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)

Drug-metabolizing enzymes are involved in the metabolic activation or detoxification of carcinogens. To evaluate animals developed as models for alternative carcinogenicity testing, we investigated whether or not a gene manipulation including the transgene of ras and the knocking out of a tumor suppressor gene such as p53 or XPA could alter the expression of representative drug-metabolizing enzymes directly or indirectly. Expression of several isoforms of cytochrome P450 (CYP) in the liver of rasH2, p53 (+/-), Tg.AC, and XPA (-/-) mice with or without treatment of prototype inducer. phenobarbital or 3-methylcholanthrene, was analyzed by Western immunoblotting in comparison with their parental strains of mice. In addition, the activities of 3 major phase II enzymes, UDP-glucronosyltransferase, sulfotransferase, and glutathione S-transferase, were compared between the gene-manipulated and the corresponding parental strains of mice. Results demonstrate that XPA gene knockout appeared to increase constitutive expression of CYP2B and CYP3A isoforms. Overexpression of human c-Ha-ras gene or p53 gene knockout appeared to increase constitutive UGT activity toward 4-nitrophenol. The content or activities of almost all other enzymes examined in the present study do not appear to be affected by the gene manipulation.
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PMID:Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice. 1169 53

Proteins of Ras family play an important role in regulation of cell growth and proliferation, and their mutations can lead to growth factor-independent proliferation due to constitutive activity of various signal transduction cascades. In the present work, we studied the activity of ERK, JNK and p38 MAP-kinase cascades in rat embryo fibroblast cells transformed with oncogenes E1A and cHa-ras. These transformed cells are characterized by a high and non-regulated activity of transcription factor AP-1 involved in the regulation of cell proliferation. Since phosphorylation of AP-1 depends on the activity of relevant MAP-kinase cascades (ERK, JNK and p38), we analysed the expression of non-phosphorylated forms of the kinases and their phosphorylated state in E1A + cHa-ras cells using antibodies specific to non-phosphorylated and phosphorylated proteins. It has been established that transformed cells contain higher amounts of non-phosphorylated ERK, JNK and p38 kinases, thus implying a reduced degradation of these and other proteins in the transformants. The content of phosphorylated (active) forms studied in Western blot-analysis with phosphoantibodies was shown to be also higher in exponentially growing E1A + cHa-ras cells. But serum stimulation of the starved cells gave insignificant rise to an increase of ERK, JNK and p38 phosphorylation. Nevertheless, an in vitro kinase assay performed with the kinases, either immunoprecipitated by antibody or bound to GST-fusion substrates, enabled us to show a certain level of stimulation of c-Jun-associated (JNK) and MEF2A-associated (p38) kinase activity in serum stimulated E1A + cHa-ras cells. Thus, the obtained results show that transformation of fibroblasts with E1A and ras oncogenes may contribute to constitutive activation of ERK, JNK and p38 kinase cascades responsible for a high and non-regulated activity of MAP-kinase-dependent transcription factors, in particular AP-1.
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PMID:[Constitutive activity of MAP kinase cascades in REF cells transformed by E1A and cHa-ras oncogenes]. 1176 29

AIM:To investigate the effect of Boschniakia rossica (BR) extract on expression of GST-P, p53 and p21(ras) proteins in early stage of chemical hepatocarcinogenesis in rats and its anti-inflammatory activities.METHODS:The expression of tumor marker-placental form glutathione S-transferase (GST-P), p53 and p21(ras) proteins were investigated by immunohisto-chemical techniques and ABC method. Anti-inflammatory activities of BR were studied by xylene and croton oil-induced mouse ear edema, carrageenin, histamine and hot scald-induced rat pow edema, adjuvant-induced rat arthritis and cotton pellet induced mouse granuloma formation methods.RESULTS:The 500mg/kg of BR-H2O extract frac-tionated from BR-Methanol extract had inhibitory effect on the formation of DEN-induced GST-P-positive foci in rat liver (GST-P staining was 78% positive in DEN+AAF group vs 20% positive in DEN+AAF+BR group, P<0.05) and the expression of mutant p53 and p21(ras) protein was lower than that of hepatic preneoplastic lesions (33% and 22% positive respectively in DEN+AAF group vs negative in DEN+AAF+BR group). Both CH(2)Cl(2) and H(2)O extracts from BR had anti-inflamatory effect in xylene and crotonoil induced mouse ear edema (inhibitory rates were 26%-29% and 35%-59%, respectively). BR H(2)O extract exhibited inhibitory effect in carrageenin, histamine and hot scald-induced hind paw edema and adjuvant-induced arthritis in rats and cotton pellet-induced granuloma formation in mice.CONCLUSION:BR extract exhibited inhibitory effect on formation of preneoplastic hepatic foci in early stage of rat chemical hepato-carcinogenesis.Both CH(2)Cl(2) and H(2)O extracts from BR exerted anti-inflammatory effect in rats and mice.
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PMID:Effect of Boschniakia rossica on expression of GST-P, p53 and p21(ras)proteins in early stage of chemical hepatocarcinogenesis and its anti-inflammatory activities in rats. 1181 1

