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)

Cancer chemopreventive agents transcriptionally induce glutathione S-transferase (GST), which can protect cells from chemical-induced carcinogenesis. Activation of either NF-E2-related factor-2 (Nrf2) or the CCAAT/enhancer binding protein-beta (C/EBPbeta) contributes to GST induction. Peroxisome proliferator-activated receptor-gamma (PPARgamma) and the retinoic acid X receptor (RXR) play roles in regulating cell differentiation and chemoprevention. This study examined GSTA2 gene induction by the PPARgamma activator and 9-cis-retinoic acid (RA), a RXR ligand, and investigated the molecular basis of PPAR-RXR-mediated GSTA2 induction in the H4IIE hepatocytes. Either 15-deoxy-delta (12, 14)-prostaglandin J(2) (PGJ(2)) or RA induced GSTA2 with Nrf2 and C/EBPbeta activation. When compared with PGJ(2) or RA alone, PGJ(2) + RA enhanced GSTA2 induction, with increases in Nrf2 and C/EBPbeta activation. PGJ(2) + RA increased the luciferase reporter gene activity in the cells transfected with the -1.65-kb flanking region of the GSTA2 gene. Thiazolidinedione PPARgamma agonists, troglitazone, rosiglitazone, and pioglitazone, in combination with RA, potentiated GSTA2 induction, confirming that the activation of the PPARgamma and RXR heterodimer contributed to GSTA2 expression. Deletion of the antioxidant response element- or C/EBP-binding sites or the overexpression of dominant-negative mutant of C/EBP abolished the reporter gene expression. PGJ2 + RA increased the binding of the PPARgamma - RXR heterodimer to the putative PPAR-response elements (PPREs) in the GSTA2 promoter. Specific mutations of these multiple PPRE sites resulted in the complete loss of its responsiveness to PGJ2 + RA, which suggests that these binding sites function as a PPRE-responsive enhancer module (PPREM). Transactivation of PPREM by the PPARgamma - RXR heterodimer was verified by the effective GSTA2 induction in the cells treated with PGJ2 + RA after transfecting them with the plasmids encoding PPARgamma1 and RXRalpha. In conclusion, the PPARgamma - RXR heterodimer promotes GSTA2 induction by activating PPREM in the GSTA2 gene, as well as inducing Nrf2 and C/EBPbeta activation.
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PMID:Transactivation of the PPAR-responsive enhancer module in chemopreventive glutathione S-transferase gene by the peroxisome proliferator-activated receptor-gamma and retinoid X receptor heterodimer. 1515 Jan 31

The level of cellular ceramide, an apoptotic rheostat, is increased by sphingomyelinase or de novo synthesis. The expression of the glutathione S-transferase (GST) gene, whose induction accounts for cell viability, is regulated by activation of CCAAT/enhancer binding protein-beta (C/EBPbeta) and NF-E2-related factor-2 (Nrf2). Hepatic nuclear factor-1 (HNF1) is a transcription factor necessary for cell survival. This study investigated the role of HNF1 in GSTA2 gene transactivation, the ubiquitin proteasomal degradation of HNF1, and the inhibition of activating HNF1 by ceramide for GSTA2 repression. C2-ceramide (C2), a cell-permeable analog, repressed the GSTA2 expression in H4IIE cells, whereas dihydro-C2, an inactive analog, had no effect. Immunoblot, immunocytochemical, and gel shift analyses revealed that C2 decreased the level of nuclear HNF1 and protein binding to the HNF response element (HRE). Deletion of the HRE or the GSTA2 gene promoter region containing the HRE reduced luciferase reporter expression. Immunoprecipitation and immunoblot analyses showed that C2 decreased the level of ubiquitinated HNF1, which was reversed by treatment with MG132, a proteasome inhibitor. C2 suppressed GSTA2 induction by oltipraz via inhibition of inducible HNF1 DNA binding. The functional role of HRE for C2 repression of GSTA2 gene transactivation by oltipraz was verified by both the luciferase reporter gene expression and the transfection experiment with DeltaHNF-pGL-1651 lacking the HRE. C2 similarly repressed the induction of GSTA2 promoter-luciferase by tert-butylhydroquinone via HNF1 suppression, suggesting that constitutive HNF1 activation is required for GSTA2 induction. C2 also inhibited GSTA3/5 expression. In conclusion, the HRE in the GSTA2 promoter region is functionally active for the constitutive and inducible gene expression, and ceramide inhibits GST gene transactivation through decrease in nuclear HNF1, which is degraded by the ubiquitin proteasome system.
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PMID:Ceramide negatively regulates glutathione S-transferase gene transactivation via repression of hepatic nuclear factor-1 that is degraded by the ubiquitin proteasome system. 1515 40

