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)

Glutathione transferase P (GST-P) is expressed at high levels in precancerous lesions and hepatocellular carcinomas from a very early stage of chemically-induced hepatocarcinogenesis in the rat. To explore the molecular mechanisms of its specific activation, we are investigating the regulation mechanisms of the GST-P gene expression. By using gene technology, we have identified a strong enhancer, GPEI, at 2.5 Kb and a silencer region at about 400 bp upstream from the transcription start site. GPEI has a palindromic structure composed of two TPA-responsive element (TRE)-like sequences and binds at least three proteins including AP-1 (c-jun/c-fos). The silencer is composed of several sequences resembling each other and binds at least three proteins including SF-B/LAP/LIP. To determine whether the GST-P gene is activated together with a putative hepato-oncogene because they are located close to each other (cis-mechanism), or because they share a trans-acting factor that can activate both genes simultaneously (trans-mechanism), transgenic rats were produced with GST-P control region connected to the CAT reporter. The results unequivocally demonstrate that GST-P gene is activated position-independently by a trans-mechanism.
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PMID:Complex regulation of a tumor marker expression. Enhancer and silencer of the GST-P gene. 130 2

The human Alpha glutathione S-transferase gene corresponding to the human liver cDNA clone pGTH2 was isolated from a cosmid genome library. The gene, represented by the clone cosGTH2, spans nearly 12 kb and contains seven exons. The intron/exon borders conform to the standard rules, and an open reading frame is present, starting at position 67 in exon 2, the double-stop codon being at position 733 in exon 7. Exons 1, 2 and 7 differ in length from the known rat gene coding for the Ya enzyme. A 209 bp 5'-upstream region contains TATA and CAT boxes and, in addition, motifs for Sp1-, NF1- and HNFI-binding factors. Clone cosGTH2 represents the less basic subunit, alpha y, of two Alpha glutathione S-transferase subunits (alpha x and alpha y) expressed in liver, which is identical with the kidney subunit alpha 2.
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PMID:Cloning, sequencing and characterization of the human alpha glutathione S-transferase gene corresponding to the cDNA clone pGTH2. 149 29

The glutathione S-transferase pi gene (GST pi) is highly expressed in estrogen receptor negative (ER-) but not expressed in ER+ human breast cancer cell lines. To define regulatory mechanisms of GST pi gene expression, we analyzed both the activity of the GST pi promoter and the posttranscriptional fate of GST pi RNA sequences in three ER+ and three ER- breast cancer cell lines. Expression of a transiently transfected CAT reporter gene driven by the GST pi promoter and 2203 nucleotides of 5'-flanking sequences were similar in all six cell lines regardless of ER status. Endogenous GST pi transcription rates in nuclei isolated from ER- cells were quite low despite high steady state levels of cytoplasmic mRNA. Furthermore, the endogenous GST pi gene was transcribed in ER+ nuclei at rates similar to those obtained in ER- nuclei. We determined the stabilities of mRNAs transcribed from the endogenous GST pi gene (ER- cells) and from a stably transfected GST pi cDNA expression vector (ER+ and ER- cells). The endogenous GST pi mRNA was extraordinarily stable in ER- cells. Comparisons between transfected ER+ and ER- cells revealed no significant differences in the stabilities of transfection-derived GST pi mRNA sequences. We conclude that GST pi mRNA stability contributes significantly to the high levels of cytoplasmic mRNA observed in ER- cells, but that the differential expression of GST pi in ER+ versus ER- cells is governed by other posttranscriptional processes.
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PMID:Posttranscriptional control of glutathione S-transferase pi gene expression in human breast cancer cells. 158 35

1. The activity of antioxidant defense enzymes (SOD, CAT, GSH-Px and GST) was analysed during the autumn and winter in the ground squirrel adapted to 30 degrees C and subsequently exposed to cold for 6 and 24 hr. 2. The liver CAT activity as well as the IBAT CAT and GSH-Px activities differed between animals adapted to 30 degrees C, studied in autumn, and those studied in winter. 3. MnSOD activity in the liver was increased in autumn but decreased in winter after 6 hr cold exposure reaching the control level 24 hr later. Cold exposure induced a decrease in CAT activity (except after 24 hr cold exposure in winter) and an increase in GSH-Px activity. Lower GST activity was found after 24 hr exposure to cold in winter. 4. The IBAT SOD activity decreased under the influence of cold during both seasons with a tendency to return to the control level only in winter. Cold exposure produced a decrease in GST in both seasons and CAT activity in autumn. GSH-Px activity was increased in winter only. 5. The results indicate a seasonal dependence of the activity of antioxidant defence enzymes in the ground squirrel. Seasonal influence was evidenced in animals exposed to cold as well.
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PMID:Seasonal dependence of the activity of antioxidant defence enzymes in the ground squirrel (Citellus citellus): the effect of cold. 161 72