Multiple genetic mutations and epigenetic methylation are believed to be involved in prostate carcinogenesis, but it is not known whether these events are independent or correlated in some fashion. We therefore studied 32 prostate adenocarcinomas not only for deletions and / or mutations of multiple suspect genes, but also for aberrant DNA methylation using methylation-specific PCR (MSP). Of those genes examined, p16(INK4a), O(6)-MGMT, and GST-P were found to be the most frequently methylated (66%, 25% and 75% of cases, respectively), while methylations of p14(ARF), RB1, p21(Waf1), and p27(Kip1) were far less common (3%, 6%, 6% and 6% of cases, respectively). Methylation of O(6)-MGMT and GST-P genes was defective in about 19% of the cases and there were occasional simultaneous deletions and methylations of p14(ARF) and p16(INK4a) genes (13% and 3% of cases, respectively). In p16(INK4a), methylation occurred in the promoter region in 9% of samples and in exon 2 in 66% of tumors. Hypermethylation of O(6)-MGMT with concurrent p53 and ras gene mutations were found in 6% and 13% of specimens, respectively; among those tumors with high Gleason scores were 2 carcinomas showing hypermethylated O(6)-MGMT with G-to-A transitions in K-ras. Our results demonstrate that multiple genes of a subset common in prostate carcinomas are methylated and not infrequently show concurrent deletions. Further, there is a suggestion that specific combinations of hypermethylation and mutation correlate to tumor malignancy.
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PMID:DNA hypermethylation status of multiple genes in prostate adenocarcinomas. 1214 42

Six families of glutathione S-transferases (GSTs), which play an important role in cellular detoxification, are identified in human cells. We report that human keratinocytes and melanocytes express significant levels of GST activity, for which GSTP1-1 is mainly responsible. But, in contrast to previous reports that GSTP1-1 level increases in skin tumor tissues, GSTP1-1 expression does not increase in transformed keratinocytes and melanocytes in culture. Although the human GSTP1 gene carries in its 5'-flanking region multiple copies of the antioxidant response element (ARE), no increase in GSTP1-1 expression was observed after treatment of human keratinocytes (HaCaT) with ARE-mediated inducers. ARE is a cis-acting DNA element and stimulates the transcription of many genes. While studies suggest that an NF-kappaB binding site in the promoter region might suppress the ARE function, such a mechanism does not appear to exist in HaCaT cells. Moreover, although ras has been shown to stimulate the expression of human GSTP1-1, the effect of c-Ha-ras on GSTP1-1 expression in HaCaT cells appears limited.
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PMID:Expression and regulation of glutathione S-transferase P1-1 in cultured human epidermal cells. 1244 43

By using human fetal lung (HFL) as experimental material, the inhibition of HFL carcinogenesis in early stage by oltipraz and its molecular mechanisms were studied. The results showed that oltipraz is effective in the inhibition of carcinogenesis prior to or at the same time with Cigarette Smoking Condensate(CSC) treatment; oltipraz can decrease GSTs activity and GST-pi protein content along with its inhibition of HFL carcinogenesis; oltipraz can decrease mp53 expression; oltipraz can prevent but can not reverse the ras gene mutation; oltipraz can induce apoptosis of GLC cell obviously in a dosage of 120 micrograms/ml. Meanwhile, it is related to high expression of c-fos and low expression of GST-pi in apoptosis; oltipraz may affect c-fos gene expression through induction of a protein factor which links with DSE.
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PMID:[Studies on inhibition of human lung carcinogenesis in early stage by oltipraz and its effects on some gene expression and regulation]. 1250 42

The differential proteomic approach (2D gel analysis coupled to MALDI-MS analysis) of nuclear proteins can provide an extremely useful tool to understand control of cell proliferation and differentiation. In order to identify possible markers of dedifferentiation between normal and cancerous thyroid cells, we used a differential proteomics approach by comparing nuclear extracts from the normal rat thyroid cell line FRTL-5 and the completely undifferentiated Ki-mol cell line, obtained by transformation with the Ki-ras oncogene. Galectin-3 (Gal-3) was identified as highly expressed, in the nuclear compartment, only in the transformed cell line. By using different human cancer cell lines, we showed that Gal-3 is maximally expressed in nuclei of papillary cancer cells. We focused on the functional relationship existing between Gal-3 and the thyroid-specific transcription factor TTF-1, whose expression is maintained in papillary cancer where it can contribute to the proliferating status. By using gel-retardation and transient tranfection assays, we demonstrate that Gal-3 upregulates the TTF-1 transcriptional activity. GST-pulldown experiments demonstrate the occurrence of interaction between Gal-3 and TTF-1 homeodomain. Since several lines of evidence suggest a role for Gal-3 in controlling proliferation and tumor progression in thyroid cancer, the stimulatory activity played by Gal-3 over TTF-1 would account for a possible molecular mechanism through which the galectin controls proliferation in thyroid cells.
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PMID:Nuclear localization of Galectin-3 in transformed thyroid cells: a role in transcriptional regulation. 1261 69