Ceramide is a sphingolipid that acts as a second messenger in signaling systems. Sphingomyelinase generates ceramide in response to cytotoxic stimuli. CCAAT/enhancer binding protein-beta (C/EBPbeta) and NF-E2-related factor-2 (Nrf2) are both involved in the regulation of the genes encoding phase II detoxification enzymes including glutathione S-transferase (GST). In the present study, we examined the effects of ceramide on C/EBPbeta or Nrf2 activation and on the inducible GSTA2 gene transactivation. C2-ceramide (C2), a cell-permeable analog, inhibited GSTA2 induction by oltipraz or tert-butylhydroquinone (t-BHQ) in H4IIE cells, whereas dihydro-C2-ceramide (dihydro-C2), an inactive analog, had no effect. Immunoblot analysis revealed that C2 prevented increase in the level of nuclear C/EBPbeta by oltipraz, whereas the level of C/EBPbeta in total cell lysates was not changed. Increase in nuclear Nrf2 by t-BHQ was also prevented by C2 treatment. Decreases in nuclear C/EBPbeta and Nrf2 by C2 were reversed by treatment of cells with N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), a proteasome inhibitor, verifying the previous observations that the transcription factors were degraded by the proteasome system. In another study, we found that ceramide decreased nuclear hepatic nuclear factor-1 (HNF1), whose binding to the HNF1-response element in the GSTA2 gene was responsible for the constitutive and inducible gene expression. To define the role of C/EBPbeta or Nrf2 repression in GST expression under the condition excluding the negative regulation by C2-mediated HNF1 suppression, luciferase activity was determined in the cells transfected with DeltaHNF-pGL-1651 plasmid lacking the HNF1-response element. In the cells transfected with DeltaHNF-pGL-1651, C2 decreased the luciferase induction by oltipraz or t-BHQ. Thus, ceramide inhibits C/EBPbeta or Nrf2 activation, which contributes to repression of GSTA2 gene transactivation.
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PMID:Ceramide, an apoptotic rheostat, inhibits CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 activation: the role in glutathione S-transferase A2 gene repression. 1531 26

