Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Major histocompatibility complex (MHC) class I ligands are mainly produced by the proteasome. Herein, we show that the processing of antigens is regulated by two distinct pathways, one requiring PA28 and the other hsp90. Both hsp90 and PA28 enhanced the antigen processing of ovalbumin (OVA). Geldanamycin, an inhibitor of hsp90, almost completely suppressed OVA antigen presentation in PA28alpha(-/-)/beta(-/-) lipopolysaccharide blasts, but not in wild-type cells, indicating that hsp90 compensates for the loss of PA28 and is essential in the PA28-independent pathway. In contrast, treatment of cells with interferon (IFN)-gamma, which induces PA28 expression, abrogated the requirement of hsp90, suggesting that IFN-gamma enhances the PA28-dependent pathway, whereas it diminishes hsp90-dependent pathway. Importantly, IFN-gamma did not induce MHC class I expressions in PA28-deficient cells, indicating a prominent role for PA28 in IFN-gamma-stimulated peptide supply. Thus, these two pathways operate either redundantly or specifically, depending on antigen species and cell type.
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PMID:Two distinct pathways mediated by PA28 and hsp90 in major histocompatibility complex class I antigen processing. 1211 43

Exposure of mammalian cells to UV radiation was proposed to stimulate the transcription factor NF-kappa B by a unique mechanism. Typically, rapid and strong inducers of NF-kappa B, such as tumor necrosis factor alpha (TNF-alpha) and bacterial lipopolysaccharide (LPS), lead to rapid phosphorylation and proteasomal degradation of its inhibitory protein, I kappa B alpha. In contrast, UV, a relatively slower and weaker inducer of NF-kappa B, was suggested not to require phosphorylation of I kappa B alpha for its targeted degradation by the proteasome. We now provide evidence to account for this peculiar degradation process of I kappa B alpha. The phospho-I kappa B alpha generated by UV is only detectable by expressing a Delta F-box mutant of the ubiquitin ligase beta-TrCP, which serves as a specific substrate trap for serine 32 and 36 phosphorylated I kappa B alpha. In agreement with this finding, we also find that the I kappa B kinase (IKK) phospho-acceptor sites on I kappa B alpha, core components of the IKK signalsome, and IKK catalytic activity are all required for UV signaling. Furthermore, deletion and point mutation analyses reveal that both the amino-terminal IKK-binding and the carboxy-terminal putative zinc finger domains of NEMO (IKK gamma) are critical for UV-induced NF-kappa B activation. Interestingly, the zinc finger domain is also required for NF-kappa B activation by two other slow and weak inducers, camptothecin and etoposide. In contrast, the zinc finger module is largely dispensable for NF-kappa B activation by the rapid and strong inducers LPS and TNF-alpha. Thus, we suggest that the zinc finger domain of NEMO likely represents a point of convergence for signaling pathways initiated by slow and weak NF-kappa B-activating conditions.
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PMID:The zinc finger domain of NEMO is selectively required for NF-kappa B activation by UV radiation and topoisomerase inhibitors. 1213 92

