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) gene expression is dominantly regulated by an upstream enhancer (GPEI) consisting of a dyad of palindromically oriented imperfect TPA (12-O-tetradecanoyl-phorbol-13-acetate)-responsive elements (TRE). GPEI is active in AP1-lacking F9 cells as well in AP1-containing HeLa cells. Despite GPEI's similarity to a TRE, c-jun co-transfection has only a minimal effect on transactivation. Antisense c-jun and c-fos co-transfection experiments further demonstrate the lack of a role for AP1 in GPEI mediated trans-activation in F9 cells, although endogenously present AP1 can influence GPEI in HeLa cells. Co-transfection of delta fosB with c-jun, which forms an inactive c-Jun/delta FosB heterodimer that binds TRE sequences, inhibits GPEI-mediated transcription in AP1-lacking F9 cells as well as AP1-containing HeLa cells. These data suggest novel factor(s) other than AP1 are influencing GPEI. Binding studies reveal multiple nucleoproteins bind to GPEI. These factors are likely responsible for the high level of GPEI-mediated transcription observed in the absence of AP1 and during hepatocarcinogenesis.
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PMID:The dyad palindromic glutathione transferase P enhancer binds multiple factors including AP1. 140 31

A strong enhancer element, GPEI, of the glutathione transferase P gene (GST-P) gene is composed of two phorbol 12-O-tetradecanoate 13-acetate (TPA) responsive element (TRE)-like sequences at opposite orientation. Unlike TRE sequences of other genes, GPEI exhibits a strong enhancer activity in F9 cells, which contains little AP-1. GPEI bound to AP-1 In vitro and GST-P expression was activated by TPA and exogenously introduced c-jun gene in a rat fibroblast cell line. Both the stimulated expression of GST-P gene by TPA and that by over-expressed c-Jun were suppressed to the basal level by dexamethasone, an inhibitor of AP-1. Basal expression of GST-P gene, however, was not inhibited by dexamethasone. Transfected chloramphenicol acetyltransferase (CAT) gene having GPEI also behaved as the endogenous GST-P gene. These results indicate that the GPEI is activated by AP-1 but constitutive activity of this enhancer in a rat fibroblast cell line 3Y1 cells is due to some unknown mechanism other than AP-1.
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PMID:Suppression of glutathione transferase P expression by glucocorticoid. 153 Jun 52

Age-associated increases of transcript levels of several genes were studied using aged rat liver. Northern hybridization showed marked increases of c-jun, c-fos, and glutathione S-transferase P (GST-P) in 24-month-old rats. These genes have the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-responsive element called TRE in their structures. Thus, TRE seems to be involved in important age-associated changes of gene expression.
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PMID:Elevated levels of c-jun and c-fos transcripts in the aged rat liver. 171 24

To investigate the transcriptional regulation of human glutathione S-transferase pi (GST pi) gene expression, we fused the GST pi promoter, including 2203 bp of the 5'-flanking region, exon 1, and most of intron 1, to the chloramphenicol acetyltransferase (CAT)-encoding reporter gene (cat). When transfected into human cell lines, this GST-cat construct (-2203 GST-cat) supported high level cat gene expression. RNase-protection and primer-extension experiments showed that the normal GST pi transcriptional start point (tsp) is utilized, and furthermore, that intron 1 is faithfully removed by splicing from the majority of primary GST-cat transcripts. A series of constructs containing deletions in the GST pi sequences of the -2203 GST-cat vector were prepared to define potential regulatory regions. Transfection of these deletion plasmids revealed that a region between GST pi sequences -80 and -8 is absolutely required for cat expression. Furthermore, transfection of the -2203 GST-cat and deletion vectors into two human cell lines--one line which does not produce endogenous GST pi (HeLa cells) and one which produces high levels of endogenous GST pi (HS 578T cells)--failed to identify sequences that differentially influence the level of transcription in either cell line. A putative TRE (TPA responsive element or AP-1 recognition sequence) strategically situated upstream from the GST pi tsp (-69 to -63) was examined by TPA treatment of HeLa cells transfected with GST-cat DNA. Additionally, the potential interaction of fos and jun proteins with the GST pi promoter was examined by co-transfection of GST-cat constructs with jun and fos expression vectors in F9 cells. Both of these treatments, which are known to enhance transcription of several genes containing 5'-flanking TREs, failed to induce GST-cat expression. These data suggest that the putative TRE sequence in GST pi is unresponsive both to phorbol esters and to these particular transcriptional activating factors of the fos and jun family.
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PMID:Regulation of human glutathione S-transferase pi gene transcription: influence of 5'-flanking sequences and trans-activating factors which recognize AP-1-binding sites. 211 5

