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)

The aim of our study was to investigate the suitability of Fao cells, derived from the Reuber H35 rat hepatoma as a tool for studying regulation of drug-metabolizing enzymes and drug metabolism. Fao cells express P450 2B, 2E, 3A and GST pi and were used to study the effects different inducers on these enzymes. Ethanol considerably increased the amounts of P450 2E and, to a lesser extent, P450 2B and GST pi mRNA and protein. Dexamethasone decreased the amounts of P450 2B, 3A and GST pi mRNAs, but had no appreciable effect per se upon the protein concentration of these enzymes. However, it antagonized the induction of P450 2E, 2B and GST pi by ethanol, even at the protein level. RU 486 decreased P450 2B protein and P450 2E mRNA and protein levels without effecting P450 3A and GST pi expression. RU 486 did not antagonize the dexamethasone effects, suggesting that at least some of these effects are not mediated by the glucocorticoid receptor. These data indicate that these cells constitute a suitable tool for studying the regulation of drug-metabolizing enzyme expression and drug metabolism.
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PMID:Effects of ethanol, dexamethasone and RU 486 on expression of cytochromes P450 2B, 2E, 3A and glutathione transferase pi in a rat hepatoma cell line (Fao). 130 37

Diacylglycerol (DG) and its analogue phorbol 12-myristate 13-acetate (PMA) activate the ubiquitous phospholipid/Ca2(+)-dependent protein kinase, protein kinase C (PKC), and cause it to become tightly associated with membranes. DG is produced transiently as it is rapidly metabolized by DG kinase (DGK) to phosphatidic acid. Phorbol esters such as PMA are not metabolized and induced a prolonged membrane association of PKC. Until recently, PKC was the only known phorbol ester receptor. We have shown that a novel brain-specific cDNA, neuronal chimaerin (NC), expressed in Escherichia coli, binds phorbol ester with high affinity, stereospecificity and a phospholipid requirement [Ahmed, Kozma, Monfries, Hall, Lim, Smith & Lim (1990) Biochem. J. 272, 767-773]. The proteins NC, PKC and DGK possess a cysteine-rich domain with the motif HX11/12CX2CXnCX2CX4HX2CX6/7C (where n varies between 12 and 14). The partial motif, CX2CX13CX2C, is present in a number of transcription factors including the steroid hormone receptors and the yeast protein, GAL4, in which zinc plays a structural role of co-ordinating cysteine residues and is essential for DNA binding (protein-nucleic acid interactions). The cysteine-rich domain of NC and PKC is required for phospholipid-dependent phorbol is required for phospholipid-dependent phorbol ester binding, suggesting an involvement of this domain in protein-lipid interactions. We have expressed recombinant NC, PKC and DGK glutathione S-transferase and TrpE fusion proteins in E. coli to investigate the relationship between the cysteine-rich motif, HX11/12CX2CX10-14CX2CX4HX2CX6/7C, zinc and phorbol ester binding. The cysteine-rich domain of NC, PKC and DGK bound 65Zn2+ but only NC and PKC bound [3H]phorbol 12,13-dibutyrate. When NC and PKC were subjected to treatments known to remove metal ions from GAL4 and the human glucocorticoid receptor, phorbol ester binding was inhibited. These data provide evidence for the role of a zinc-dependent structure in phorbol ester binding.
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PMID:The cysteine-rich domain of human proteins, neuronal chimaerin, protein kinase C and diacylglycerol kinase binds zinc. Evidence for the involvement of a zinc-dependent structure in phorbol ester binding. 166 Feb 66

Rodent milk consists mainly of caseins and whey proteins. A major component of the latter group is the whey acidic proteins (WAP) the gene for which has been cloned recently and shown to contain several potential glucocorticoid receptor binding sites. Studies on the regulation of this gene by glucocorticoids would be greatly enhanced by the availability of a radioimmunoassay for WAP. Rat milk was obtained from lactating Sprague-Dawley rats and the WAP purified to homogeneity by ammonium sulphate fractionation, gel filtration and ion exchange chromatography. Rabbit polyclonal antibodies were raised against the purified WAP and used to probe a Western blot of whey proteins. The major band recognized by the antibody corresponded in molecular weight to purified WAP. Problems associated with radiolabelling the tyrosine-free WAP molecule necessitated the fusion of a tyrosine containing protein with the rat milk protein. A rat WAP cDNA clone was ligated to the glutathione transferase gene, the fusion protein expressed in Escherichia coli and purified by a one-step procedure on a glutathione affinity column. Purified WAP readily displaced the radiolabelled recombinant tracer in a radioimmunoassay.
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PMID:Generation of polyclonal antibodies against purified rat whey acidic proteins and the synthesis of a tracer fusion protein suitable for use in radioimmunoassays. 275 23