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

It is well established that cytokines can induce the production of chemokines, but the role of chemokines in the regulation of cytokine expression has not been fully investigated. Exposure of rat cardiac-derived endothelial cells (CDEC) to lipopolysaccharide-induced CXC chemokine (LIX), and to a lesser extent to KC and MIP-2, activated NF-kappaB and induced kappaB-driven promoter activity. LIX did not activate Oct-1. LIX-induced interleukin-1beta and tumor necrosis factor-alpha promoter activity, and up-regulated mRNA expression. Increased transcription and mRNA stability both contributed to cytokine expression. LIX-mediated cytokine gene transcription was inhibited by interleukin-10. Transient overexpression of kinase-deficient NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK), and dominant negative IkappaB significantly inhibited LIX-mediated NF-kappaB activation in rat CDEC. Inhibition of G(i) protein-coupled signal transduction, poly(ADP-ribose) polymerase, phosphatidylinositol 3-kinase, and the 26 S proteasome significantly inhibited LIX-mediated NF-kappaB activation and cytokine gene transcription. Blocking CXCR2 attenuated LIX-mediated kappaB activation and kappaB-driven promoter activity in rat CDEC that express both CXCR1 and -2, and abrogated its activation in mouse CDEC that express only CXCR2. These results indicate that LIX activates NF-kappaB and induces kappaB-responsive proinflammatory cytokines via either CXCR1 or CXCR2, and involved phosphatidylinositol 3-kinase, NIK, IKK, and IkappaB. Thus, in addition to attracting and activating neutrophils, the ELR(+) CXC chemokines amplify the inflammatory cascade, stimulating local production of cytokines that have negative inotropic and proapoptotic effects.
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PMID:Chemokine-cytokine cross-talk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway. 1246 47

Cystathionine beta-synthase (CBS) catalyzes the first of two steps in the transsulfuration pathway that converts homocysteine to cysteine, a precursor of glutathione, a major intracellular antioxidant. Tumor necrosis factor-alpha (TNFalpha), which is known to enhance production of reactive oxygen species, increased CBS activity and glutathione levels in HepG2 cells. Western blot analysis revealed that the higher CBS activity correlated with cleavage of the enzyme to a truncated form. This cleavage was suppressed by inhibitors of superoxide production or by transfection with an expression vector for manganese superoxide dismutase. The commonly used proteasome inhibitors, MG132 and lactacystin but not N-acetyl-Leu-Leu-norleucinal, suppressed the TNFalpha-induced response. Targeted proteolysis of CBS was also observed in livers of mice injected with lipopolysaccharide, which is known to induce TNFalpha. Together, these data reveal a novel and previously unknown mechanism of regulation for homocysteine-linked glutathione homeostasis in cells challenged by oxidative stress.
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PMID:Tumor necrosis factor-alpha-induced targeted proteolysis of cystathionine beta-synthase modulates redox homeostasis. 1261 17

MafBx and Murf are two new rat E3 ubiquitin ligases induced in muscle atrophy. Our goal was to investigate whether lipopolysaccharide (LPS) injection, a model of muscle catabolism, is associated with increased expression of MafBx and Murf. LPS (750 microg/100 g body weight) induces MafBx and Murf mRNA (respectively, 23-fold and 33-fold after 12 h; P<0.001). A transient induction of tumor necrosis factor-alpha mRNA (21-fold; P<0.001 at 3 h) and a decrease of insulin like growth factor-I mRNA (50%; P<0.001 at 6 h), two potential regulators of the ubiquitin-proteasome system were also demonstrated. In summary, MafBx and Murf mRNA are up-regulated in response to LPS and might play a role in the muscle proteolysis observed.
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PMID:Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection. 1278 19

The mechanisms involved in the anti-angiogenic actions of the proteasome inhibitors are poorly understood. Here, we report that the gene expression of the VEGF receptor Flt-1 (vascular endothelial growth factor receptor 1) was down-regulated by the reversible proteasome inhibitor MG262 in explant cultures of the developing chicken pecten oculi, a vascular organ consisting of endothelial cells, pericytes, and macrophages. In addition, the inhibitor prevented the induction of Flt-1 by lipopolysaccharide (LPS) in macrophages and down-regulated the expression of Flt-1 after LPS induction. Flt-1 gene expression was also down regulated by MG262 in cultures of human microvascular endothelial cells. Interestingly, a transcript of Flt-1, coding for a soluble form of the receptor (sFlt-1) with anti-angiogenic properties, was not down-regulated in the same extent. Only a small decrease in the expression of VEGF and Ang-2 was detected in the pecten oculi upon inhibition of the proteasome, while no major changes were observed in the expression of other angiogenic molecules, such as KDR or Ang-1. Since recent experiments have demonstrated the importance of anti-Flt-1 therapy in the inhibition of tumor angiogenesis, retinal angiogenesis, arthritis, and atherosclerosis (Luttun et al. [2002]: Nat Med 8:831-840), our observation on down-regulation of Flt-1 in microvascular endothelial cells and macrophages by MG262 supports the postulated role of the proteasome inhibitors as potential candidates for therapeutic modulation of angiogenesis and inflammation.
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PMID:Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262. 1289 12