To obtain a profile of erythrocyte antioxidant defense potential during late fetal development, we studied selected antioxidant parameters in blood samples from 65 neonates with birth wt between 520 and 4210 g and from 12 healthy adults. Erythrocyte superoxide dismutase activity did not change significantly with maturation and no significant differences were observed among preterm infants grouped in increasing birth wt categories, term neonates, and adults. Erythrocyte catalase and glutathione peroxidase, as well as plasma vitamin E levels, showed highly significant positive correlations (p less than 0.001) with increasing fetal wt and gestational age; by term, CAT activity reached a level similar to the adult control group, but glutathione peroxidase activity, as well as plasma vitamin E levels, were markedly lower in all the preterm and in the term groups than in adults (p less than 0.01). Erythrocyte glutathione S-transferase activity showed a negative correlation with increasing gestational age (p less than 0.01) and the adult values were considerably lower than any of the neonatal levels (p less than 0.001). The role of glutathione S-transferase in erythrocyte metabolism remains obscure. Maturational changes in the activity of the red cell enzymes that were studied and in the plasma vitamin E level were apparent from about 31-36 wk of gestation, suggesting that the stimulation for these changes may have commenced from about 28-31 wk.
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PMID:Developmental patterns of antioxidant defense mechanisms in human erythrocytes. 279 51

We studied the effect of supplementation with vitamins C, E and beta-carotene (PARABION, produced by Syndipharma) on antioxidative status in kidneys of male Wistar rats with diabetes induced by intravenous application of streptozotocin (45 mg.kg-1 of body weight). The animals received subtherapeutic doses of Insulin Interdep (6 U.kg-1 of body weight). A significant decrease of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione and reduction of the activities of Se-glutathione peroxidase (Se-GSH-PX, EC. 1.11.1.9.) and glutathione S-transferase (GST, EC. 2.5.1.18.) were observed in kidneys of diabetic rats treated with these vitamins. On the contrary, the activity of CuZn-superoxide dismutase (CuZn-SOD, EC. 1.15.1.1) and the level of vitamin C (vit. C) increased significantly. No changes were observed for vitamin E (vit. E), beta-carotene and catalase (CAT, EC. 1.11.1.6). Supplementation with vitamins C, E and beta-carotene resulted in an improvement of antioxidative status of kidneys of rats with streptozotocin-induced diabetes.
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PMID:Effect of intake of exogenous vitamins C, E and beta-carotene on the antioxidative status in kidneys of rats with streptozotocin-induced diabetes. 747 41

The Ras GTPase-activating protein (GAP) is a target for protein tyrosine kinases of both the receptor and cytoplasmic classes and may serve to integrate tyrosine kinase and Ras signaling pathways. In this report, we provide evidence that GAP is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase Hck, which has been implicated in the regulation of myeloid cell growth, differentiation, and function. Wild-type (WT) or kinase-inactive (K269E) mutant Hck proteins were co-expressed with bovine GAP using the baculovirus/Sf-9 cell system. GAP was readily phosphorylated on tyrosine by WT but not K269E Hck. GAP was present in WT Hck immunoprecipitates from the co-infected cells, indicative of Hck.GAP complex formation. Unexpectedly, GAP also associated with the kinase-inactive mutant of Hck, suggesting that tyrosine autophosphorylation of Hck is not required for complex formation. The WT and K269E forms of Hck also associated with GAP mutants lacking either the C-terminal catalytic domain (delta CAT) or the Src homology region (delta SH), indicating that these GAP domains are dispensable for complex formation. Recombinant GST fusion proteins containing the Hck, Src, Fyn, or Lck SH3 domains associated with full-length GAP, delta CAT, and delta SH, all of which share an N-terminal proline-rich region resembling an SH3-binding motif (PPLPPPPPQLP). Deletion of the highly conserved YXY sequence from the Hck SH3 domain abolished binding. GAP-SH3 interaction was also inhibited by the proline-rich peptide GFPPLPPPPPQLPTLG, which corresponds to N-terminal amino acids 129-144 of bovine GAP. An N-terminal deletion mutant of GAP lacking this proline-rich region did not bind to the Hck SH3 domain. These data implicate the Hck SH3 domain in GAP interaction, and suggest a general function for the SH3 domains of Src family kinases in recognition of GAP via its proline-rich N-terminal domain.
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PMID:The Ras GTPase-activating protein (GAP) is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase, Hck. 778 36