Glutathione transferase-P (GST-P) in rats is specifically expressed in precancerous lesions and in hepatomas induced by carcinogens or spontaneously arising hepatomas. GST-P expression in preneoplastic lesions is suppressed by peroxisome proliferators. To determine the mechanism of suppression of GST-P expression by peroxisome proliferators on a molecular level, we have analyzed the effects of peroxisome proliferators and their receptor (peroxisome proliferator-activated receptor alpha, PPAR alpha) on GST-P expression. GST-P gene expression linked to a reporter gene was specifically suppressed by cotransfection with a PPAR alpha expression plasmid in the presence of the peroxisome proliferator, clofibrate. The target element of the suppression was a 12-O-tetradecanoylphorbol-13-acetate-responsive element located 61 nucleotides upstream from the cap site, which is also internal to a Maf consensus binding sequence. Both Jun and Maf bind to this element and activate the gene having this element, but only Jun-activated expression was specifically inhibited by PPAR alpha. Expression of a transfected reporter gene linked to a PPAR-responsive element was inhibited by cotransfection with a Jun expression plasmid. These results suggest that PPAR alpha and Jun interact and share inhibitory activities, similar to Jun and the glucocorticoid receptor.
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PMID:Suppression of rat glutathione transferase P expression by peroxisome proliferators: interaction between Jun and peroxisome proliferator-activated receptor alpha. 758 3

A number of genes under the control of the arylhydrocarbon (Ah) receptor were tested for the effects of glucocorticoids on their expression in cultured primary rat hepatocytes. Treatment of cultured hepatocytes with 1.0 microM dexamethasone potentiated the induction (2- to 3-fold) of cytochrome P4501A1, glutathione S-transferase Ya subunit (GSTYa), and UDP-glucuronosyltransferase gene expression by polycyclic aromatic hydrocarbons (PAH), whereas the glucocorticoid agonist suppressed PAH induction of NAD(P)H:quinone oxidoreductase (QOR) subunit and aldehyde dehydrogenase 3C gene expression by 60-80%. These results were seen at the level of enzyme activity for induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin and at the level of enzyme activity, protein, and specific mRNA for induction by 1,2-benzanthracene. Two of these rat genes, GSTYa and QOR are also induced by electrophilic agents, such as t-butylhydroquinone. In the presence of t-butylhydroquinone, dexamethasone caused a similar level of potentiation of GSTYa subunit expression and suppression of QOR subunit expression as was seen with the PAH, 1,2-benzanthracene. Studies using the glucocorticoid receptor antagonist, RU38486, demonstrated that the modulation of PAH induction by glucocorticoids of cytochrome P4501A1 and QOR activity is apparently dependent on action of the glucocorticoid receptor. These results suggest that the positive and negative changes observed are the result of specific alterations in the rates of transcription of these genes because of the action of the glucocorticoid receptor, thereby affecting regulation of GSTYa and QOR by both Ah receptor-dependent and independent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes. 758 46

Rat Rev-erbA alpha (rRev), which is related to thyroid hormone receptor (TR), is a conserved member of the nuclear hormone receptor superfamily whose physiological roles are unknown ("orphan" receptor). We studied DNA binding of rRev in vitro by electrophoretic mobility shift assay. A fusion protein was constructed, called NGR.Rev, containing part of the N terminus of the glucocorticoid receptor fused to nearly full-length rRev. Inasmuch as rRev and TR share homology in their DNA-binding domains, we tested binding to three different thyroid hormone response elements (TREs) in which the half-sites are arranged in different orientations. NGR.Rev bound direct repeats (DR4), but not palindromic (TREpal) or inverted palindromic (F2H) repeats. Also, transfection of CV1 cells with a reporter gene containing the luciferase gene under control of the inducible thymidine kinase promoter resulted in an increase in luciferase activity when NGR.Rev was cotransfected and when the thymidine kinase promoter contained DR4. In addition, a series of deletions in the ligand-binding domain of NGR.Rev revealed regions that can modulate DNA binding. Finally, we studied DNA binding of bacterially produced fusion proteins that contain the DNA-binding domains of rRev or rTR alpha fused to glutathione S-transferase, to a panel of natural TREs. Our results indicate that Rev binds DNA with a different specificity than TR alpha-1 and might be involved in the regulation of a subset of thyroid hormone-regulated genes.
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PMID:Rat Rev-erbA alpha, an orphan receptor related to thyroid hormone receptor, binds to specific thyroid hormone response elements. 801 47

Based on the finding that glutathione S-transferase Yb1 (GST) gene expression is elevated in the regressing prostate of androgen-ablated rats, we analyzed GST transcript levels during steroid-induced lymphocyte cell death. It was found that GST gene expression was induced in steroid-sensitive cells within 4 hr of dexamethasone treatment, required functional glucocorticoid receptor, and was dose-dependent with regard to hormone. GST expression was not induced in an apoptosis-defective variant that contained normal levels of functional receptor, indicating that GST up-regulation was the result of secondary events that occur during steroid-mediated apoptosis. Using the calcium ionophore A23817 to induce lymphocyte cell death, GST RNA levels were increased in both steroid-sensitive and steroid-resistant cell lines, supporting the conclusion that elevated GST expression was the result of cellular processes associated with apoptosis, rather than a direct consequence of steroid-mediated transcriptional control. The cells were also treated with dibutyryl cAMP to cause cell death; however, this mode of killing did not result in GST up-regulation. Taken together, these results suggest that GST induction in dexamethasone-treated T-lymphocytes occurs early in the steroid-regulated apoptotic pathway and that this may be a marker of calcium-stimulated cell death. Based on the known function of GST as an antioxidant defense enzyme and its transcriptional regulation by reactive oxygen intermediates, we propose that the gene product of a primary GR target gene(s) directly or indirectly effects the redox state of the cell. Thus activation of GST gene expression in apoptotic lymphocytes is likely a indicator of oxidative stress, rather than a required step in the pathway.
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PMID:Elevated glutathione S-transferase gene expression is an early event during steroid-induced lymphocyte apoptosis. 838 11