The Kunjin virus (KUNV) has provided a useful laboratory model for Flavivirus RNA replication. The synthesis of progeny RNA(+) strands occurs via asymmetric and semiconservative replication on a template of recycling double-stranded RNA (dsRna) or replicative form (RF). Kinetics of viral RNA synthesis indicated a cycle period of about 15 min during which, on average, a single nascent RNA (+) strand displaces the pre-existing RNA(+) strand in the replicative intermediate. Data on the composition of the replication complex (RC) in KUNV-infected cells were obtained from several sources, including analyses of the partially-purified still active RC, immunogold labeling of cryosections using monospecific antibodies to the nonstructural proteins and to the dsRNA, radioimmunoprecipitations of cell lysates using antibodies to dsRNA and to an RC-associated cell marker, and pull-down assays of cell lysates using fusion proteins GST-NS2A and GST-NS4A. These results yeilded a consensus composition of NS1, NS2A, NS3, NS4A, and NS5 strongly associated with the dsRNA template. The RC was located in induced membranes described as vesicle packets. The RNA-dependent RNA polymerase activity late in infection did not require continuing protein synthesis. Replication of genomic RNA was completely dependent on the presence of conserved complementary or cyclization sequences near the 5' and 3' ends. Assembly of the RC during translation in cis and the relationships, particularly those of NS1 and NS5 among the components, were deduced from an extensive set of complementation experiments in trans involving mutations/deletions in all the nonstructural proteins and use of KUN or alphahavirus replicons as helpers. The KUN replicon has found useful applications also as a noncytopathic vector for the continuing expression of foreign genes, delivered either as packaged RNA or as plasmid DNA.
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PMID:Kunjin RNA replication and applications of Kunjin replicons. 1469 28

The present study was to investigate the chemopreventive effects of tea pigments. In vitro study showed that tea pigments induced QR activity and GST activity in Hep G2 cells. Three animal models were used to observe the preventive effects of tea pigments on liver cancer, colorectal cancer and oral cancer. Oral administration of 0.1% tea pigments increased GST activity in rat liver by 18%, and this increase was accompanied by the significant increase of GST 1-1, 1-2, and 3-3 protein expression in rat liver. Tea pigments inhibited the proliferating cell nuclear antigen labeling index (PCNA-LI), the expression of Bcl-2 protein and ras-p21 protein, and induced the expression of Bax protein in rat colorectal cancer. PCNA-LI, silver-stained nucleolar organizer regions (AgNOR) and epidermal growth factor receptor (EGFR) expression were also inhibited by tea pigments in hamster oral cancer. Our results suggested that tea pigments had chemopreventive effects on cancer, and the anti-cancer properties may be due to the activation of detoxifying enzymes such as QR and GST, the inhibition of cell proliferation and the induction of apoptosis.
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PMID:[Studies on cancer chemoprevention by tea pigments]. 1496 10

We have previously found that the pi-isozyme of glutathione-S-transferase (GST-pi) is a strong and selective inhibitor of the phosphorylation of the transcriptional activating protein jun by its activating kinase, jun-N-terminal kinase (JNK). We further performed molecular dynamics calculations on the 3-dimensional structure of GST-pi free and bound to an inhibitor that blocks its ability to inhibit the JNK-jun activation. We thus identified 4 putative domains that may be involved in the interaction between GST-pi and the JNK-jun complex: residues 34-50, 99-121, 165-182 (with 2 overlapping sub-domains 165-175 and 169-182), and 194-201. We have synthesized each of these domains and tested them for their abilities to affect the GST-JNK-jun system, first in a cell-free system. We find that peptides corresponding to residues 99-121 and 194-201 strongly inhibit the binding of GST to the JNK-jun complex but do not inhibit JNK-induced phosphorylation of jun, while peptides corresponding to residues 34-50 and 165-182 do not inhibit GST binding but, except for the 165-175 subdomain peptide, strongly inhibit jun phosphorylation. A control peptide, X13, had no effect on either process. Peptide effects on jun phosphorylation appear to be selective for the JNK-jun system since the 34-50 peptide has no effect on other kinase systems (eg, casein kinase, MAP kinase). Three of the domain peptides, 34-50, 165-175, and 194-201 have been attached on their carboxyl-terminal ends to a penetratin sequence, enabling transmembrane transport into cells, and have been introduced into human astrocytes in which JNK was activated with anisomycin. We find that the 34-50-penetratin peptide strongly inhibits intracellular jun phosphorylation while the 194-201-penetratin peptide has no effect; the 165-175-penetratin peptide has a weak effect on this process. Thus, the effects in cells parallel those in the cell-free system. We conclude that all putative domains, identified in our prior structural studies, appear to interact with the JNK-jun complex. The 34-50 peptide may be useful in selectively blocking uncontrolled mitogenic signaling involving the JNK-jun pathway and may be a potential agent for blocking oncogenic ras-p21-induced cell transformation.
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PMID:Effector peptides from glutathione-S-transferase-pi affect the activation of jun by jun-N-terminal kinase. 1503 66


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