The protective adaptive response to electrophiles and reactive oxygen species is mediated by the induction of phase II detoxifying genes including glutathione S-transferases (GSTs). NF-E2-related factor-2 (Nrf2) phosphorylation by protein kinase C (PKC) is a critical event for its nuclear translocation in response to oxidative stress. Previously, we have shown that peroxynitrite plays a role in activation of Nrf2 and Nrf2 binding to the antioxidant response element (ARE) via the pathway of phosphatidylinositol 3-kinase (Pl3-kinase) and that nitric oxide synthase in hepatocytes is required for GSTA2 induction. In view of the importance of PKC and Pl3-kinase in Nrf2-mediated GST induction, we investigated the role of these kinases in peroxynitrite formation for GSTA2 induction by oxidative stress and determined the relationship between PKC and Pl3-kinase. Although PKC activation by phorbol 12-myristate-13-acetate (PMA) did not increase the extents of constitutive and inducible GSTA2 expression, either PKC depletion by PMA or PKC inhibition by staurosporine significantly inhibited GSTA2 induction by tert-butylhydroquinone (t-BHQ) a prooxidant chemical. Therefore, the basal PKC activity is requisite for GSTA2 induction. 3-Morpholinosydnonimine (SIN-1), which decomposes and yields peroxynitrite, induced GSTA2, which was not inhibited by PKC depletion, but slightly enhanced by PKC activation, suggesting that PKC promotes peroxynitrite formation for Nrf2-mediated GSTA2 induction. Treatment of cells with S-nitroso-N-acetyl-penicillamine (SNAP), an exogenous NO donor, in combination with t-BHQ may produce peroxynitrite. GSTA2 induction by SNAP + t-BHQ was not decreased by PKC depletion, but rather enhanced by PKC activation, showing that the activity of PKC might be required for peroxynitrite formation. LY294002 a Pl3-kinase inhibitor blocked GSTA2 induction by t-BHQ, which was reversed by PMA-induced PKC activation. These results provide evidence that PKC may play a role in formation of peroxynitrite that activates Nrf2 for GSTA2 induction and that PKC may serve an activator for GSTA2 induction downstream of Pl3-kinase.
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PMID:PKC downstream of Pl3-kinase regulates peroxynitrite formation for Nrf2-mediated GSTA2 induction. 1535 4

To elucidate drug deposition and metabolism in cultured marine fishes, in a previous study we isolated and purified the GSTs (glutathione S-transferases) from the hepatopancreas of the red sea bream Pagrus major that contained 25 and 28 kDa GST subunits. The 25 kDa GST subunits encoded by two genes (GSTA1 and GSTA2) have been identified as Alpha-class GSTs. In the present study, we performed the molecular cloning and characterization of the GSTR1 gene encoding the 28 kDa GST subunit from the Pa. major hepatopancreas. The nucleotide sequence of GSTR1 was composed of an ORF (open reading frame) of 675 bp encoding a protein of 225 residues with a predicted molecular mass of 25.925 Da. A search of the BLAST protein database revealed that the deduced amino acid sequence of GSTR1 was structurally similar to that of GSTs derived from other fishes such as largemouth bass (Micropterus salmoides) and plaice (Pleuronectes platessa). The genomic DNA containing the GSTR1 gene was found to consist of six exons and five introns quite distinct from mammalian Theta-class GSTs. We have purified and characterized the recombinant GSTR1 enzyme (pmGSTR1-1) which showed activity only towards 1-chloro-2,4-dinitrobenzene, although it had no detectable activity towards cumene hydroperoxide, 1,2-dichloro-4-nitrobenzene, ethacrynic acid, 4-hydroxynonenal and p-nitrobenzyl chloride. Moreover, pmGSTR1-1 revealed remarkable heat instability (melting temperature Tm=30.3+/-0.11 degrees C). Collectively, our results indicated that the characteristic GST genes including GSTR1 have been conserved and functional in fishes. Therefore we designate them 'Rho-class', a new class of GSTs.
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PMID:A new class of glutathione S-transferase from the hepatopancreas of the red sea bream Pagrus major. 1561 66

