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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NF-kappaB1 p105 functions both as a precursor of NF-kappaB1 p50 and as a cytoplasmic inhibitor of NF-kappaB. Following the stimulation of cells with tumor necrosis factor alpha (TNF-alpha), the IkappaB kinase (IKK) complex rapidly phosphorylates NF-kappaB1 p105 on serine 927 in the PEST region. This phosphorylation is essential for TNF-alpha to trigger p105 degradation, which releases the associated Rel/NF-kappaB subunits to translocate into the nucleus and regulate target gene transcription. Serine 927 resides in a conserved motif (Asp-Ser(927)-Gly-Val-Glu-Thr-Ser(932)) homologous to the IKK target sequence in IkappaBalpha. In this study, TNF-alpha-induced p105 proteolysis was revealed to additionally require the phosphorylation of serine 932. Experiments with IKK1(-/-) and IKK2(-/-) double knockout embryonic fibroblasts demonstrate that the IKK complex is essential for TNF-alpha to stimulate phosphorylation on p105 serines 927 and 932. Furthermore, purified IKK1 and IKK2 can each phosphorylate a glutathione S-transferase-p105(758-967) fusion protein on both regulatory serines in vitro. IKK-mediated p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of an SCF-type ubiquitin E3 ligase, and depletion of betaTrCP by RNA interference blocks TNF-alpha-induced p105 ubiquitination and proteolysis. Phosphopeptide competition experiments indicate that betaTrCP binds p105 more effectively when both serines 927 and 932 are phosphorylated. Interestingly, however, betaTrCP affinity for the IKK-phosphorylated sequence on p105 is substantially lower than that on IkappaBalpha. Thus, it appears that reduced p105 recruitment of betaTrCP and subsequent ubiquitination may contribute to delayed p105 proteolysis after TNF-alpha stimulation relative to that for IkappaBalpha.
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PMID:betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. 1248 91

Caffeic acid phenethyl ester (CAPE), a natural honeybee product exhibits a spectrum of biological activities including anti-microbial, anti-inflammatory, antioxidant and anti-tumoral actions. CAPE is also chemopreventive against intestinal, colon and skin cancer. Our aim was to extend the study of its chemoprotective features to the promotion of hepatocarcinogenesis. Male Wistar rats were subjected to a protocol under a modified promotion regimen of the resistant hepatocyte model. The altered hepatic foci (AHF) were quantitatively analyzed by histochemistry and image processing. When given during promotion, CAPE (20 mg/kg) decreased the expression of number and area gamma-glutamyl transpeptidase (GGT) positive AHF by 91% and 97%, respectively. When GGT expression was analyzed by RT-PCR, CAPE drastically decreased and prevented expression of almost all GGT transcripts at this stage of the carcinogenic process. Glutathione S-transferase placental form (GST-P), another protein marker for preneoplastic lesions was measured by Western blot and a decrease of 82% was observed. Additionally, we evaluated the effect of CAPE on the expression of nuclear factor NF-kappaB and found an 85% decrease in nuclear localization of the p65 subunit of NF-kappaB; however, their repressor, IkappaBalpha was not modified. Our results showed that CAPE given during promotion in hepatocarcinogenesis protects against induction of GGT-positive AHF, GST-P protein, GGT mRNA expression and translocation of p65. This phenomenon was independent of IkappaBalpha degradation.
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PMID:Chemoprotective effect of caffeic acid phenethyl ester on promotion in a medium-term rat hepatocarcinogenesis assay. 1469 11

Infection with lesion-derived Leishmania mexicana amastigotes inhibited LPS-induced IL-12 production by mouse bone marrow-derived macrophages. This effect was associated with expression of cysteine peptidase B (CPB) because amastigotes of CPB deletion mutants had limited ability to inhibit IL-12 production, whereas preincubation of cells with a CPB inhibitor, cathepsin inhibitor IV, was able to suppress the effect of wild-type amastigotes. Infection with wild-type amastigotes resulted in a time-dependent proteolytic degradation of IkappaBalpha and IkappaBbeta and the related protein NF-kappaB. This effect did not occur with amastigotes of CPB deletion mutants or wild-type promastigotes, which do not express detectable CPB. NF-kappaB DNA binding was also inhibited by amastigote infection, although nuclear translocation of cleaved fragments of p65 NF-kappaB was still observed. Cysteine peptidase inhibitors prevented IkappaBalpha, IkappaBbeta, and NF-kappaB degradation induced by amastigotes, and recombinant CPB2.8, an amastigote-specific isoenzyme of CPB, was shown to degrade GST-IkappaBalpha in vitro. LPS-mediated IkappaBalpha and IkappaBbeta degradation was not affected by these inhibitors, confirming that the site of degradation of IkappaBalpha, IkappaBbeta, and NF-kappaB by the amastigotes was not receptor-driven, proteosomal-mediated cleavage. Infection of bone marrow macrophages with amastigotes resulted in cleavage of JNK and ERK, but not p38 MAPK, whereas preincubation with a cysteine peptidase inhibitor prevented degradation of these proteins, but did not result in enhanced protein kinase activation. Collectively, our results suggest that the amastigote-specific cysteine peptidases of L. mexicana are central to the ability of the parasite to modulate signaling via NF-kappaB and consequently inhibit IL-12 production.
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PMID:Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway. 1532 92