Growth related oncogene protein-alpha (GRO-alpha) is a member of C-X-C chemokine and plays an important role in inflammatory responses. Expression of GRO gene family is regulated by a number of factors at both transcriptional and posttranscriptional levels. In the present study, we have addressed the possible regulation of GRO-alpha expression by ubiquitin-proteasome system. Cultures of human umbilical vein endothelial cells were treated with a proteasome inhibitor, MG132, and the levels of GRO-alpha mRNA were analyzed by reverse transcription-polymerase chain reaction or northern blotting. Levels of GRO-alpha protein in the cell-conditioned medium were determined by enzyme-linked immunosorbent assay. MG132 alone increased the levels of GRO-alpha mRNA and protein; however, it did not affect the GRO-alpha mRNA induced by lipopolysaccharide (LPS) and inhibited the LPS-induced decrease in IkappaB levels. Other proteasome inhibitors, MG115 and lactacystin, also induced the expression of GRO-alpha mRNA. MG132 induced the phosphorylation of p38 MAPK, MEK and JNK. Pretreatment of the cells with SB203580, an inhibitor of p38 MAPK, suppressed the MG132-induced GRO-alpha expression, but pretreatment of the cells with U0126, PD98059 or SP600125, inhibitors of MEK1/2 or JNK, did not influence the effect of MG132. We conclude that MG132 upregulates GRO-alpha expression in vascular endothelial cells, at least in part, through the activation of p38 MAPK.
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PMID:Effect of MG132, a proteasome inhibitor, on the expression of growth related oncogene protein-alpha in human umbilical vein endothelial cells. 1458 Oct

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

Regulation of intracellular protein stability by the ubiquitin-dependent proteasome system plays a crucial role in cell function. HO-1 (haem oxygenase) is a stress response protein, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homoeostasis. In the present study, we found a novel action of proteasome inhibitors MG132 and MG262 on HO-1 induction, and characterized the underlying mechanisms. MG132 (> or =0.1 microM) treatment resulted in a marked time- and concentration-dependent induction of the steady-state level of HO-1 mRNA in RAW264.7 macrophages, followed by a corresponding increase in HO-1 protein. Actinomycin D and cycloheximide inhibited MG132-responsive HO-1 protein expression, indicating a requirement for transcription and de novo protein synthesis. The involvement of signal pathways in MG132-induced HO-1 gene expression was examined using chemical inhibitors. Antioxidant N -acetylcysteine and SB203580, an antioxidant and inhibitor of p38 MAPK (mitogen-activated protein kinase), abolished MG132-inducible HO-1 expression. Furthermore, MG132 activated the p38 MAPK pathway. The half-life of HO-1 protein was prolonged by MG132, indicating that the upregulation of HO-1 by proteasome inhibitor is partially attributable to the inhibition of protein degradation. MG132 can ablate IkappaBalpha degradation and NF-kappaB (nuclear factor kappaB) activation induced by lipopolysaccharide, similar to the effect of another NF-kappaB inhibitor pyrrolidine dithiocarbamate. We found HO-1 upregulation by MG132 and pyrrolidine dithiocarbamate is unrelated to their inhibition of NF-kappaB, since leptomycin B, another NF-kappaB inhibitor, did not elicit similar induction of HO-1. Taken together, we found a novel effect of proteasome inhibitor on induction of HO-1 expression. This action is ascribed to the activation of the p38 MAPK pathway, but is not dependent on NF-kappaB inhibition.
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PMID:Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition. 1473 Nov 12


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