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)

Some human tumor cells exhibit deficient expression of the peptide transporters TAP1 and TAP2 and of the proteasome subunits low molecular weight protein (LMP)-2 and LMP-7, which could be partially restored by cytokine treatment. Here, we show that IFN-gamma stimulation of human renal cell carcinoma lines increased the MHC class I, transporter associated with antigen processing (TAP), and LMP transcript and protein levels, but TAP and LMP expression are more rapidly induced by IFN-gamma than MHC class I molecules. No correlation between the level of induction of the MHC class I antigen presentation genes and IFN sensitivity/resistance was detected. The IFN-gamma-mediated increase of MHC class I, TAP-1, and LMP-2 expression was independent of de novo protein synthesis. Analysis of the dual TAP-1/LMP-2 promoter activity revealed that TAP-1 and LMP-2 expression are controlled by IFN-gamma at the transcriptional level. Site-specific mutations in the IFN-gamma-responsive element of the TAP-1/LMP-2 promoter blocked induction by IFN-gamma. Thus, the IFN-gamma-mediated coordinated transcriptional up-regulation of TAP-1 and LMP-2 expression occurs through the use of a common regulatory element, which might result in enhanced recognition of renal cell carcinoma cells by the immune system.
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PMID:IFN-gamma-mediated coordinated transcriptional regulation of the human TAP-1 and LMP-2 genes in human renal cell carcinoma. 981 22

The effects of a Ca2(+)-ATPase inhibitor, cyclopiazonic acid (CPA), and two hydroquinone-antioxidants, 2,5-di-(tert-butyl)-1,4-hydroquinone (DTBHQ) and 2,5-di-(tert-amyl)-1,4-hydroquinone (DTAHQ) on the release of IL-4 and MCP-1 from RBL-2H3 cells were investigated. CPA, DTBHQ and DTAHQ, all of which induce intracellular free Ca2+ concentration ([Ca2+]i) increase, induced IL-4 and MCP-1 release in a dose-dependent manner. The release of TNF-alpha required both a Ca2(+)-ATPase inhibitor and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the Ca2(+)-ATPase inhibitors induced IL-4 and MCP-1 production without TPA. The release of IL-4 and MCP-1 reached a maximum at 9 and 6 h, respectively. IL-4 and MCP-I release was inhibited by treatment with the immunosuppressant FK-506 and actinomycin D. Therefore, in our system IL-4 and MCP-1 release involves Ca2(+)-dependent and FK-506-sensitive signaling pathways. This is the first report about Th-2 type cytokine and chemokine production in RBL-2H3 cells.
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PMID:Ca2+-ATPase inhibitor induces IL-4 and MCP-1 production in RBL-2H3 cells. 986 97

The cytokine tumor necrosis factor alpha (TNF-alpha) induces expression of inflammatory gene networks by activating cytoplasmic to nuclear translocation of the nuclear factor-kappaB (NF-kappaB) transcription factor. NF-kappaB activation results from sequential phosphorylation and hydrolysis of the cytoplasmic inhibitor, IkappaBalpha, through the 26 S proteasome. Here, we show a parallel proteasome-independent pathway for cytokine-inducible IkappaBalpha proteolysis in HepG2 liver cells mediated by cytosolic calcium-activated neutral protease (calpains). Pretreatment with either calpain- or proteasome-selective inhibitors partially blocks up to 50% of TNF-alpha-inducible IkappaBalpha proteolysis; pretreatment with both is required to completely block IkappaBalpha proteolysis. Similarly, in transient cotransfection assays, expression of the specific inhibitor, calpastatin, partially blocks TNF-alpha-inducible NF-kappaB-dependent promoter activity and IkappaBalpha proteolysis. In TNF-alpha-stimulated cells, a rapid (within 1 min), 2.2-fold increase in cytosolic calpain proteolytic activity is measured using a specific fluorescent assay. Inducible calpain proteolytic activity occurs coincidentally with the particulate-to-cytosol redistribution of the catalytic m-calpain subunit into the IkappaBalpha compartment. Addition of catalytically active m-calpain into broken cells was sufficient to produce ligand-independent IkappaBalpha proteolysis and NF-kappaB translocation. As additional evidence for calpain-dependent IkappaBalpha proteolysis and NF-kappaB activation, we demonstrate that this process occurs in a cell line (ts20b) deficient in the ubiquitin-proteasome pathway. Following inactivation of the temperature-sensitive ubiquitin-activating enzyme, IkappaBalpha proteolysis occurs in a manner sensitive only to calpain inhibitors. Our results demonstrate that TNF-alpha activates cytosolic calpains, a parallel pathway that degrades IkappaBalpha and activates NF-kappaB activation independently of the ubiquitin-proteasome pathway.
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PMID:Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation. 987 17

