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 human transcriptional enhancer factor (TEF) family includes TEF-1, TEF-3, TEF-4, and TEF-5. The TEFs share a highly conserved 68-amino acid TEA/ATTS DNA-binding domain, which binds to SV40 GT-IIC (GGAATG), SphI (AGTATG), SphII (AGCATG), and muscle-specific M-CAT (GGTATG) enhansons. We determined the optimal DNA-binding consensus sequence for TEF-1. Using a purified GST-TEF-1 fusion protein and a random pool of synthetic oligonucleotides, 31 independent clones were obtained after six rounds of binding site selection. DNA sequences analysis revealed that 16 clones contained direct repeats with a 3-bp spacer (DR3), and 15 clones contained a single binding site. The predominate consensus half-site was GGAATG (67%), and the other elements were of the form G(A)GA(T/C)ATG. The TEF-1 bound to the DR3 as a dimer in a cooperative manner. Cooperative binding was dependent on the spacing and orientation of the half-sites and was inhibited by deoxycholate treatment, providing evidence that protein-protein interactions were involved. The data suggest that TEF dimerization is important for its ability to modulate gene transcription.
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PMID:Cooperative binding of TEF-1 to repeated GGAATG-related consensus elements with restricted spatial separation and orientation. 1097 68

Toxic metals occur naturally at low concentrations throughout the environment, but are found in higher concentrations at many of the hazardous waste sites on the EPA Superfund list. As part of the Agency for Toxic Substances and Disease Registry (ATSDR) mandate to evaluate the toxicity of metals and mixtures, we chose four of the high-priority metal pollutants from ATSDR's HAZDAT list, including arsenic, cadmium, chromium, and lead, to test in a commercially developed assay system, CAT-Tox(L) (Xenometrix). This assay employs a battery of recombinant HepG2 cell lines to test the transcriptional activation capacity of xenobiotics in any of 13 different signal transduction pathways. Our specific aims were to identify metal-responsive promoters and determine whether the pattern of gene expression changed with a mixture of metals. Humic acid was used in all assays as a carrier to help solubilize the metals and, in all cases, the cells were exposed to the humic acid-metal mixture for 48 h. Humic acid alone, at 50-100 microM, showed moderate activation of the XRE promoter, but little other notable activity. As(V), at doses of 50-250 microM, produced a complex profile of activity showing significant dose-dependent induction of the hMTIIA, GST Ya, HSP70, FOS, XRE, NFkappaBRE, GADD153, p53RE, and CRE promoters. Pb(II) showed dose-related induction of the GST Ya, XRE, hMTIIA, GRP78, and CYP IA1 promoters at doses in the range of 12-100 microM. Cd(II), at 1.25-15 microM, yielded significant dose-dependent induction of hMTIIA, XRE, CYP IA1, GST Ya, HSP70, NFkappaBRE, and FOS. Whereas Cr(III) yielded small, though significant inductions of the CRE, FOS, GADD153, and XRE promoters only at the highest dose (750 microM), Cr(VI) produced significant dose-related inductions of the p53RE, FOS, NFkappaBRE, XRE, GADD45, HSP70, and CRE promoters at much lower doses, in the range of 5-10 microM. Assays testing serial dilutions of a mixture comprising 7.5 microM Cd(II), 750 microM Cr(III), and 100 microM Pb(II) (the combination of metals most frequently found at National Priority List sites) showed significant dose-dependent induction of the hMTIIA promoter, but failed to show dose-related induction of any other promoter and showed no evidence of synergistic activation of gene expression by the metals in this mixture. Our results thus show metal activation of gene expression through several previously unreported signal transduction pathways, including As(V) induction of GST Ya, FOS, XRE, NFkBRE, GADD153, p53RE, and CRE; Pb(II) induction of GST Ya, XRE, Cyp IA1, and GADD153; Cd(II) induction of NFkBRE, Cyp IA1, XRE, and GST Ya; and Cr(VI) induction of p53RE, XRE, GADD45, HSP70, and CRE promoters, and thus suggest new insights into the biochemical mechanisms of toxicity and carcinogenicity of metals. It is also an important finding that no evidence of synergistic activity was detected with the mixture of Cd(II), Cr(III), and Pb(II) tested in these assays.
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PMID:Effects of arsenic, cadmium, chromium, and lead on gene expression regulated by a battery of 13 different promoters in recombinant HepG2 cells. 1103 63

