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)

This review will discuss the recent literature on the molecular mechanism of NF-kappaB activation, with special focus on IkappaB alpha dynamism involved in iNOS- and chemokine-induction in glial cells. NF-kappaB, a heterotrimer composed of p50, p65 (Rel A) and IkappaB alpha, has been shown to be activated by elimination of the regulatory subunit IkappaB alpha from the heterotrimer. The elimination of IkappaB alpha (formation of active NF-kappaB, p50-p65) is due to phosplorylation of serines 32 and 36 of IkappaB alpha, followed by polyubiquitination and 26S proteasomal degradation of IkappaB alpha. Experiments using stable clones of rat C6 glioma cells transfected with dominant negative IkappaB alpha (serines 32 and 36 replaced by alanine) suggest that NF-kappaB activation (phosphorylation of IkappaB alpha) is involved in LPS/IFNgamma- or IL-1beta/IFNgamma-induced iNOS expression. Furthermore, the time courses of phosphorylation, ubiquitination of IkappaB alpha and proteasome activity after IL-1beta treatment also suggest that 26S proteasomal degradation of IkappaB alpha is more crucial for chemokine expression in glial cells.
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PMID:NF-kappaB activation and IkappaB alpha dynamism involved in iNOS and chemokine induction in astroglial cells. 1127 Jun 16

The ubiquitin/proteasome pathway plays an essential role in protein turnover in vivo, and contributes to removal of oxidatively damaged proteins. We examined the effects of proteasome inhibition on viability, oxidative damage and antioxidant defences in NT-2 and SK-N-MC cell lines. The selective proteasome inhibitor, lactacystin (1 microM) caused little loss of viability, but led to significant increases in levels of oxidative protein damage (measured as protein carbonyls), ubiquitinated proteins, lipid peroxidation and 3-nitrotyrosine, a biomarker of the attack of reactive nitrogen species (such as peroxynitrite, ONOO(-)) upon proteins. Higher levels (25 microM) of lactacystin did not further increase the levels of carbonyls, lipid peroxidation, 3-nitrotyrosine, or ubiquitinated proteins, but produced increases in the levels of 8-hydroxyguanine (a biomarker of oxidative DNA damage) and falls in levels of GSH. Lactacystin (25 microM) caused loss of viability, apparently by apoptosis, and also increased production of nitric oxide (NO.) (measured as levels of NO2- plus NO3-) by the cells; this was inhibited by N-nitro-L-arginine methyl ester (L-NAME), which also decreased cell death induced by 25 microM lactacystin and decreased levels of 3-nitrotyrosine. The NO. production appeared to involve nNOS; iNOS or eNOS were not detectable in either cell type. Another proteasome inhibitor, epoxomicin, had similar effects.
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PMID:Effect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production. 1143 71

Moloney murine leukemia virus (MoMuLV)-ts1-mediated neuronal degeneration in mice is likely due to loss of glial support and release of inflammatory cytokines and neurotoxins from surrounding ts1-infected glial cells including astrocytes. NF-kappaB is a transcription factor that participates in the transcriptional activation of a variety of immune and inflammatory genes. We investigated whether ts1 activates NF-kappaB in astrocytes and examined the mechanism(s) responsible for the activation of NF-kappaB by ts1 infection in vitro. Here we present evidence that ts1 infection of astrocytes in vitro activates NF-kappaB by enhanced proteolysis of the NF-kappaB inhibitors, IkappaBalpha and IkappaBbeta. In in vitro studies using protease inhibitors, IkappaBalpha proteolysis in ts1-infected astrocytes was significantly blocked by a specific calpain inhibitor calpeptin but not by MG-132, a specific proteasome inhibitor, whereas rapid IkappaBbeta proteolysis was blocked by MG-132. Furthermore, treatment with MG-132 increased levels of multiubiquitinated IkappaBbeta protein in ts1-infected astrocytes. These results indicate that the calpain proteolysis is a major mechanism of IkappaBalpha proteolysis in ts1-infected astrocytes. Additionally, ts1 infection of astrocytes in vitro increased expression of inducible nitric oxide synthase (iNOS), a NF-kappaB-dependent gene product. Our results suggest that NF-kappaB activation in ts1-infected astrocytes is mediated by enhanced proteolysis of IkappaBalpha and IkappaBbeta through two different proteolytic pathways, the calpain and ubiquitin-proteasome pathways, resulting in increased expression of iNOS, a NF-kappaB-dependent gene.
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PMID:Enhanced proteolysis of IkappaBalpha and IkappaBbeta proteins in astrocytes by Moloney murine leukemia virus (MoMuLV)-ts1 infection: a potential mechanism of NF-kappaB activation. 1158 19