Gastric epithelial cells were incubated with a panel of clinical isolates of Helicobacter pylori, including nonulcer dyspepsia with gastritis (HS, n = 20), gastric ulcer (HU, n = 20), duodenal ulcer (HD, n = 21), and gastric cancer (HC, n = 20). HC strains induced a higher cyclooxygenase-2 (COX-2) expression than those from HS, HD, and HU. The bacterial virulence factors and the host cellular pathways were investigated. Virulence genes of iceA, vacA, babA2, cagA 3' repeat region, and hrgA failed to show any association with the disease status and COX-2 expression. Methylation-specific polymerase chain reaction revealed HC strains not affecting the methylation status of COX-2 promoter. Nuclear factor (NF)-kappaB, NF-interleukin 6, and cAMP response element were found to be involved in COX-2 induction. We explored a novel NF-kappaB activation pathway. The mutants of TLR2 and TLR9, but not TLR4, inhibited H. pylori-induced COX-2 promoter activity, and neutralizing antibodies for TLR2 and TLR9 abolished H. pylori-induced COX-2 expression. Phosphatidylinositol-specific phospholipase C (PI-PLC), protein kinase C (PKC), and Src inhibitors inhibited COX-2 induction. The dominant-negative mutants of NIK and various IkappaB kinase complexes, including IKKbeta (Y188F), IKKbeta (Y199F), and IKKbeta (FF), inhibited the COX-2 promoter activity. Phosphorylation of GST-IKKbeta (132-206) at Tyr188 and Tyr199 by c-Src was found after H. pylori infection. In summary, H. pylori induces COX-2 expression via activations of NF-kappaB, NF-interleukin 6, the cAMP response element. In NF-kappaB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCgamma/PKCalpha/c-Src/IKKalpha/beta and the cascade of NIK/IKKalpha/beta, resulting in the IkappaBalpha degradation and the expression of COX-2 gene. The COX-2 overexpression may contribute to the carcinogenesis in patients colonized with these strains.
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PMID:Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. 1545 96

Expression of proinflammatory cytokines by monocytes is tightly regulated by transcription factors such as NF-kappaB. In this study, we show that, in LPS-stimulated human peripheral monocytes, the pentacyclic triterpenes acetyl-alpha-boswellic acid (AalphaBA) and acetyl-11-keto-beta-boswellic acid (AKbetaBA) down-regulate the TNF-alpha expression. AalphaBA and AKbetaBA inhibited NF-kappaB signaling both in LPS-stimulated monocytes as detected by EMSA, as well as in a NF-kappaB-dependent luciferase gene reporter assay. By contrast, the luciferase expression driven by the IFN-stimulated response element was unaffected, implying specificity of the inhibitory effect observed. Both AalphaBA and AKbetaBA did not affect binding of recombinant p50/p65 and p50/c-Rel dimers to DNA binding sites as analyzed by surface plasmon resonance. Instead, both pentacyclic triterpenes inhibited the LPS-induced degradation of IkappaBalpha, as well as phosphorylation of p65 at Ser(536) and its nuclear translocation. AalphaBA and AKbetaBA inhibited specifically the phosphorylation of recombinant IkappaBalpha and p65 by IkappaBalpha kinases (IKKs) immunoprecipitated from LPS-stimulated monocytes. In line with this, AalphaBA and AKbetaBA also bound to and inhibited the activities of active human recombinant GST-IKKalpha and His-IKKbeta. The LPS-triggered induction of TNF-alpha in monocytes is dependent on IKK activity, as confirmed by IKK-specific antisense oligodeoxynucleotides. Thus, via their direct inhibitory effects on IKK, AalphaBA and AKbetaBA convey inhibition of NF-kappaB and subsequent down-regulation of TNF-alpha expression in activated human monocytes. These findings provide a molecular basis for the anti-inflammatory properties ascribed to AalphaBA- and AKbetaBA-containing drugs and suggest acetyl-boswellic acids as tools for the development of novel therapeutic interventions.
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PMID:Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases. 1561 Dec 76