In search of proteins which interact with activated steroid hormone receptors, we screened a human liver lambda gt11 expression library with the glucocorticoid receptor. We identified and cloned a cDNA sequence of 1322 bp that encodes a protein of 274 aa. This protein consists predominantly of hydrophilic amino acids and contains a putative bipartite nuclear localization signal. The in vitro translated receptor-associating protein runs in SDS/polyacrylamide gels with an apparent molecular mass of 46 kDa. By use of the bacterially expressed fusion protein with glutathione S-transferase we have found that interaction is not limited to the glucocorticoid receptor but included other nuclear receptors--most notably, the estrogen and thyroid receptors. Binding also occurs with the glucocorticoid receptor complexed with the antiglucocorticoid RU 38486, with the estrogen receptor complexed with the antiestrogen 4-hydroxytamoxifen or ICI 164,384, and even with receptors not complexed with ligand. Association with steroid hormone receptors depends on prior receptor activation--i.e., release from heat shock proteins. The sequence identified here appears to be a general partner protein for nuclear hormone receptors, with the gene being expressed in a variety of mammalian tissues.
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PMID:A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning. 852 84

The regulation of hepatic P450s has been the focus of numerous studies because of the importance of these proteins in endocrinology, oncology, and toxicology, as well as drug development. Considerable evidence exists demonstrating that many hepatic P450s are regulated by developmental, sex, or hormonal factors in addition to receptors that interact with foreign chemicals. The focus of work in our laboratory has been on the effects of steroid hormones, especially glucocorticoids, on expression of genes regulated by the Ah receptor. We have shown that most rat hepatic genes of the Ah receptor gene battery are regulated by glucocorticoids. We have used glucocorticoid-deficient animal models to demonstrate that these steroids do modulate the expression (basal and inducible) of these genes in vivo. Using cultured rat hepatocytes, we have demonstrated that polycyclic aromatic hydrocarbon (PAH) induction of cytochrome P4501A1, glutathione S-transferase Ya1, and UDP-glucuronosyltransferase 1*6 are apparently potentiated two- to fourfold upon inclusion of glucocorticoids in the media to activate the glucocorticoid receptor and further, that the receptor antagonist RU 38486 reverses these phenomenon. NAD(P)H:quinone oxidoreductase and aldehyde dehydrogenase 3 gene expression were repressed 70-80% by glucocorticoids in cultured hepatocytes through a glucocorticoid receptor-mediated process as well. The effect of glucocorticoid concentration on PAH induction of glutathione S-transferase Ya1 subunit for glucocorticoids was biphasic, but at physiological concentrations gene expression was repressed to approximately 20-40% of control. At supraphysiological concentrations, glucocorticoids alone induced expression two- to threefold and potentiated the PAH-inducible expression of the Ya1 subunit gene. Subsequent work in our laboratory has focused on defining the molecular basis of this hormonal regulation, specifically elucidating responsive elements responsible for the action of the glucocorticoid receptor and the mechanisms by which some of these genes are positively regulated and others are negatively regulated.
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PMID:Hormonal regulation of hepatic enzymes involved in foreign compound metabolism. 890 7

We have shown that the Ada adaptor complex is important for the gene activation capacity of the glucocorticoid receptor in yeast. The recently isolated human Ada2 protein also increases the potency of the receptor protein in mammalian cells. The Ada pathway is of key significance for the tau1 core transactivation domain (tau1c) of the receptor, which requires Ada for activity in vivo and in vitro. Ada2 can be precipitated from nuclear extracts by a glutathione S-transferase-tau1 fusion protein coupled to agarose beads, and a direct interaction between Ada2 and tau1c can be shown by using purified proteins. This interaction is strongly reduced by a mutation in tau1c that reduces transactivation activity. Mutations affecting the Ada complex do not reverse transcriptional squelching by the tau1 domain, as they do for the VP16 transactivation domain, and thus these powerful acidic activators differ in at least some important aspects of gene activation. Mutations that reduce the activity of the tau1c domain in wild-type yeast strains cause similar reductions in ada mutants that contain little or no Ada activity. Thus, gene activation mechanisms, in addition to the Ada pathway, are involved in the activity of the tau1c domain.
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PMID:Role of the Ada adaptor complex in gene activation by the glucocorticoid receptor. 915 5


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