Intracellular iron homeostasis is regulated posttranscriptionally by iron regulatory proteins 1 and 2 (IRP1 and IRP2). In the absence of iron in the labile pool, IRPs bind to specific nucleotide sequences called iron responsive elements (IREs), which are located in the 5' untranslated region of ferritin mRNA and the 3' untranslated region of transferrin receptor mRNA. IRP binding to the IREs suppresses ferritin translation and stabilizes transferrin receptor mRNA, whereas the opposite scenario develops in iron-replete cells. Binding of IRPs to the IREs is also affected by nitrogen monoxide (NO), but there are conflicting reports regarding the effect of NO on ferritin synthesis. In this study, we demonstrated that a short exposure of RAW 264.7 cells (a macrophage cell line) to the NO+ donor, sodium nitroprusside (SNP), resulted in a dramatic increase in ferritin synthesis. The SNP-mediated increase of ferritin synthesis could be blocked by MG132, an inhibitor of proteasome-dependent protein degradation, which also prevented the degradation of IRP2 caused by SNP treatment. Moreover, treatment of RAW 264.7 cells with IFN-gamma and lipopolysaccharide caused IRP2 degradation and stimulated ferritin synthesis, changes that could be prevented by specific inhibitors of inducible nitric oxide synthase. Furthermore, the SNP-mediated increase in ferritin synthesis was associated with a significant enhancement of iron incorporation into ferritin. These observations indicate that NO+-mediated modulation of IRP2 plays an important role in controlling ferritin synthesis and iron metabolism in murine macrophages.
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PMID:Nitrogen monoxide-mediated control of ferritin synthesis: implications for macrophage iron homeostasis. 1220 9

Nitric oxide (NO) is a potent cell-signaling, effector, and vasodilator molecule that plays important roles in diverse biological effects in the kidney, vasculature, and many other tissues. Because of its high biological reactivity and diffusibility, multiple tiers of regulation, ranging from transcriptional to posttranslational controls, tightly control NO biosynthesis. Interactions of each of the major NO synthase (NOS) isoforms with heterologous proteins have emerged as a mechanism by which the activity, spatial distribution, and proximity of the NOS isoforms to regulatory proteins and intended targets are governed. Dimerization of the NOS isozymes, required for their activity, exhibits distinguishing features among these proteins and may serve as a regulated process and target for therapeutic intervention. An increasingly wide array of proteins, ranging from scaffolding proteins to membrane receptors, has been shown to function as NOS-binding partners. Neuronal NOS interacts via its PDZ domain with several PDZ-domain proteins. Several resident and recruited proteins of plasmalemmal caveolae, including caveolins, anchoring proteins, G protein-coupled receptors, kinases, and molecular chaperones, modulate the activity and trafficking of endothelial NOS in the endothelium. Inducible NOS (iNOS) interacts with the inhibitory molecules kalirin and NOS-associated protein 110 kDa, as well as activator proteins, the Rac GTPases. In addition, protein-protein interactions of proteins governing iNOS transcription function to specify activation or suppression of iNOS induction by cytokines. The calpain and ubiquitin-proteasome pathways are the major proteolytic systems responsible for the regulated degradation of NOS isozymes. The experimental basis for these protein-protein interactions, their functional importance, and potential implication for renal and vascular physiology and pathophysiology is reviewed.
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PMID:Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. 1284 59