Butyrate, formed by bacterial fermentation of plant foods, has been suggested to reduce colon cancer risks by suppressing the proliferation of tumor cells. In addition, butyrate has been shown to induce glutathione S-transferases (GSTs) in tumor cell lines, which may contribute to the detoxification of dietary carcinogens. We hypothesize that butyrate also affects biotransformation in non-transformed colon cells. Thus, we have investigated the gene expression of drug metabolism genes in primary human colon tissue, premalignant LT97 adenoma and HT29 tumor cells cultured in an appropriate medium+/-butyrate. A total of 96 drug metabolism genes (including 12 GSTs) spotted on cDNA macroarrays (Superarray; n = 3) were hybridized with biotin-labeled cDNA probes. To validate the expression detected with Superarray, samples of LT97 cells were also analyzed with high density microarrays (Affymetrix U133A), which include biotransformation genes that overlap with the set of genes represented on the Superarray. Relative expression levels were compared across colon samples and for each colon sample+/-butyrate. Compared with fresh tissue, 13 genes were downregulated in primary cells cultivated ex vivo, whereas 8 genes were upregulated. Several genes were less expressed in LT97 (40 genes) or in HT29 (41 and 17 genes, grown for 72 and 48 h, respectively) compared with primary colon tissue. Butyrate induced GSTP1, GSTM2, and GSTA4 in HT29 as previously confirmed by other methods (northern blot/qPCR). We detected an upregulation of GSTs (GSTA2, GSTT2) that are known to be involved in the defence against oxidative stress in primary cells upon incubation with butyrate. The changes in expression detected in LT97 by Superarray and Affymetrix were similar, confirming the validity of the results. We conclude that low GST expression levels were favourably altered by butyrate. An induction of the toxicological defence system possibly contributes to reported chemopreventive properties of butyrate, a product of dietary fibre fermentation in the gut.
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PMID:Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S-transferases genes, an approach in nutrigenomics. 1574 63

The anti-malarial artesunate (ART) also inhibits the growth of cancer cells. The active moiety is an endoperoxide bridge whose cleavage generates reactive oxygen species and free radicals. We analyzed whether glutathione-related enzymes contribute to tumor resistance to ART and to the low toxicity of ART towards normal organs. The microarray-based mRNA expression of dihydrodiol dehydrogenase, gamma-glutamylcysteine synthase (gamma-GCS), glutathione S-transferases GSTM4, GSTT2, GSTZ1, and microsomal glutathione S-transferase MGST3 showed significant relationships (p <0.05) to cellular response to ART in 55 cell lines of the National Cancer Institute, USA. A tendency for correlation (0.05<p<0.1) was observed for GSTA1, GSTA2, GSTP1 and MGST1. A further 12 glutathione-related genes were not linked to ART resistance. MSC-HL13 cells transfected with cDNAs for heavy and light subunits of gamma-GCS were more resistant to ART than mock control vector-transfected MSV-PC4 cells. L-buthionine sulfoximine, a gamma-GCS inhibitor that depletes cellular glutathione pools, completely reversed ART resistance in MSV-HL13 cells, while a partial reversion was obtained by ethacrynic acid, an inhibitor of GST. The expression of GST-P was analyzed immunohistochemically in normal rat organs. GST-P immunostaining was found in all organs analyzed, albeit with varying staining intensities and in different histological structures of the organs. GST expression in normal organs may, therefore, contribute to the good tolerability and minimal toxicity of ART in normal organs.
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PMID:Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate. 1579 79

The expression of the glutathione S-transferase gene (GST), whose induction accounts for cancer chemoprevention, is regulated by activation of CCAAT/enhancer binding protein beta (C/EBPbeta) and NF-E2-related factor 2 (Nrf2). The present study investigated the repressing effects of activating glucocorticoid receptor (GR) on C/EBPbeta- and Nrf2-mediated GSTA2 gene induction and the mechanism. Dexamethasone that activates GR inhibited constitutive and oltipraz- or tert-butylhydroquinone (t-BHQ)-inducible GSTA2 expression in H4IIE cells. Also, dexamethasone repressed GSTA2 promoter-luciferase gene activity. Dexamethasone-GR activation did not inhibit nuclear translocation of C/EBPbeta or Nrf2 nor their DNA binding activities induced by oltipraz or t-BHQ. Deletion of the glucocorticoid response element (GRE) in the GSTA2 promoter abolished dexamethasone inhibition of the gene induction. Immunoprecipitation-immunoblotting, chromatin immunoprecipitation, and GST pull-down assays revealed that silencing mediator for retinoid and thyroid hormone receptors (SMRT), a corepressor recruited to steroid-GR complex for histone deacetylation, bound to TAD domain of C/EBPbeta and Neh4/5 domain of Nrf2. The GSTA2 promoter-luciferase activities were decreased by SMRT but not by truncated SMRTs. The small interference RNA (siRNA) against SMRT abolished SMRT repression of the gene induction by C/EBPbeta or Nrf2. The plasmid transfection and siRNA experiments directly evidenced the functional role of SMRT in GSTA2 repression. In conclusion, dexamethasone antagonizes C/EBPbeta- and Nrf2-mediated GSTA2 gene induction via ligand-GR binding to the GRE, and steroid-mediated GSTA2 repression involves inactivation of C/EBPbeta and Nrf2 by SMRT recruited to steroid-GR complex.
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PMID:Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. 1587 Feb 85

