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)

Three factors involved in the Solt and Farber model of rat liver carcinogenesis were studied alone and in various combinations: diethylnitrosamine (DEN) initiating dose, 2-acetylaminofluorene (2-AAF) feeding and partial hepatectomy. The administration of DEN alone (200 mg/kg) was able to switch on glutathione-S-transferase, placental type (GST-P) expression 3 weeks later at a low level (85 U/micrograms protein) which was stable for 10 weeks in the absence of histopathological lesions. During the same time, gamma-glutamyl transpeptidase (GGT) activity presented 2 waves of increase. The feeding of 0.03% 2-AAF for 2 weeks appeared as a determinant factor in the expression of GST-P protein as well as GGT induction (15- and 7-fold versus DEN alone, respectively). The addition of partial hepatectomy enhanced again GST-P expression (1.5-fold) and GGT induction (2-fold). However, GST-P foci increased in size, not in number while GGT foci increased both in size and in number. These data indicated that 2-AAF was a crucial component of the selection procedure since partial hepatectomy alone, with or without DEN initiation was inefficient in promoting GST-P expression. Therefore, 2-AAF would be able to promote the growth of GST-P-positive cells initiated by DEN, a mechanism likely responsible for its tumor-promoting effect.
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PMID:Role of diethylnitrosamine, 2-acetylaminofluorene and partial hepatectomy in the expression of glutathione-S-transferase-P and gamma-glutamyltranspeptidase in the early steps of rat liver carcinogenesis. 135 47

Many structurally unrelated nonmutagenic peroxisome proliferators induce altered areas, neoplastic nodules, and hepatocellular carcinomas in rats. Unlike the lesions induced by genotoxic hepatocarcinogens, these lesions do not stain positively for the phenotypic markers gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase P (GST-P). To ascertain whether the absence of immunocytochemically detectable GST-P and GGT proteins in peroxisome proliferator-induced neoplastic lesions is due to the absence of specific mRNAs, we analyzed the total RNA isolated from hepatocellular carcinomas induced by three different peroxisome proliferators (ciprofibrate, Wy-14643, and BR-931) and the genotoxic carcinogens, 2-acetylaminofluorene and aflatoxin B1 (AFB), for the presence of GST-P, GGT, and alpha-fetoprotein (AFP) mRNAs. Northern and dot blot analysis of total RNA isolated from liver tumors induced by three different peroxisome proliferators revealed no detectable GST-P, GGT, and AFP mRNAs. GST-P mRNA was also not detected in a transplantable hepatocellular carcinoma established from a liver tumor induced by ciprofibrate. In contrast, GST-P mRNA levels were high in primary liver tumors induced by both 2-acetylaminofluorene and AFB and the two transplantable hepatocellular carcinomas established from such tumors. By immunoblot method, GST-P protein was found to be abundant in both primary and transplantable liver tumors induced by genotoxic carcinogens but not in those derived from peroxisome proliferator treatment. The GGT and AFP mRNAs were also not found in all 18 liver tumors induced by peroxisome proliferators that were analyzed and also in the ciprofibrate-derived transplantable liver tumor. The expression of GGT and AFP genes in liver tumors induced by 2-acetylaminofluorene and AFB was variable. These studies with peroxisome proliferators show that the GST-P and GGT gene derepression is not essential for the hepatocarcinogenesis or successful tumor transplantation. Further characterization of the molecular basis for the differential expression, particularly of the GST-P gene in liver tumors, may help identification of the critical event(s) in hepatocarcinogenesis by genotoxic carcinogens and nongenotoxic peroxisome proliferators.
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PMID:Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators. 245 33

We have isolated the rat placental-type glutathione S-transferase (GST-P) gene from a lambda phage library using GST-P cDNA clone, pGP5 (Sugioka, Y., Kano, T., Okuda, A., Sakai, M., Kitagawa, T., and Muramatsu, M. (1985) Nucleic Acids Res. 13, 6049-6057), as a probe. The rat GST-P gene is about 3 kilobase pairs long and contains 7 exons and 6 introns, encoding the same GST-P protein specified by pGP5. The cap site maps 70 nucleotides upstream from the translation initiation site. The canonical promoter "TATA" box was found 27 base pairs upstream from the putative cap site. Two hundred base pairs upstream from the cap site are rich in G + C residues (61%), and the hexanucleotide sequence 5'-GGGCGG-3' is found at position -47 to -42. We have also isolated several processed-type pseudogenes which were presumably originated by reverse transcription followed by insertion at target sites.
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PMID:The structure of the rat glutathione S-transferase P gene and related pseudogenes. 302 28