Serum response factor is a MADS box transcription factor that binds to consensus sequences CC(A/T)(6)GG found in the promoter region of several serum-inducible and muscle-specific genes. In skeletal myocytes serum response factor (SRF) has been shown to heterodimerize with the myogenic basic helix-loop-helix family of factors, related to MyoD, for control of muscle gene regulation. Here we report that SRF binds to another myogenic factor, TEF-1, that has been implicated in the regulation of a variety of cardiac muscle genes. By using different biochemical assays such as affinity precipitation of protein, GST-pulldown assay, and coimmunoprecipitation of proteins, we show that SRF binds to TEF-1 both in in vitro and in vivo assay conditions. A strong interaction of SRF with TEF-1 was seen even when one protein was denatured and immobilized on nitrocellulose membrane, indicating a direct and stable interaction between SRF and TEF-1, which occurs without a cofactor. This interaction is mediated through the C-terminal subdomain of MADS box of SRF encompassing amino acids 204-244 and the putative 2nd and 3rd alpha-helix/beta-sheet configuration of the TEA/ATTS DNA-binding domain of TEF-1. In the transient transfection assay, a positive cooperative effect of SRF and TEF-1 was observed when DNA-binding sites for both factors, serum response element and M-CAT respectively, were intact; mutation of either site abolished their synergistic effect. Similarly, an SRF mutant, SRFpm-1, defective in DNA binding failed to collaborate with TEF-1 for gene regulation, indicating that the synergistic trans-activation function of SRF and TEF-1 occurs via their binding to cognate DNA-binding sites. Our results demonstrate a novel association between SRF and TEF-1 for cardiac muscle gene regulation and disclose a general mechanism by which these two super families of factors are likely to control diversified biological functions.
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PMID:Physical interaction between the MADS box of serum response factor and the TEA/ATTS DNA-binding domain of transcription enhancer factor-1. 1113 26

Three biomarkers (glutathione S-transferase [GST] activity, catalase [CAT] activity, and malonedialdehyde [MDA] levels) were measured in specimens of the mussel Mytilus galloprovincialis collected from two different stations (BC and MJ) in the lagoon of Bizerta (Tunisia). Animals were allowed to acclimate in the laboratory for some days. They were then exposed for 48 h to two concentrations of pp'DDE and two doses of mercury chloride. The acclimation period increased CAT activities and MDA levels in control mussels from both sites. GST activities were not modified during the acclimation period, whereas the sampling site of mussels appeared to exert a significant influence (higher values in control mussels from MJ than in those from BC). The treatment with both contaminants also increased GST activities of mussels from BC and not from MJ. It is hypothesized that animals from this last location are more exposed to the urban waste waster disposal, their biochemical response (GST activity) to pollutant exposure will be less marked. The treatment with pp'DDE or mercury did not show significant trend in CAT activities or MDA levels due to the variation of controls, and comparison of sites for mussels exposed to either pollutant therefore seems difficult. The acclimation period in the laboratory and the origin of mussels must be taken into consideration when studying the biochemical responses of mussels experimentally exposed to chemical pollutants.
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PMID:Biochemical response of the mussel Mytilus galloprovincialis from Bizerta (Tunisia) to chemical pollutant exposure. 1124 24