Fluoroacetate-specific defluorinase (FSD) is a critical enzyme in the detoxication of fluoroacetate. This study investigated whether FSD can be classed as a glutathione S-transferase (GST) isoenzyme with a high specificity for fluoroacetate detoxication metabolism. The majority of FSD and GST activity, using 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) as GST substrates, in rat liver was cytosolic. GSTT1 specific substrate, EPNP caused a slight non-competitive inhibition of FSD activity. CDNB, a general substrate of GST isoenzyme, was a more potent non-competitive inhibitor of FSD activity. The fluoroacetate defluorination activity by GST isoenzymes was determined in this study. The results showed that the GSTZ1C had the highest fluoroacetate defluorination activity of the various GST isoenzymes studied, while GSTA2 had a limited activity toward fluoroacetate. The human GSTZ1C recombinant protein then was purified from a human GSTZ1C cDNA clone. Our experiments showed that GSTZ1C catalysed fluoroacetate defluorination. GSTZ1 shares many of the characteristics of FSD; however, it accounts only for 3% of the total cytosolic FSD activity. GSTZ1C based enzyme kinetic studies has low affinity for fluoroacetate. The evidence suggests that GSTZ1 may not be the major enzyme defluorinating fluoroacetate, but it does detoxify the fluoroacetate. To clarify the identity of enzymes responsible for fluoroacetate detoxication, further studies of the overall FSD activity are needed.
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PMID:Is fluoroacetate-specific defluorinase a glutathione S-transferase? 1646 Oct 14

Synthetic triterpenoid analogues of oleanolic acid are potent inducers of the phase 2 response as well as inhibitors of inflammation. We show that the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), is a highly potent chemopreventive agent that inhibits aflatoxin-induced tumorigenesis in rat liver. The chemopreventive potency of CDDO-Im was evaluated by measuring inhibition of formation of putative preneoplastic lesions (glutathione S-transferase P positive foci) in the liver of rats exposed to aflatoxin B1. CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 micromol/kg body weight and a >99% reduction at 100 micromol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by approximately 40% to 90% over the range of 1 to 100 micromol/kg body weight. Additionally, changes in mRNA levels of genes involved in aflatoxin metabolism were measured in rat liver following a single dose of CDDO-Im. GSTA2, GSTA5, AFAR, and EPHX1 transcripts are elevated 6 hours following a 1 micromol/kg body weight dose of CDDO-Im. Microarray analysis using wild-type and Nrf2 knockout mice confirms that many phase 2 and antioxidant genes are induced in an Nrf2-dependent manner in mouse liver following treatment with CDDO-Im. Thus, low-micromole doses of CDDO-Im induce cytoprotective genes, inhibit DNA adduct formation, and dramatically block hepatic tumorigenesis. As a point of reference, oltipraz, an established modulator of aflatoxin metabolism in humans, is 100-fold weaker than CDDO-Im in this rat antitumorigenesis model. The unparalleled potency of CDDO-Im in vivo highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids.
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PMID:Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. 1648 57


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