Toxoplasma gondii activates the NF-kappaB pathway in the infected host cell resulting in upregulation of pro-survival genes and prevention of apoptosis. Manipulation of the NF-kappaB cascade by T. gondii correlates with the localization of phosphorylated IkappaB at the parasitophorous vacuole membrane (PVM). This suggests a parasite-mediated event, involving the recruitment and activation of the host IkappaB kinase (IKK) complex, as has been observed with the related protozoan Theileria parva. In contrast to Theileria, confocal microscopy studies showed no apparent hijacking of IKKalpha, IKKbeta, or their activated phosphorylated forms at the T. gondii PVM. Remarkably, phosphorylation of IkappaBalpha at Ser 32/36 was observed at the PVM of T. gondii-infected IKKalpha-/-, IKKbeta-/- and IKKalpha/beta double-knockout (IKKalpha/beta-/-) fibroblasts, suggesting the involvement of a parasite kinase activity independent of host IKK. The presence of a putative T. gondii IkappaB kinase was examined by in vitro kinase assays using GST-IkappaBalpha constructs and protein extracts from both extracellular parasites and PVM fractions. Interestingly, an activity capable of phosphorylating IkappaBalpha at the critical Ser 32/36 sites was identified in parasite extracts, a property restricted to the IKK signalosome. Taken together, our data support the role for a T. gondii kinase involved in phosphorylation of host cell IkappaBalpha and suggest an unusual mechanism utilized by an intracellular pathogen capable of manipulating the NF-kappaB pathway.
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PMID:Detection of a novel parasite kinase activity at the Toxoplasma gondii parasitophorous vacuole membrane capable of phosphorylating host IkappaBalpha. 1567 38

Serum and glucocorticoid inducible protein kinase (SGK) plays a crucial role in promoting cell survival, but the mechanisms for this response are not clear. We show that SGK is involved in the regulation of apoptosis in breast cancer cells by modulating the transcriptional activity of nuclear transcription factor kappaB (NF-kappaB). High levels of SGK expression were observed in human breast cancer samples. When SGK was reduced the apoptotic rate increased, and increased SGK activity prevents serum withdrawal-induced apoptosis. SGK-induced cell survival was abolished by a dominant-negative form of IkappaB kinase beta (IKKbeta, K44A) or a null mutation of IKKbeta in mouse embryonic fibroblast cells indicating involvement of the NF-kappaB pathway. Serum-induced SGK or increased expression of SGK activated NF-kappaB transcriptional activity, whereas small interference RNA to SGK blocked NF-kappaB activity. Coexpression of SGK and IKKbeta significantly increased the activation of NF-kappaB (versus expression of IKKbeta alone). Expression of dominant-negative IKKbeta K44A, IkappaBalpha AA, and kinase-dead SGK (127KM) blocked the ability of SGK to stimulate NF-kappaB activity, suggesting that IKKbeta is a target of SGK. We also show that SGK enhances the ability of IKKbeta to phosphorylate endogenous IkappaBalpha in cells or recombinant glutathione S-transferase-IkappaBalpha in vitro and increases IkappaBalpha degradation; SGK physically associates with and activates IKKbeta in MDA231 cells via phosphorylation of Ser(181) in IKKbeta. Taken together, we conclude that SGK acts as an oncogene in breast cancer cells through activation of the IKK-NF-kappaB pathway, thereby preventing apoptosis. Blocking SGK expression/activity represents a potential therapeutic approach for breast cancer treatment.
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PMID:Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase. 1569 87

The transcription factor nuclear factor-kappa B (NF-kappaB) subunit p65 is phosphorylated by IkappaB kinase (IKK) at S536 in transactivation domain (TAD) 1. In this study, we investigate the presence of IKK sites in TAD2 of p65. Recombinant IKKbeta, but not IKKalpha, phosphorylated a GST-p65 substrate in which TAD1 was deleted. Mutational analysis revealed S468 as the only IKK site in TAD2. S468 phosphorylation occurred rapidly after TNF-alpha and IL-1beta in T cell, B cell, cervix carcinoma, hepatoma, breast cancer, and astrocytoma lines and in primary hepatic stellate cells as well as peripheral blood mononuclear cells. S468-phosphorylated p65 coimmunoprecipitated with IkappaBalpha, indicating that p65 is phosphorylated while bound to IkappaBalpha. Dominant negative IKKbeta or pharmacological IKK inhibition blocked S468 phosphorylation after TNF-alpha or IL-1beta, whereas dominant negative IKKalpha or inhibitors of MEK, p38, JNK, PI-3 kinase, or GSK-3 had no effect. p65S468A-reconstituted p65-/- mouse embryonic fibroblasts (MEFs) showed a small, but significant, elevation of NF-kappaB-driven luciferase activity and RANTES mRNA levels after TNF-alpha and IL-1beta in comparison to wtp65-reconstituted MEFs. p65 nuclear translocation was not altered in p65S468A-expressing MEFs. In conclusion, our results indicate that 1) IKKbeta phosphorylates multiple p65 sites, 2) IKKbeta phosphorylates p65 in an IkappaB-p65 complex, and 3) S468 phosphorylation slightly reduces TNF-alpha- and IL-1beta-induced NF-kappaB activation.
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PMID:IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. 1604 71