The mechanism of specific expression of glutathione transferase P gene during hepatocarcinogenesis of the rat has been investigated by cloning the gene and determining the upstream regulatory sequences. Two enhancers and a silencer are located within 3 kb upstream of the promoter. The stronger enhancer designated GPEI has two TPA (12-O-tetradecanoyl phorbol 13-acetate)-response element (TRE)-like sequences arranged in a palindrome at a 3 base pairs spacing. This special combination was found to form a very strong enhancer which could act efficiently even in F9 cells where the collagenase enhancer with a singlet TRE cannot work due to the low c-jun content. Whether this structure is operating with a very low concentration of c-jun/c-fos heterodimer or with any other proteins remains to be determined. These findings suggest that new and more efficient enhancers evolve by a combination of basic enhancer elements. The silencer region consists of several sequences that can bind specific protein(s) and works cooperatively.
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PMID:Mechanism of specific expression of glutathione transferase P gene during hepatocarcinogenesis. 213 78

We have recently identified an enhancer, termed GPEI, in the 5'-flanking region of the rat glutathione transferase P gene, that is composed of two imperfect TPA (phorbol 12-O-tetradecanoate 13-acetate) responsive elements (TREs). Unlike other TRE-containing enhancers, GPEI exhibits a strong transcriptional enhancing activity in F9 embryonic stem cells. Mutational analyses have revealed that the high activity of GPEI is mediated by two imperfect TREs. Each TRE-like sequence has no activity by itself but acts synergistically to form a strong enhancer which is active even in the very low level of AP-1 activity in F9 cells. Furthermore, we show that synthetic DNAs containing two perfect TREs in certain arrangements have strong transcriptional enhancing activities in F9 cells and the activity is greatly influenced by the relative orientation and the distance of two TREs.
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PMID:Functional cooperativity between two TPA responsive elements in undifferentiated F9 embryonic stem cells. 232 34

Detoxication (phase 2) enzymes, such as glutathione S-transferases (GSTs), NAD(P)H:(quinone-acceptor) oxidoreductase (QR), and UDP-glucuronsyltransferase, are induced in animal cells exposed to a variety of electrophilic compounds and phenolic antioxidants. Induction protects against the toxic and neoplastic effects of carcinogens and is mediated by activation of upstream electrophile-responsive/antioxidant-responsive elements (EpRE/ARE). The mechanism of activation of these enhancers was analyzed by transient gene expression of growth hormone reporter constructs containing a 41-bp region derived from the mouse GST Ya gene 5'-upstream region that contains the EpRE/ARE element and of constructs in which this element was replaced with either one or two consensus phorbol 12-tetradecanoate 13-acetate (TPA)-responsive elements (TREs). When these three constructs were compared in Hep G2 (human) and Hepa 1c1c7 (murine) hepatoma cells, the wild-type sequence was highly activated by diverse inducers, including tert-butylhydroquinone, Michael reaction acceptors, 1,2-dithiole-3-thione, sulforaphane,2,3-dimercapto-1-propanol, HgCl2, sodium arsenite, and phenylarsine oxide. In contrast, constructs with consensus TRE sites were not induced significantly. TPA in combination with these compounds led to additive or synergistic inductions of the EpRE/ARE construct, but induction of the TRE construct was similar to that induced by TPA alone. Transfection of the EpRE/ARE reporter construct into F9 cells, which lack endogenous TRE-binding proteins, produced large inductions by the same compounds, which also induced QR activity in these cells. We conclude that activation of the EpRE/ARE by electrophile and antioxidant inducers is mediated by EpRE/ARE-specific proteins.
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PMID:Electrophile and antioxidant regulation of enzymes that detoxify carcinogens. 756 53