The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) is reported to have anticancer activity in vivo. Induction of cell cycle arrest and apoptosis in cancer cell lines refractory to standard retinoids suggests a retinoid-independent mechanism of action for AHPN. Conformational studies suggested that binding of AHPN does not induce an unusual conformation in retinoic acid receptor (RAR) gamma. The 3-chloro AHPN analogue MM11453 inhibited the growth of both retinoid-resistant (HL-60R leukemia, MDA-MB-231 breast, and H292 lung) and retinoid-sensitive (MCF-7 breast, LNCaP prostate, and H460 lung) cancer cell lines by inducing apoptosis at similar concentrations. Before apoptosis, MM11453 induced transcription factor TR3 expression and loss of mitochondrial membrane potential characteristic of apoptosis. MM11453 lacked the ability to significantly activate RARs and retinoid X receptor alpha to initiate (TREpal)(2)-tk-CAT reporter transcription. These results, differential proteolysis-sensitivity assays, and glutathione S-transferase-pulldown experiments demonstrate that, unlike AHPN or the natural or standard synthetic retinoids, MM11453 does not behave as a RAR or retinoid X receptor alpha transcriptional agonist. These studies strongly suggest that AHPN exerts its cell cycle arrest and apoptotic activity by a signaling pathway independent of retinoid receptor activation.
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PMID:Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. 1140 43

A novel cDNA, insulinoma-associated antigen-1 (IA-1), containing five zinc-finger DNA-binding motifs, was isolated from a human insulinoma subtraction library. IA-1 expression is restricted to fetal but not adult pancreatic and brain tissues as well as tumors of neuroendocrine origin. Using various GAL4 DNA binding domain (DBD)/IA-1 fusion protein constructs, we demonstrated that IA-1 functions as a transcriptional repressor and that the region between amino acids 168 and 263 contains the majority of the repressor activity. Using a selected and amplified random oligonucleotide binding assay and bacterially expressed GST-IA-1DBD fusion protein (257-510 a.a.), we identified the consensus IA-1 binding sequence, TG/TC/TC/TT/AGGGGG/TCG/A. Further experiments showed that zinc-fingers 2 and 3 of IA-1 are sufficient to demonstrate transcriptional activity using an IA-1 consensus site containing a reporter construct. A database search with the consensus IA-1 binding sequence revealed target sites in a number of pancreas- and brain-specific genes consistent with its restricted expression pattern. The most significant matches were for the 5'-flanking regions of IA-1 and NeuroD/beta2 genes. Co-transfection of cells with either the full-length IA-1 or hEgr-1AD/IA-1DBD construct and IA-1 or NeuroD/beta2 promoter/CAT construct modulated CAT activity. These findings suggest that the IA-1 protein may be auto-regulated and play a role in pancreas and neuronal development, specifically in the regulation of the NeuroD/beta2 gene.
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PMID:Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence. 1184 16

The present investigation focused, firstly, on the effects of oral administration of thymoquinone (TQ) on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase activity in hepatic, cardiac and kidney tissues of normal mice. Superoxide dismutase (SOD; E.C:1.15.1.1), catalase (CAT; E.C:1.11.1.6), glutathione peroxidase (GSH-Px; E.C:1.11.1.9), glutathione-S-transferase (GST; E.C:2.5.1.18), and DT-diaphorase (E.C:1.6.99.2) enzyme activities in each tissue type were determined. Treatment of mice with the different doses of TQ (25, 50 and 100 mg kg(-1) day(-1) orally) for 5 successive days, produced significant reductions in hepatic SOD, CAT and GSH-Px activities. In addition cardiac SOD activity was markedly inhibited with the higher doses of TQ, (namely 50 and 100 mg kg(-1)). Moreover, TQ (100 mg kg(-1)) significantly reduced hepatic and cardiac lipid peroxidation as compared with the respective control group. Conversely, TQ (50,100 mg kg(-1)) and TQ (100 mg kg(-1)) enhanced cardiac and renal DT-diaphorase activity respectively. However, the selected doses of TQ neither produced any change in GST activity nor influenced reduced glutathione content in all tissues studied. TQ was tested, secondly, as a substrate for hepatic, cardiac and renal DT-diaphorase of normal mice in the presence of NADPH. Kinetic parameters for the reduction of TQ to dihydrothymoquinone (DHTQ) indicated that DT-diaphorase of different tissues can efficiently reduce TQ to DHTQ. K(m) and V(max) values revealed that hepatic DT-diaphorase exhibited the higher values, while the lower values were associated with renal DT-diaphorase. TQ and DHTQ were tested, thirdly, as specific scavengers for superoxide anion (generated biochemically) or as general scavengers for free radicals (generated photochemically). The results revealed that TQ and DHTQ acted not only as superoxide anion scavengers but also as general free radical scavengers. The IC(50) for TQ and DHTQ in biochemical and photochemical assays were in the nanomolar and micromolar range respectively. Our data may explain at least partly the reported beneficial in vivo protective effects of TQ through the combined antioxidant properties of TQ and its metabolite DHTQ.
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PMID:Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action. 1197 10