Although vitamin B6 has been supposed to have anti-inflammatory effects, the molecular mechanism is not fully understood. To explore the mechanism of anti-inflammatory effects of vitamin B6, we have examined the effect of vitamin B6 on lipopolysaccharide (LPS)-stimulated inflammatory response in RAW 264.7 macrophages. This study demonstrated that vitamin B6 (pyridoxal) pretreatment of RAW cells inhibited LPS-induced expression of iNOS and COX-2 at the mRNA and protein levels. Vitamin B6 inhibited LPS-induced nuclear translocation of the NF-kappaB, the proinflammatory transcription factor, with reduction of the extent of LPS-induced IkappaBalpha degradation in RAW cells. Although vitamin B6 did not affect cellular proteasome activity, in vitro phosphorylation analysis with glutathione S-transferase-fused IkappaBalpha has shown that vitamin B6 suppressed LPS-induced IkappaB kinase activation. Furthermore, we demonstrated that elevating dietary vitamin B6 suppressed NO production in vivo in response to LPS administration. These observations suggest that the anti-inflammatory effect of vitamin B6 is mediated by suppression of NF-kappaB activation.
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PMID:Vitamin B6 suppresses NF-kappaB activation in LPS-stimulated mouse macrophages. 1627 88

Leukotriene (LT) C4 (LTC4) synthesis enzymes including LTC4 synthase (LTC4S), microsomal glutathione S-transferase (MGST) 2 and MGST3 can all conjugate LTA4 and reduced glutathione (GSH) to form LTC4, which is related to hepatic ischemia/reperfusion (I/R) injury. The relationship between nitric oxide (NO) and cysteinyl LTs has been shown in previous studies. However, the mechanisms of NO action on gene expression of LTC4 synthesis enzymes are still largely unclear during hepatic I/R. Adult male Sprague-Dawley rats were divided into 5 groups: a sham group (control), an I/R group, and sodium nitroprusside (SNP, 2.5, 5 and 10 microg/kg/min)+I/R groups. Livers were subjected to 60 min of partial hepatic ischemia followed by 5 h of reperfusion, saline or SNP (2.5, 5 and 10 microg/kg/min) administered intravenously. The mRNA levels of LTC4 synthesis enzymes, inducible NO synthase (iNOS) and endothelial No synthase (eNOS) in rat liver tissue were examined by RT-PCR; the protein expressions of NF-kappaB p65, p50 and IkappaBalpha in liver cell lysates and nuclear extracts were detected by Western blot analysis, and serum NO2. levels were also evaluated. Serum NO2. levels, the protein expressions of NF-kappaB p65 and p50 in the nucleus extract, and hepatic mRNA expressions of LTC4S and iNOS were decreased while hepatic mRNA of eNOS was increased in the SNP (5 and 10 microg/kg/min)+I/R groups when compared with those in the I/R group. SNP (2.5 microg/kg/min) promoted the mRNA expressions of both MGST2 and MGST3, whereas SNP (10 microg/kg/min) increased MGST2 mRNA but decreased MGST3 mRNA compared to those in I/R group. Compared with control, the mRNA expression of MGST2 and MGST3 were elevated in SNP (2.5 microg/kg/min)+I/R group, MGST3 mRNA was significantly declined in the SNP (5 and 10 microg/kg/min)+I/R groups. Immunohistochemistry staining revealed that I/R liver exhibited strong cytoplasmic and nuclear staining for NF-kappaB p65, but the livers of the SNP (2.5 microg/kg/min)+I/R group presented slight cytoplasmic and nuclear staining. But IkappaBalpha protein in all groups remains unchanged. It was concluded that SNP downregulated LTC4S mRNA expression by inhibiting NF-kappaB activation independent of IkappaBalpha, but appeared to have a dual influence on the mRNA expressions of MGST2 and MGST3 by other signaling pathways during hepatic I/R injury.
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PMID:Sodium nitroprusside regulates mRNA expressions of LTC4 synthesis enzymes in hepatic ischemia/reperfusion injury rats via NF-kappaB signaling pathway. 1749 35


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