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

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

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

Glutathione transferase P gene becomes highly and constitutively expressed in the course of chemical hepatocarcinogenesis of the rat. To understand the mechanism of this specific gene activation and also to obtain an insight into the general mechanism of tumor marker expression, we have been studying the regulation of a cloned gene of this enzyme. Analysis of the GST-P cDNA clone revealed that this enzyme consists of 209 amino acid residues and that homologies with other isozymes, Ya and Yc, were both about 32%. The rat GST-P gene consists of seven exons and six introns. Multiple regulatory elements were found in the 5' flanking region including two TPA responsive elements (TRE), a GC box, viral enhancer, core-like elements, and a silencer. This gene was activated by a tumor promoter TPA in certain cell lines. The rat cDNA clone or a TRE binding protein, c-jun oncogene, was isolated and characterized. Analysis of the tissue distribution and expression during chemical hepatocarcinogenesis of the c-jun mRNA suggests that the GST-P gene is regulated, at least in part, by the c-jun product. Further investigation of the mechanism of expression of GST-P, particularly in terms of the interaction with c-jun products, is now underway.
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PMID:Regulation of glutathione transferase P (GST-P) gene expression during chemical hepatocarcinogenesis. 239 67

The carboxyl-terminal domain of the zeta 1 subunit of the mouse NMDA receptor channel produced as a fusion protein with GST was phosphorylated in vitro by PKC. A mutant of the zeta 1 subunit without serine or threonine residues in the carboxyl-terminal domain (zeta 1-2-NST) was constructed and was expressed alone or together with the epsilon 2 subunit in Xenopus oocytes. Current responses of the zeta 1-2-NST homomeric and epsilon 2/zeta 1-2-NST heteromeric NMDA receptor channels were enhanced by treatment with TPA, a PKC activator, and the extents of potentiation were comparable with the corresponding wild-type channels. These results suggest that the phosphorylation of the carboxyl-terminal domain of the zeta 1 subunit is not responsible for potentiation of NMDA receptor channels by the TPA treatment.
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PMID:Phosphorylation of the carboxyl-terminal domain of the zeta 1 subunit is not responsible for potentiation by TPA of the NMDA receptor channel. 750 80

In the NCI, Chemoprevention Branch drug development program, potential chemopreventive agents are evaluated for efficacy against chemical carcinogen-induced tumors in animal models. This paper summarizes the results of 144 agents in 352 tests using various animal efficacy models. Of these results, 146 were positive, representing 85 different agents. The target organs selected for the animals model are representative of high-incidence human cancers. The assays include inhibition of tumors induced by MNU in hamster trachea, DEN in hamster lung, AOM in rat colon (including inhibition of AOM-induced aberrant crypts), MAM in mouse colon, DMBA and MNU in rat mammary glands, DMBA promoted by TPA in mouse skin, and OH-BBN in mouse bladder. The agents tested may be classified into various pharmacological and chemical structural categories that are relevant to their chemopreventive potential. These categories include antiestrogens, antiinflammatories (e.g., NSAIDs), antioxidants, arachidonic acid metabolism inhibitors, GST and GSH enhancers, ODC inhibitors, protein kinase C inhibitors, retinoids and carotenoids, organosulfur compounds, calcium compounds, vitamin D3 and analogs, and phenolic compounds (e.g., flavonoids). The various categories of compounds have different spectra of efficacy in animal models. In hamster lung, GSH-enhancing agents and antioxidants appear to have high potential for inhibiting carcinogenesis. In the colon, NSAIDs and other antiinflammatory agents appear particularly promising. Likewise, NSAIDs are very active in mouse bladder. In rat mammary glands, retinoids and antiestrogens (as would be expected) are efficacious. Several of the chemicals evaluated also appear to be promising chemopreventive agents based on their activity in several of the animal models. Particularly, the ODC inhibitor DFMO was active in the colon, mammary glands, and bladder models, while the dithiolthione, oltipraz, was efficacious in all the models listed above (i.e., lung, colon, mammary glands, skin, and bladder).
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PMID:Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models: methods and results from the NCI Chemoprevention Drug Development Program. 761 52

By use of an isolation procedure including centrifugal elutriation and density gradient centrifugation, relatively pure fractions of Clara cells and type II cells were obtained from rabbit lungs. These cells and alveolar macrophages isolated by lavage were exposed to methyl methanesulfonate (MMS), 1,2-dibromo-3-chloropropane (DBCP), 1-nitropyrene (1-NP), 2-nitrofluorene (2-NF), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosonornicotine (NNN), N-nitrosoheptamethyleneimine (NHMI) or phorbol 12-myristate 13-acetate (TPA). DNA damage measured as alkali-labile sites and/or single-strand breaks was then determined in the different lung cells by an automated alkaline elution system. The direct-acting compound MMS showed similar DNA-damaging effect in Clara cells, type II cells and alveolar macrophages. The nematocide DBCP, activated by both P450- and glutathione S-transferase(s)-dependent pathways, caused considerably less DNA damage in macrophages than in Clara or type II cells. Similar differences between the lung cells in induction of DNA damage as observed with DBCP were demonstrated after exposure to the activation-dependent nitrosamines NNK and NHMI and the tumor promoter TPA. The other test substances (1-NP, 2-NF, NNN) did not cause any marked DNA damage measured by the alkaline elution technique. These findings are in agreement with the known metabolic capacity of these cell types, indicating that Clara and type II cells are possible primary targets for lung toxic/carcinogenic compounds.
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PMID:Chemically induced DNA damage in isolated rabbit lung cells. 767 4

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


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