A neutral isoenzyme of glutathione transferase designated glutathione-S-transferase 7-7, but also referred to as glutathione-S-transferase P (GST-P) is absent from adult rat liver hepatocytes, but expressed at a very early stage in chemically induced in vivo hepatocarcinogenesis. The expression of this enzyme in a range of aflatoxin B1 (AFB1) associated hepatocarcinogenic systems has been examined, including in vivo induced preneoplastic and neoplastic liver tissue, cell lines derived from hepatomas, primary hepatocytes in culture and an immortalized rat liver cell line before and after transformation in vitro either by transfection with ras oncogenes or by treatment with metabolically activated AFB1. Analyses of total cytosol proteins using a polyclonal antibody to GST-P did not detect the presence of GST-P protein in cytosols from control or regenerating liver. A low level of expression was detected in the immortalized, non-transformed epithelial cell line, but a greatly induced level occurred subsequent to transformation of these cells by either of the two techniques used. High levels of the protein were detected in in vivo induced preneoplastic and neoplastic tissues, and in the cell lines derived from them. Total RNA fractions isolated from the various cells or tissues, when examined with a cDNA probe for GST-P mRNA, showed it to be absent from control and regenerating rat liver. It was present at low levels in the untransformed cell line and primary hepatocytes after 48 h in culture, but present at greatest abundance in the in vivo and in vitro transformed cells. The results indicate that the highest elevation in expression of this protein is associated with the stage of definitive malignant transformation in in vitro carcinogenesis, and this could have relevance in defining comparable events in the in vivo multistage sequence.
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PMID:Transformation related expression of glutathione-S-transferase P in rat liver cells. 311 38

Since the expression of glutathione S-transferase P-form (GST-P) has been suggested from in vitro studies to be partly regulated by the oncogene product, c-Jun and c-Fos, their distributions were compared in normal rat tissues and preneoplastic hepatic lesions induced by the Solt-Farber protocol. Immunohistochemically demonstrated GST-P protein was positively correlated with expression of both c-Jun and c-Fos in the epidermis of the skin and the smooth muscle of adult lung and with either c-Jun or c-Fos respectively in the bile ducts and bronchial epithelium. However, GST-P expression was also observed in proximal and distal straight segments of the kidney and other tissues negative for c-Jun and c-Fos and both c-Jun and c-Fos were present in the renal proximal and distal convoluted tubules, where GST-P was lacking. Thus, the localization of GST-P was in some cases clearly separable from those of c-Jun or c-Fos. GST-P was found to be focally expressed from an early stage of hepatocarcinogenesis, when c-Jun was not detectable. At later stages, this oncogene product was stained in 35.7% of GST-P-positive foci, with a clear relation to the degree of GST-P staining. Since GST-P is not always accompanied by appreciable c-Jun or c-Fos, these oncogene products are apparently not prerequisites for its expression. However, c-Jun may be partly responsible for maintaining high levels of GST-P in hepatic foci at later stages of hepatocarcinogenesis.
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PMID:Lack of correlated expression between the glutathione S-transferase P-form and the oncogene products c-Jun and c-Fos in rat tissues and preneoplastic hepatic foci. 769 15

Expression of the placental form of glutathione S-transferase (GST-P) in 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloro-ethyl)-3-nitrosourea hydrochloride (ACNU)-sensitive 9L and C6 glioma cells, and ACNU-resistant 9L (9LR) and C6 (C6R) glioma cells was investigated by Northern blot analysis for GST-P mRNA and Western blot analysis for GST-P protein. The sensitivity of 9L, 9LR, C6 and C6R cell lines to ACNU was evaluated by microculture tetrazolium assay. Localization of GSTP-P protein in these cell lines was investigated by immunocytochemical method. Expression level of GST-P mRNA in 9LR cells was 3 times that of 9L cells and the level of GST-P protein in 9LR cells was 1.7 times that of 9L cells. On the contrary, the amount of GST-P mRNA of C6R cells was 1.3-fold larger than C6 cells and that of GST-P protein of C6R cells was 1.3-fold larger than C6 cells. Immunocytochemical investigation revealed that 9LR cells had stronger expression of GST-P in their cytoplasm than 9L cells. Expression of GST-P in both C6R and C6 cells was less than 9L and 9LR cells, and the amount was similar to each other. The present study suggests that GST-P may play an important role in detoxification of anti-cancer drugs in some glioma cells.
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PMID:Identification of placental form of glutathione S-transferase in ACNU-resistant murine glioma cell lines. 816 57

