheimer mutations fail to generate the 28K degradation product in contrast to PC12 cells transfected with wild type PS1. Our results indicate that missense mutations in this form of familial Alzheimer disease may act via a mechanism of impaired proteolytic processing of PS1.
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PMID:[Biochemistry of presenilin 1]. 965 56

We investigated whether proteasomes were involved in the invasiveness of oral squamous cell carcinoma (SCC) cells. The migration of SCC cells through a gelatin-coated membrane was enhanced with tumor necrosis factor alpha (TNF alpha), which was strongly inhibited by a peptide aldehyde, N-acetyl-Leu-Leu-norleucinal (ALLN), but not by its structurally related compound, N-acetyl-Leu-Leu-methioninal (ALLM). Since ALLN is a more potent inhibitor against proteasomal proteolysis than ALLM, cell migration inhibited by ALLN may thus likely depend on proteasomes. The TNF alpha-induced migration through gelatin appeared to be associated with the gelatinolytic activity from the cells, since TNF alpha strongly enhanced the production of matrix metalloproteinase (MMP)-9/gelatinase B in the SCC cells, as detected by gelatin zymography. The production of MMP-9 was also inhibited by pretreatment with ALLN, but not ALLM, in a dose-dependent manner. Moreover, ALLN could block the activation and nuclear translocation of a transcription-activating factor, NF-kappaB, which is known to regulate MMP-9 expression in TNF alpha-stimulated SCC cells. The TNF alpha-induced degradation of IkappaB alpha was also suppressed by ALLN treatment, thus implying that the molecule linking proteasome to MMP-9 production should be IkappaB alpha. We finally reconfirmed the involvement of proteasomes in the invasive behavior of oral SCC using lactacystin, a specific proteasome inhibitor, which could prevent TNF alpha from enhancing MMP-9 production, NF-kappaB activation, induction of MMP-9 mRNA and cell migration.
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PMID:Involvement of proteasomes in migration and matrix metalloproteinase-9 production of oral squamous cell carcinoma. 967 62

Deoxycorticosterone acetate (DOCA)-salt-treated rats developed marked hypertension after 4 weeks with an increase in aortic endothelin-1. Treatment of DOCA-salt hypertensive rats with a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, significantly reduced the elevation in systolic blood pressure and the effect was accompanied by a decrease in aortic endothelin- content. Thus, a proteasome-dependent proteolytic pathway appears to play an important role in the enhanced production of endothelin-1 in blood vessels and the consequent increase in blood pressure in this model of hypertension.
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PMID:A proteasome inhibitor lessens the increased aortic endothelin-1 content in deoxycorticosterone acetate-salt hypertensive rats. 968 28

Objectives were to investigate the role of the proteasome and m-calpain to muscle cell differentiation. Accordingly, we investigated the effects of lactacystin, a proteasome inhibitor, and calpain inhibitor-II (CI-II) on L8 muscle cell differentiation and assessed concentrations of proteasomal and calpain subunit mRNAs during differentiation. L8 myoblasts were induced to differentiate by culturing in mitogen-depleted medium. To assess the importance of the proteasome and calpain to differentiation, we examined effects of lactacystin and CI-II on creatine kinase (CK) activity. In the absence of inhibitor, CK activity was detectable within 48 h of mitogen depletion and myotubes were formed. Addition of lactacystin or CI-II to cultures drastically reduced CK activity and prevented formation of myotubes. Hence, proteasome and calpain are both necessary for differentiation. In order to identify which proteasomal subunits were regulated during differentiation, we examined the concentrations of two 20S core subunits (C8 and C9) and three 22S ATPases (MSS1, S4 and TBP1) during differentiation. Concentrations of m-calpain and beta-tubulin mRNAs were also assessed. Differentiation was associated with slight increases (ca. 30%) in concentrations of mRNAs encoding the proteasomal 20S core subunits (C8 and C9) and with large increases (approximately 2-fold) in mRNAs encoding the regulatory subunit ATPases. m-calpain mRNA concentration also increased two-fold following mitogen depletion. beta-Tubulin mRNA concentration remained unchanged early in the differentiation process and thereafter declined. Of interest, changes in proteasomal and m-calpain mRNAs occurred within 6-24 h of mitogen depletion (i.e., at least 24-36 h prior to detectable changes in creatine kinase activity). These results indicate that changes in expression of proteasome and calpains subunits occur early in the differentiation process. These changes may be required for the normal course of differentiation to proceed. Differentiation is associated with larger changes in proteasomal ATPase mRNAs than in 20S core particle mRNAs indicating that either turnover rates of the 22S ATPase subunits are more rapid in differentiating cells than of the 20S core particles or that functions of the regulatory subunits become more important during muscle cell differentiation.
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PMID:Evidence for the participation of the proteasome and calpain in early phases of muscle cell differentiation. 969 25


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