We tested the influence of IFNgamma on proteasome activity in parental Hep G2 cells that do not metabolize ethanol, as well as in recombinant Hep G2-derived cells that express either or both alcohol dehydrogenase (ADH) and cytochrome P4502E1 (CYP2E1). IFNgamma treatment increased proteasome activity in VL-17A (ADH(+), CYP2E1(+)) and E-47 (CYP2E1(+)) cells, but not in Hep G2, VI-R2 (parental cells with empty vectors) or in VA-13 (ADH(+)) cells. Proteasome activation by IFNgamma correlated positively with the level of CYP2E1 activity. Treatment of VL-17A cells with agents that inhibit CYP2E1 or the inducible nitric oxide synthase (iNOS) or that prevent the formation of peroxynitrite also blocked proteasome activation by IFNgamma, indicating that the proteasome may be directly activated by products of CYP2E1 and iNOS catalysis. While IFNgamma treatment increased proteasome activity, it also decreased CYP2E1 activity. Both effects were mediated via the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT1) pathway, as both were blocked by the JAK2 inhibitor, tyrphostin AG 490. Ethanol treatment of VL-17A cells also caused a similar blockage of these same IFNgamma-mediated effects, by inhibiting STAT1 phosphorylation. This inhibition was largely due to ethanol metabolism, as 4-methylpyrazole, an ethanol metabolism inhibitor, restored IFNgamma-mediated STAT1 phosphorylation in ethanol-treated cells. Our results lead us to propose that IFNgamma initiates signal transduction, which alters the activities of CYP2E1 and iNOS, thereby producing reactive oxygen species. One of these oxidants, possibly peroxynitrite, may be directly involved in proteasome activation. Ethanol metabolism by VL-17A cells suppresses IFNgamma-mediated induction of proteasome activity, in part, by preventing STAT1 phosphorylation.
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PMID:Interferon gamma enhances proteasome activity in recombinant Hep G2 cells that express cytochrome P4502E1: modulation by ethanol. 1294 50

Biochemical and pharmacological studies have suggested that NOS2 (inducible nitric oxide synthase) has a functional role in the blood pressure response to increases in dietary salt intake. On a high-salt diet, the Dahl/Rapp salt-sensitive (S) strain of rat, a genetic model of salt-sensitive hypertension, did not show increased nitric oxide production. NOS2 from S rats possesses a point mutation that results in substitution of proline for serine at position 714. In the present study, rat NOS2 was shown to be ubiquitinated in vitro and in vivo and to be degraded by the proteasome; this process was accelerated for the S714P mutant. Accelerated degradation of the S714P mutant enzyme accounted for the diminished enzyme activity of this mutant. Hsp90 (heat-shock protein 90) associated with NOS2 and modulated degradation, but was not responsible for the accentuated degradation of the S714P mutant enzyme. The combined findings demonstrate the integral role of ubiquitination and degradation by the proteasome in the regulation of NO production by rat NOS2. Demonstrating that this process is responsible for the abnormal function of the S714P mutant NOS2 in S rats confirms the physiological importance of the proteasome in NOS2 function.
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PMID:Accelerated ubiquitination and proteasome degradation of a genetic variant of inducible nitric oxide synthase. 1295 38

Brain inflammation is accompanied by transection of axons and death of neurons in the acute lesions of multiple sclerosis. We explored mechanisms of inflammatory damage to neurons in vitro using cocultures of rat embryonal cortical neurons with microglia activated by interferon-gamma (IFNgamma) and lipopolysaccharide (LPS). Previously, we have demonstrated that microglia are highly toxic to neurons and that nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) is necessary and sufficient to mediate this toxicity. Here, we show that addition of dexamethasone (1 micro M) to activated cocultures provides effective neuroprotection. We demonstrate that dexamethasone down-regulates NO production of primary microglia by approximately 50% and reduces steady-state iNOS protein and mRNA expression by approximately 70%. These changes were reversed by the glucocorticoid receptor blocker RU-486. Furthermore, we analysed the stability of iNOS protein and show that whilst inhibitors of the proteasome blocked iNOS degradation they did not reverse the dexamethasone effect. Our results indicate that the main mechanism of corticosteroid activity on iNOS is reduction in protein synthesis, not destabilization as previously suggested.
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PMID:Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitro. 1462 53

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Intermittent hypoxia (IH) during sleep, a hallmark of sleep apnea, is associated with neurobehavioral impairments, regional neurodegeneration and increased oxidative stress and inflammation in rodents. Platelet-activating factor (PAF) is an important mediator of both normal neural plasticity and brain injury. We report that mice deficient in the cell surface receptor for PAF (PAFR-/-), a bioactive mediator of oxidative stress and inflammation, are protected from the spatial reference learning deficits associated with IH. Furthermore, PAFR-/- exhibit attenuated elevations in inflammatory signaling (cyclo-oxygenase-2 and inducible nitric oxide synthase activities), degradation of the ubiquitin-proteasome pathway and apoptosis observed in wild-type littermates (PAFR+/+) exposed to IH. Collectively, these findings indicate that inflammatory signaling and neurobehavioral impairments induced by IH are mediated through PAF receptors.
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PMID:Platelet-activating factor receptor-deficient mice are protected from experimental sleep apnea-induced learning deficits. 1503 Apr 3


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