NF-kappaB is an important transcription factor complex that appears to play a fundamental role in regulating acute inflammation through activation of the cytokine cascade and production of other pro-inflammatory mediators. There is increasing evidence that NF-kappaB is important in the pathobiology of disease states such as SIRS, MODS and ARDS; therefore, therapeutic interventions aimed at limiting NF-kappaB activation and down-regulating production of inflammatory mediators could prove to be beneficial in decreasing host-derived tissue injury and organ dysfunction. Specific interventions that hold promise for suppressing NF-kappaB activation include the use of antioxidants, inhibition of NIK and the IKK signalsome, treatment with proteasome inhibitors, induction of endotoxin tolerance and, possibly the use of corticosteroids in selected patients.
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PMID:Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. 987 73

In-situ hybridization with labeled oligonucleotide probes was applied to explore cytokine and chemokine mRNA expression in sections of striated muscle, the target organ in experimental autoimmune myasthenia gravis (EAMG), induced in Lewis rats by immunization with acetylcholine receptor (AChR) and complete Freund's adjuvant (CFA). A transient burst of TNF-alpha, IL-1beta and IL-6 mRNA expressing cells was detected during the early phase of EAMG. This cytokine pattern was related to muscular infiltration of macrophages. Levels of IL-4, IL-10, IFN-gamma, cytolysin and TGF-beta mRNA expressing cells were low and observed mainly during the early phase of EAMG. C-C chemokine RANTES, MCP, MIP-1alpha and MIP-2 mRNA expressing cells were not detected over the course of EAMG. The low and transient expression of cytokines in EAMG muscle tissues suggests that the immune effector responses are unlikely operated by infiltrating cells in muscle. Muscular infiltrations in EAMG are unlikely due to local accumulation of C-C chemokines.
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PMID:Cytokine and chemokine mRNA expressing cells in muscle tissues of experimental autoimmune myasthenia gravis. 987 80

Nuclear factor kappa B (NF-kappaB) is an important transcription factor for the genes of many pro-inflammatory proteins and is strongly activated by the cytokines interleukin-1 and tumor necrosis factor (TNF)alpha under various pathological conditions. In nonstimulated cells, NF-kappaB is present in the cytosol where it is complexed to its inhibitor IkappaB. Activation of NF-kappaB depends on the signal-induced phosphorylation of IkappaB by specific IkappaB kinases which initiates the inhibitor's conjugation to ubiquitin and subsequent degradation by the proteasome. We used both TNF-stimulated and okadaic-acid-stimulated HeLa cells to purify three biochemically distinct kinase activities targeting one or both of the two serines (S32 and S36) in IkappaBalpha which induce its rapid degradation upon cytokine stimulation. All three activities correspond to known IkappaB kinases: the mitogen-activated 90 kDa ribosomal S6 kinase (p90rsk1), the IkappaB kinase 1/2 complex (IKK1/2) and casein kinase II (CK II). However, we found that only one of the activities, namely the IKK1/2 complex, exists as a pre-assembled kinase-substrate complex in which the IKKs are directly or indirectly associated with several NF-kappaB-related and IkappaB-related proteins: RelA, RelB, cRel, p100, p105, Ikappa Balpha, Ikappa Bbeta and Ikappa Bepsilon. The existence of stable kinase-substrate complexes, the presence of all three known IkappaB isoforms in these complexes and our observation that the IKK complex is capable of phosphorylating Ikappa Balpha-, Ikappa Bbeta- and Ikappa Bepsilon-derived peptides at the respective degradation-relevant serines suggests that the IKK complex exerts a broad regulatory role for the activation of different NF-kappaB species. In contrast to previous studies, which locate CK II phosphorylation sites exclusively to the C-terminal PEST sequence of Ikappa Balpha, we observed efficient phosphorylation of serine 32 in Ikappa Balpha by the purified endogenous CK II complex. Therefore, both p90rsk1 and CK II have the same preference for phosphorylating only one of the two serines which are relevant for inducible degradation.
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PMID:All three IkappaB isoforms and most Rel family members are stably associated with the IkappaB kinase 1/2 complex. 991

