Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

Glutathione transferase P (GST-P) gene is specifically and highly activated during rat chemical hepatocarcinogenesis. We have previously cloned the GST-P gene and have identified putative regulatory regions. To further explore regulatory mechanisms, deletion constructs of the GST-P gene fused to the chloramphenicol acetyltransferase (CAT) structural gene were introduced into primary cultured rat hepatocytes by electroporation, and their activity was determined. The expression of the GST-P-CAT fusion gene is quite low in these cells as compared to that in both a rat fibroblast cell line, 3Y1 cells, and a rat hepatoma cell line, dRLh84. The presence of the strong enhancer GPEI did not elicit any enhancing activity at its original position, or when it was located 3' of the CAT gene, although this element does enhance CAT activity significantly when located adjacent to the promoter. Cotransfection of neither c-jun nor c-fos expression vector, nor both vectors, could enhance the CAT activity, even though GPEI consists of two phorbol ester response element-like sites. Furthermore, the expression of jun family gene was not correlated with GST-P gene expression either in primary cultured hepatocytes or in hepatoma cell lines.
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PMID:Analysis of glutathione transferase P gene regulation with liver cells in primary culture. 144 99

The glutathione transferases, a family of multifunctional proteins, catalyze the glutathione conjugation reaction with electrophilic compounds biotransformed from xenobiotics, including carcinogens. In preneoplastic cells as well as neoplastic cells, specific molecular forms of glutathione transferase are known to be expressed and have been known to participate in the mechanisms of their resistance to drugs. In this article, following a brief description of recently identified molecular forms, we review new findings regarding the respective molecular forms involved in carcinogenesis and anticancer drug resistance, with particular emphasis on Pi class forms in preneoplastic tissues. The rat Pi class form, GST-P (GST 7-7), is strongly expressed not only in hepatic foci and hepatomas, but also in initiated cells that occur at the very early stages of chemical hepatocarcinogenesis, and is regarded as one of the most reliable markers for preneoplastic lesions in the rat liver. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-responsive element-like sequences have been identified in upstream regions of the GST-P gene, and oncogene products c-jun and c-fos are suggested to activate the gene. The Pi-class forms possess unique enzymatic properties, including broad substrate specificity, glutathione peroxidase activity toward lipid hydroperoxides, low sensitivity to organic anion inhibitors, and high sensitivity to active oxygen species. The possible functions of Pi class glutathione transferases in neoplastic tissues and drug-resistant cells are discussed.
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PMID:Glutathione transferases and cancer. 152 61

The expression of nine proto-oncogenes (c-myc, N-myc, c-fos, c-jun, p53, H-ras, N-ras, c-raf, hst) and other three genes (AFP, PCNA, GST-P) were investigated during spontaneous development to hepatocellular carcinomas (HCCs) in LEC rats. Expressions of c-myc, H-ras, N-ras, c-raf, p53, and PCNA genes were detected but did not significantly change during the development to HCCs in LEC rats. Expressions of N-myc, hst, and AFP genes were not detectable since 5 weeks after birth. Expression of c-fos gene was detected in one out of four HCCs. Significantly increased expression of c-jun gene was observed in the liver tissues of LEC rats aged 8 months. The high expression was decreased in HCCs. On the other hand, the expression of GST-P gene increased in parallel with the clinical course of the development to HCCs in LEC rats. The increased expression of GST-P gene was observed in the liver tissues of LEC rats aged 8 months, and HCCs showed very high expression of GST-P gene. These observations suggest that both c-jun and GST-P genes may play a role in the spontaneous development to HCCs in LEC rats.
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PMID:[A study on expression of various oncogenes and tumor-associated genes in LEC rats spontaneously developing hepatitis and hepatoma]. 169 10

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

An electrophile-responsive element (EpRE) in the 5' flanking region of the mouse glutathione S-transferase Ya subunit gene was recently found to be responsible for the induction of gene expression by xenobiotics that contain or acquire by metabolism an electrophilic center. We now find that this EpRE is composed of two adjacent 9-base-pair motifs related in sequence to the AP-1 binding site, a transcriptional enhancer originally identified as the phorbol 12-myristate 13-acetate (PMA) response element and known to be regulated by the binding of protein products of c-jun and c-fos genes. Synthetic oligonucleotides representing each of the AP-1-like binding sites of the EpRE and the AP-1 site consensus sequence were prepared and assayed for their enhancer activity and inducibility by tert-butylhydroquinone, beta-naphthoflavone, and PMA. Single AP-1-like sequences showed a lower enhancer activity than an AP-1 consensus sequence and no inducibility. Two adjacent AP-1-like sites were found to act synergistically and to confer inducibility beyond that observed for a single AP-1 consensus sequence. Examination of the PMA-responsive region of a number of genes shows the presence of adjacent AP-1-like sites and indicates that the structure of the EpRE found in the Ya gene may occur more generally and may be important in regulating the magnitude of the electrophilic response. The present study demonstrates the binding and transactivation of the EpRE by Jun and Fos and indicates that the AP-1 site is part of the EpRE. The induction by PMA or tert-butylhydroquinone appears to be independent of protein kinase C activity since it is not affected by inhibitors of this enzyme.
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PMID:Two adjacent AP-1-like binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene. 173 39

The effects of epidermal growth factor (EGF) (10 ng/ml) and insulin (100 nM) on the expression of glutathione S-transferases (GSTs), especially the GST-P form (GST 7-7), were examined in primary cultured rat hepatocytes in serum-free medium. On culture with EGF and insulin, the GST activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene were transiently decreased on day 2 to 10% of those of freshly isolated hepatocytes and then increased to 60 to 100% of those of freshly isolated cells on day 4. Western blot analysis of GSTs revealed that GST-P, which is not present in freshly isolated hepatocytes, was markedly induced and that GST subunits 3 and 4 of the Mu class also increased after addition of EGF and/or insulin, while the subunits 1 and 2 of the Alpha class disappeared. Northern blot analysis showed that on addition of EGF and insulin the level of GST-P mRNA was also elevated and expressions of the nuclear oncogenes c-jun and c-fos were enhanced. These results suggest that the enhanced expression of GST-P induced by EGF or insulin in primary cultured rat hepatocytes might be regulated by JUN and FOS proteins.
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PMID:Induction of glutathione S-transferase P-form in primary cultured rat hepatocytes by epidermal growth factor and insulin. 190 48

We have studied the expressions of nine proto-oncogenes (c-myc, N-myc, c-fos, C-jun, p53, H-ras, N-ras, c-raf, hst) and two other genes (PCNA, GST-P) during the spontaneous development of hepatocellular carcinomas (HCCs) in LEC rats. Expression of c-myc, H-ras, N-ras, C-raf, p53 and PCNA genes was detected, but this did not significantly change during the development of HCCs in LEC rats. Expression of N-myc and hst genes was not detectable. Expression of c-fos gene was detected in one HCC case out of four. Significantly increased expression of c-jun gene was observed in the liver tissues of LEC rats aged 8 months. This high expression was decreased with the development of HCCs. On the other hand, the expression of GST-P gene increased in parallel with the clinical course of the development of HCCs in LEC rats. The pattern of c-jun mRNA augmentation was different from that of GST-P mRNA. These observations suggest that c-jun gene may play a role in the spontaneous development of HCCs in LEC rats.
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PMID:Increased expression of c-jun gene during spontaneous hepatocarcinogenesis in LEC rats. 197 34

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


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