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)

We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-kappaB (NF-kappaB). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of IkappaB-alpha and -beta, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-kappaB binding activity and NF-kappaB transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1beta (IL-1beta), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of IkappaB-alpha and -beta, efficiently blocked the production of TNF and, to a lesser extent, IL-1beta, whereas that of IL-8 was not inhibited. The expression of NF-kappaB-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.
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PMID:Effect of proteasome inhibitors on monocytic IkappaB-alpha and -beta depletion, NF-kappaB activation, and cytokine production. 950 May 29

Regulated proteolysis has been postulated to be critical for proper control of cell functions. Muscle development, in particular, involves a great deal of structural adaptation and remodeling mediated by proteases. The transcription factor YY1 represses muscle-restricted expression of the sarcomeric alpha-actin genes. Consistent with this repressor function of YY1, the nuclear regulator is down-regulated at the protein level during skeletal as well as cardiac muscle cell differentiation. However, the YY1 message remains relatively unaltered throughout the myoblast-myotube transition, implicating a post-translational regulatory mechanism. We show that YY1 can be a substrate for cleavage by the calcium-activated neutral protease calpain II (m-calpain) and the 26 S proteasome. The calcium ionophore A23187 destabilized YY1 in cultured myoblasts, and the decrease in YY1 protein levels could be prevented by calpain inhibitor II and calpeptin. Treatment with the proteasome inhibitors MG132 and lactacystin resulted in the stabilization of YY1 protein, which is consistent with the finding that YY1 is readily polyubiquitinated in reticulocyte lysates. We further show that proteolytic targeting by calpain II and the proteasome involves different structural elements of YY1. This study thus illustrates two proteolytic pathways through which the transcriptional regulator can be differentially targeted under different cell growth conditions.
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PMID:Proteolytic regulation of the zinc finger transcription factor YY1, a repressor of muscle-restricted gene expression. 950 62

The regulation of cell cycle progression is a complex process which involves kinase cascades, protease action, production of second messengers and other operations. Increasing evidence now compellingly suggests that changes in the intracellular Ca2+ concentration may also have a crucial role. Ca2+ transients occur at the awakening from quiescence, at the G/S transition, during S-phase, and at the exit from mitosis. They may lead to the activation of Ca2+ binding proteins like S-100, but the key decoder of the Ca2+ signals in the cycle is calmodulin. Activation of calmodulin leads to the stimulation of protein kinases, i.e., CaM-kinase II, and of the CaM-dependent protein phosphatase calcineurin. Ample evidence now indicates the G/S transition, the progression from G2 to M, and the metaphase/anaphase transition as specific points of intervention of CaM-kinase II. Another attractive possibility for the role of Ca2+ in the cycle is through the activation of the Ca(2+)-dependent protease calpain: other proteases (e.g., the proteasome) have been suggested to be responsible for the degradation of some of cyclins, which is essential to the progression of the cycle. One of the cyclins, however, (D1) is instead degraded by calpain, which has been shown to promote both mitosis and meiosis when injected into somatic cells or oocytes.
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PMID:The role of calcium in the cell cycle: facts and hypotheses. 951 55

N-myc is a short-lived transcription factor, frequently amplified in human neuroblastomas. The ubiquitin-proteasome system is involved in the degradation of many short-lived cellular proteins and previous studies have shown that ubiquitin-dependent proteolysis is implicated in the turn-over of N-myc in vitro. However, calpain has also been implicated in N-myc degradation in vitro. Here we report that, in vivo, N-myc is a sensitive substrate for the 26S proteasome in N-myc amplified neuroblastoma cells. We observed that inhibition of the 26S proteasome with two inhibitors, ALLnL and lactacystin, led to an elevation of the N-myc protein steady-state and increased N-myc protein polyubiquitination, as revealed by ubiquitin Western blotting. Pulse-chase experiments have shown that the increased N-myc levels resulted from stabilization of the protein. In contrast treatment with several calpain and cathepsin inhibitors failed to block N-myc degradation in vivo. Furthermore, fluorescence microscopy of ALLnL-treated cells localized N-myc exclusively to the nuclear compartment, suggesting the absence of a requirement for transport to the cytoplasm prior to degradation.
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PMID:In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome. 952 55