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet beta-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha, whereas both subsets produced macrophage inflammatory protein-1beta. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing beta-cells are protected or destroyed.
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PMID:Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. 1007 90

The basal transcription of the CXC chemokine, melanocyte growth stimulatory activity (MGSA)/growth-regulated protein (GRO)-alpha, is up-regulated in Hs294T melanoma cells compared with the normal retinal pigment epithelial (RPE) cells. Previous studies characterized a cytokine-inducible, functional nuclear factor (NF)-kappaB consensus element in the immediate 5' regulatory region of the MGSA/GRO-alpha gene at -78 bp. Although the cytokine-inducible mechanisms for transcription of this gene are fairly well delineated, the mechanisms involved in its basal up-regulation of transcription in Hs294T melanoma cells are poorly understood. Recently, we demonstrated an increased rate of IkappaB-alpha degradation in Hs294T cells, which leads to an increased nuclear localization of NF-kappaB (R. L. Shattuck-Brandt and A. Richmond. Cancer Res., 57: 3032-3039, 1997). Here we demonstrate that Hs294T melanoma cells have elevated basal IkappaB kinase (IKK) activity relative to RPE cells, causing an increased constitutive IkappaB-alpha phosphorylation and degradation. We also show here that the resultant elevated nuclear NF-kappaB (p50/p65) in these cells is responsible for the increased basal transcription of MGSA/GRO-alpha. Pretreatment of Hs294T or RPE cells with proteasome inhibitors MG115 or MG132 captures the slower migrating, constitutively phosphorylated form of IkappaB-alpha in Hs294T melanoma cells, but not in RPE cells. In addition, a phospho-specific antibody that specifically recognizes the inhibitory form of IkappaB that is phosphorylated at Ser-32 reacted with IkappaB-alpha in Hs294T cell, but not in unstimulated RPE cells. Although the basal level of protein expression of IKK-alpha or IKK-beta are the same in both Hs294T and RPE cells, immunoprecipitation with IKK-alpha antibody combined with activity assay reveal a constitutively active IKK complex in Hs294T melanoma cells. Cotransfection of a 350-bp MGSA/GRO-alpha promoter-luciferase reporter construct with either the dominant negative IKK-alpha or the repressors of NF-kappaB, the IkappaB-alpha wild type or mutants lacking the inducible phosphorylation sites, demonstrates that the increased basal MGSA/GRO-alpha transcription in the Hs294T cells is due to the enhanced nuclear activation of NF-kappaB.
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PMID:Elevated constitutive IkappaB kinase activity and IkappaB-alpha phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO-alpha transcription. 1009 73

Cytokine and proto-oncogene messenger RNAs (mRNAs) are rapidly degraded through AU-rich elements in the 3' untranslated region. Rapid decay involves AU-rich binding protein AUF1, which complexes with heat shock proteins hsc70-hsp70, translation initiation factor eIF4G, and poly(A) binding protein. AU-rich mRNA decay is associated with displacement of eIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of hsp70 by heat shock, down-regulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 all result in hsp70 sequestration of AUF1 in the perinucleus-nucleus, and all three processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway.
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PMID:Control of mRNA decay by heat shock-ubiquitin-proteasome pathway. 1020 60

The generation of antigenic peptides bound and presented to the immune system by MHC class I molecules predominantly depends on the function of the proteasome system. Stimulation of cells with interferon gamma induces the incorporation of three active site bearing beta-subunits into the 20S proteasome and the formation of the PA28 proteasome modulator complex. PA28 alters the cleavage properties of the proteasome and enhances MHC class I antigen presentation. Thus, by cytokine induced change of the proteasome system cells may alter the proteolytic properties of the 20S proteasome and may render an organism more flexible in its peptide generation capacity.
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PMID:The role of the proteasome system and the proteasome activator PA28 complex in the cellular immune response. 1022 31


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