The antioxidant response element (ARE) found in the 5'-flanking region of the rat quinone reductase gene has been further characterized by mutational and deletion analysis. The results indicate that the 31-base pair ARE, which contains a 13-base pair palindromic sequence, can be further separated into three regions, all three of which are required for elevated basal level gene expression. These three regions include the proximal and distal half-sites as well as a 3'-flanking region consisting of 4 adenine nucleotides. Neither the proximal nor the distal half-site alone mediates transcriptional activation by beta-naphthoflavone. However, when placed together the two half-sites restore responsiveness to the inducer. Interestingly, the presence of only 1 of the 4 adenine nucleotides in the 3'-flanking region of the proximal half-site is required for responsiveness to the inducer. Point mutations within the ARE indicate that several nucleotides in both the proximal and distal half-sites are required for basal level gene expression. Electrophoretic mobility shift analysis using the ARE as the probe indicates that enhancers found in the glutathione S-transferase Ya and P genes recognize a similar trans-acting factor(s) found in crude nuclear extracts from human Hep G2 cells. Further, this complex can be detected in nuclear extracts from rat liver and rat hepatoma cells but not in mouse Hepa 1c1c7 cells or in human HeLa cells. The ARE-nucleoprotein complex can also be detected in F9 cells which lack significant levels of Jun/Fos proteins. Although the rat ARE resembles the human quinone reductase ARE which contains a consensus TRE, the 2-nucleotide change in the core sequence (TGACTCA versus TGACTTG) eliminates the high affinity TRE motif in the rat ARE. The rat ARE forms a nucleoprotein complex in Hep G2 and other cells with different properties than AP-1.
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PMID:The rat quinone reductase antioxidant response element. Identification of the nucleotide sequence required for basal and inducible activity and detection of antioxidant response element-binding proteins in hepatoma and non-hepatoma cell lines. 759 62

The rat glutathione transferase P gene has a strong enhancer element, termed GPE I, which is composed of a dyad of palindromicly oriented TPA (phorbol 12-O-tetradecanoate 13-acetate) responsive element (TRE)-like sequences. TRE is a binding sequence of the transcription factor AP-1, which consists of several closely related proteins belonging to the Jun and Fos family. The gel retardation experiments show that all the heterodimers formed between the Jun and Fos related gene products bind to the GPE I as well as to the TRE. In spite of the fact that the GPE I has a stronger activity than the TRE, the binding affinities of these heterodimers to the GPE I are much lower than to the TRE. Co-transfection studies of the reporter construct containing the GPE I and expression constructs of each of the Jun and Fos family cDNAs indicate that FosB and delta FosB repress transcription through the GPE I enhancer. These results suggests that some of Jun/Fos family may regulate the rat GST-P gene expression through the GPE I in vivo.
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PMID:Jun and Fos related gene products bind to and modulate the GPE I, a strong enhancer element of the rat glutathione transferase P gene. 791 48

The Tax protein of the Human T-cell Leukemia Virus (HTLV) activates the expression of viral mRNA through a three 21 bp repeat enhancer located within the HTLV-1 LTR. Since Tax does not bind to the 21 bp DNA repeats directly, it has been speculated that Tax interacts with cellular protein(s) which mediate binding to the enhancer. We employed the yeast two hybrid system to identify host proteins that are potentially relevant to Tax transactivation. We identified a Tax binding protein encoded from a cDNA expression library derived from peripheral blood lymphocytes. The corresponding cDNA has sequence identity with a known transcription factor, activating factor-4 (ATF-4). ATF-4 also binds to GST-Tax fusion protein in vitro. Tax mutants that did not transactivate the HTLV-1 LTR also failed to bind ATF-4. The critical domain for Tax binding resides in a 85 amino acid stretch in the C-terminus of ATF-4, which contains the basic domain and leucine zipper. We further demonstrated that both full length and N-terminal truncated ATF-4 were able to enhance Tax transactivation. Thus, ATF-4 may act as an adapter between Tax and the TRE (Tax responsive element), and play an important role in Tax-mediated transactivation.
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PMID:Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). 919 Aug 94


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