Amyloid beta-protein (Abeta) is classified into two subspecies defined by its C-terminal length, designated Abeta40 and Abeta42. Although Abeta42 accounts for only approximately 10% of secreted Abeta, this particular species is the most dominant species in Abeta deposits in Alzheimer's disease (AD) and normal aged brains and appears to be the initially deposited species. Secretion levels of Abeta42 have been shown to increase in patients affected by any form of early-onset familial AD. Thus, the suppression of Abeta42 production or secretion could be a therapeutic strategy for AD. In this study, we examined whether protease inhibition affects the Abeta42 secretion ratio (Abeta42: total Abeta). Using specific inhibitors, we determined that the inhibition of calpain but not proteasome induces an increased Abeta42 secretion in cultured cells. These data suggest that calpain differentially affects the gamma-secretases generating Abeta40 and Abeta42 and indicate the possibility of developing compounds that reduce Abeta42 production and secretion though this pathway.
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PMID:Effects of specific protease inhibitors on amyloid beta-protein 42 secretion. 956 73

Proteolysis is a key event in the control of the cell cycle. Most of the proteins which are degraded at specific cycle points, e.g. cyclins A, B, and E, are substrates of the ubiquitin/proteasome pathway. The Ca2+ dependent neutral protease calpain also cleaves cell cycle proteins, among them cyclin D1 and the c-mos proto-oncogene product which is a component of the CSF. The proteasome itself, however, may be under Ca2+ control through the binding of Ca2+ to its 29 kDa regulatory subunit. Calpain undergoes relocation among cell compartments during the various steps of the mitotic and meitotic cycles. It promotes the initiation and the progression of mitosis when injected into the perinuclear space of synchronized PtK1 cells, and the resumption of meiosis when directly injected into the nuclei of prophase-arrested starfish oocytes. Apart from the proteins mentioned above, most of the substrates of calpain which become cleaved during mitosis and meiosis are still unknown. Microtubule-associated proteins are likely candidates.
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PMID:Calcium, protease action, and the regulation of the cell cycle. 960 7

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

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

In proliferating cells the turnover rate of proteins responsible for regulation of the cell cycle progression, namely cyclins and inhibitors of the cyclin-dependent kinases (CDKs) and phosphatases, is rapid and their cellular level is modulated at the transcriptional, translational and/or degradation (via proteasome pathway) stages. Inhibition of proteasome function results in accumulation of rapidly turning over proteins and, thus, causes an imbalance of the cell cycle regulatory components, and loss of their regulatory function. Indeed, it has been shown that proteasome inhibitors perturb the cell cycle progression. Onconase, a novel RNase which has anti-tumor activity and is in clinical trials, has previously been shown to suppress protein synthesis, presumably by degradation of intracellular RNA, preferentially tRNA. By interfering with regulation of expression of cyclins and/or CDK-inhibitors, onconase also may induce the imbalance of these proteins and potentiate the effect of proteasome inhibitors. In the present study, we observed that the combinations of onconase with peptide-aldehyde inhibitors of calpain and proteasome such as the N-acetyl-leucinyl-leucinyl-norleucinal (LLnL) and the N-acetyl-leucinyl-valinyl-phenylalaninal (LVP), but not N-acetyl-leucinyl-leucinyl-methioninal (LLM), were synergistic in suppressing cell proliferation and inducing apoptosis in three human tumor cell lines: A-549 lung adenocarcinoma, DU-145 prostatic carcinoma, and MDA-MB-231 breast carcinoma. The observed cytotoxicity may also be a result of prevention of the induction of the 'survival' genes by the nuclear factor kappaB (NFkappaB) by onconase and proteasome inhibitors. The data indicate that such combinations should be further tested as potential anti-cancer regimens.
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PMID:Enhanced in vitro cytotoxicity and cytostasis of the combination of onconase with a proteasome inhibitor. 973 89

In a previous report we suggested that muscle fibers in distal myopathy with rimmed vacuoles (DMRV) were degraded by both lysosomal proteolysis (cathepsins) and Ca2+-dependent, nonlysosomal proteolysis (calpain). Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, we examined the role of the ATP-ubiquitin-dependent proteolytic pathway (proteasomes) in myofiber degradation in this myopathy. Immunohistochemically, proteasomes (26S) were located in the cytoplasm in normal human muscle, but the staining intensity was weak. Quantitative analysis showed more reactivity for proteasomes in DMRV muscles and, to a lesser extent, in muscles from muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis patients. In DMRV, proteasomes often were located within or on the rim of rimmed vacuoles, and in the cytoplasm of atrophic fibers. Ubiquitin accumulation was marked within rimmed vacuoles and was seen less extensively in the cytoplasm of atrophic fibers. The latter proteins colocalized well. In other diseased muscles, proteasomes and ubiquitin showed a positive reaction in the atrophic or necrotic fibers. The results indicate increased proteasome and ubiquitin in these muscle fibers as well as in other diseased muscle fibers. We suggest that the ATP-ubiquitin-proteasome proteolytic pathway as well as the nonlysosomal calpain and the lysosomal proteolytic pathway may participate in the muscle fiber degradation in DMRV.
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PMID:Proteasomes in distal myopathy with rimmed vacuoles. 980 76


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