In recent years, numerous reports have been published on the identification of novel, naturally occurring antioxidants from plants, animals, microbial sources and processed food products. Most natural antioxidants are phenolic compounds, which have a modulatory role on physiological functions and biotransformation reactions involved in the detoxification process, thereby affording protection from cytotoxic, genotoxic and metabolic actions of environmental toxicants. As part of our program on evaluation of food, beverage and traditional medicinal plants for their anticarcinogenic activity, the present report deals with the evaluation of aqueous infusion of Black tea (Camellia sinensis), Black tea extract (80% Theaflavins) & EGCG on mice exposed to the chemical carcinogen DMBA. All the four detoxification enzymes studied viz, GST, GPx, SOD and CAT were found to be activated to different degrees following treatment with black tea and two of its active compounds. The activation of the enzymes was accompanied by significant reduction in lipid peroxidation. The effect on apoptosis and cell proliferation was also studied in mice skin following administration of DMBA. Theaflavins, and EGCG significantly inhibited cell proliferation and induced apoptosis. The observation suggests chemopreventive potential of black tea infusion, black tea extract Theaflavins and the compound EGCG.
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PMID:Elimination of Deleterious Effects of Free Radicals in Murine Skin Carcinogenesis by Black Tea Infusion, Theaflavins & Epigallocatechin Gallate. 1271 79

The modifying effects of the aqueous extract of saffron (dried stigmas of Crocus sativus Linn.) on cisplatin (CIS), cyclophosphamide (CPH), mitomycin-C (MMC) and urethane (URE) induced alterations in lipid peroxidation and antioxidant status were investigated in Swiss albino mice. Three doses of saffron (20, 40 and 80 mg/kg body weight) were orally administered to mice for 5 consecutive days prior to administration of genotoxins. A significant reduction in the extent of lipid peroxidation with a concomitant increase in the liver enzymatic (SOD, CAT, GST, GPx) and non-enzymatic antioxidants (reduced glutathione) were observed in saffron pretreated animals compared with the genotoxins alone treated animals. However, the modulatory effects were not always dose dependent. Our data suggest that saffron may exert its chemopreventive effects by modulation of lipid peroxidation, antioxidants and detoxification systems.
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PMID:Protective effects of saffron (Crocus sativus Linn.) on genotoxins-induced oxidative stress in Swiss albino mice. 1282 Feb 27

A GST (EC 2.5.1.18) gene (Gst-cr 1) from cotton was introduced into Nicotiana tabacum by Agrobacterium tumefaciens-mediated transformation. Transgenic tobacco plants overexpressing Gst-cr1 were normal in growth and mature compared with control, but had much higher levels of GST and GPx activities and showed an enhanced resistance to oxidative stress induced by a low concentration of methyl viologen (MV). Six antioxidant enzymes, glutathione S-transferase, glutathione peroxidase (EC 1.11.1.9), superoxide dismutase (EC 1.15.1.1), peroxidase (EC 1.11.1.7), catalase (EC 1.11.1.6), and ascorbate peroxidase (EC 1.11.1.11) were monitored in transgenic lines and non-transgenic control during MV treatments. When they were treated with 0.03 mmol/L of MV, both transgenic lines and control showed a rapid increase in the activities of GST, GPx, SOD, POD, APx, while the activity of CAT seemed to be irregular. The percent of the increase in SOD and POD activities was much higher in control than in transgenic plants. When treated with 0.05 mmol/L of MV, both control and transgenic plants were severely damaged, and the activities of the six enzymes decreased sharply.
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PMID:Transgenic tobacco plants overexpressing cotton glutathione S-transferase (GST) show enhanced resistance to methyl viologen. 1465 82


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