The expression of the Epstein-Barr virus LMP1 oncogene is regulated by viral and non-viral factors in a tissue dependent fashion. The virus encoded transcription factor EBNA2 induces its expression in human B-cells. However, this induction also requires the contribution of cellular and/or other viral factors. In nasopharyngeal carcinoma cells and in cells from Hodgkin's lymphoma, LMP1 gene transcription is independent of viral products. Here we show that the effect of a factor binding to a cAMP responsive-like element (CRE) in the LMP1 gene transcription regulatory sequence (LRS) is essential for efficient promoter activity in the DG75 B-cell line and that elevation of cAMP levels in the cells induces LRS-derived CAT activity in a CRE dependent fashion. Incubation of two EBV-immortalized B-cell lines expressing endogenous EBNA2A with 8-Br cAMP increased the levels of the latency associated 66 kDa LMP1 within 2 h. Interestingly, LMP1 expression in DG75 cells conferred resistance to the inhibitory effect of 8-Br cAMP on cell proliferation. The protein phosphatase 1 and 2A (PP1 and PP2A, respectively) inhibitor okadaic acid also stimulated LRS-CAT activity in DG75 cells. EBNA2A from an EBV-immortalized B-cell line co-immunopurified with a PP1-like protein. An EBNA2A fragment spanning residues 324-436 fused to the GST protein specifically rescued a PP1/PP2A-like component from DG75 cell extracts. This GST-EBNA2A fusion product inhibited a PP1-like activity in nuclear extracts from these cells.
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PMID:Response to cAMP levels of the Epstein-Barr virus EBNA2-inducible LMP1 oncogene and EBNA2 inhibition of a PP1-like activity. 781 42

The DNA-binding domain of Nuclear Factor I (NFIBD) enhances initiation of adenovirus DNA replication up to 50-fold by binding to the auxiliary region of the origin and positioning the viral DNA polymerase. To study if and when NFIBD dissociates from the template, we immobilized origin DNA to glutathione-agarose beads by means of a GST-NFIBD fusion protein. This immobilized template is active in replication. By analyzing the release of prelabeled templates from the beads under different conditions, we show that NFIBD dissociates already early during initiation. During preinitiation NFIBD remains bound, but as soon as dCTP, dATP or dTTP are added, efficient dissociation occurs. A much lower dissociation level was induced by addition of dGTP. Since dCTP, dATP and dTTP are required for formation of a pTP-CAT initiation intermediate, we explain our results by conformational changes occurring in the polymerase during initiation leading to disruption of both the interaction between the polymerase and NFI as well as the interaction between NFI and the DNA.
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PMID:Early dissociation of nuclear factor I from the origin during initiation of adenovirus DNA replication studied by origin immobilization. 781 11

Human NAD(P)H:quinone oxidoreductase2 (NQO2) gene, 1336 base pairs (bp) of the 5'-flanking region and 165 bp of the 3'-flanking region, have been sequenced. NQO2 gene is 20 kilobase pairs in length and have seven exons interrupted by six introns as compared to the previously cloned NQO1 gene which contains six exons. 187 bp of the first exon in the NQO2 gene are noncoding and are absent in the NQO1 gene. 92 bp of the second exon in the NQO2 gene corresponded to the first exon of the NQO1 gene and so on. The sizes and nucleotide sequences of exons 3-6 are highly conserved between NQO2 and NQO1 genes. The last exon in the NQO2 gene is 1603 bp shorter than the last exon of the NQO1 gene and encodes for 58 amino acids as compared to 101 amino acids encoded by the NQO1 gene. This makes NQO2 protein 43 amino acids shorter than the NQO1 protein. The high degree of conservation between NQO2 and NQO1 gene organization and sequence confirmed that NQO2 gene encodes for a second member of the NQO gene family in human. Nucleotide sequence analysis of the 5'-flanking region of the NQO2 gene revealed presence of four SP1 binding sites at positions -214, -170, -106, and -75, a single copy of the antioxidant response element (ARE) at nucleotide -936, and three copies of xenobiotic response element (XRE) at positions -708, -557, and -51. ARE and XRE elements have previously been found in the promoters of the NQO1 and glutathione S-transferase Ya subunit genes and mediate increases in their expression in response to polycyclic aromatic compounds, phenolic antioxidants, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. The NQO2 cDNA-derived protein in monkey kidney COS1 cells efficiently catalyzed nitroreduction of anti-tumor compound CB10-200, an analog of nitrophenylaziridine. Northern blot analysis indicates that NQO2 gene is expressed in human heart, brain, lung, liver, and skeletal muscle but does not express in placenta. In contrast, the NQO1 gene was expressed in all human tissues. Large variations were noticed for expression of the NQO2 and NQO1 genes among various tissues, 1336 bp of the 5'-flanking region of the NQO2 gene containing ARE and XRE was found sufficient to increase expression of the CAT gene in response to beta-naphthoflavone and tCDD in transfected human hepatoblastoma (Hep-G2) cells.
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PMID:Human NAD(P)H:quinone oxidoreductase2. Gene structure, activity, and tissue-specific expression. 818 56


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