Hepatocytes in vivo express Alpha and Mu but not Pi forms of glutathione S-transferase (GST). GST P (a fetal Pi form) appears in rat hepatocytes after 2 days in primary culture, which suggests that hepatocytes may undergo dedifferentiation [Abramovitz, Ishigaki and Listowsky (1989) Hepatology 9, 235-239]. However, in this and other studies, primary rat hepatocyte cultures were shown by immunohistochemistry to contain significant numbers of lipocytes (Ito cells). Freshly isolated lipocytes contained GST activity when assayed with chlorodinitrobenzene (680 nmol/min per mg), and expression of Alpha, Mu and Pi forms of GST was detected by Western-blot analysis. Expression of GST P persisted during culture of the lipocytes. In situ hybridization of the cultured cells was performed to define whether hepatocytes, lipocytes or both expressed the enzyme. Lipocytes in culture contained abundant GST P transcripts. Hepatocytes contained no GST P transcripts after 12 h in culture, and after 24 h, only a few hepatocytes expressed this enzyme. After 48 h in culture all hepatocytes contained GST P transcripts, and the number of transcripts continued to increase up until 72 h. Therefore, in freshly isolated preparations of hepatocytes and early in hepatocyte culture, measurable levels of GST P protein or message appeared to reflect the presence of lipocytes. After 48 h in culture almost all of the GST P reflected expression by the hepatocytes. Lipocytes constitutively expressed Alpha-, Mu- and Pi-class GSTs and had significant intracellular levels of GSH (5.2 nmol/mg of protein). Lipocytes are capable therefore of detoxifying a number of injurious compounds.
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PMID:Cellular sources of glutathione S-transferase P in primary cultured rat hepatocytes: localization by in situ hybridization. 816 62

While glutathione S-transferase P form (GST-P), a reliable marker for preneoplastic lesions induced by mutagenic hepatocarcinogens, is generally not expressed in rat liver foci, hyperplastic nodules and hepatomas induced by peroxisome proliferators (PPs), such lesions can be detected due to their peroxisomal enzyme-negative nature. For comparative purposes we examined the inducibility of enoyl CoA hydratase (ECH), a key peroxisomal enzyme, in rat hepatic preneoplastic lesions induced by mutagenic carcinogens. Clofibrate (CF) was therefore administered for 2 or 4 weeks following performance of the Solt-Farber protocol using diethylnitrosamine and 2-acetylaminofluorene. Immunohistochemical examination revealed no or only very weak expression of ECH within the induced foci in clear contrast to the strong staining of surrounding parenchyma. ECH expression was thus diametrically opposed to that of GST-P which was found only in foci. Although ECH was completely lacking in GST-P-strongly positive foci, it was expressed in GST-P-negative hepatocytes inside some foci otherwise positive for GST-P. CF administration resulted in a significant decrease in the numbers and areas of foci exhibiting strongly positive or positive GST-P staining; this being reflected in a lowering of GST-P protein levels. Furthermore, in primary cultured rat hepatocytes, clofibric acid as well as dexamethasone suppressed the expression of both GST-P and the oncogene, c-jun. These results taken together suggest that possible interaction of the PP receptor with JUN might be involved in loss of ECH expression in GST-P-strongly positive foci.
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PMID:Lack of peroxisomal enzyme inducibility in rat hepatic preneoplastic lesions induced by mutagenic carcinogens: contrasted expression of glutathione S-transferase P form and enoyl CoA hydratase. 845 14

Measles virus (MV) expresses at least 3 proteins from the phosphoprotein (P) cistron. Alternative translation initiation directs synthesis of the C protein from the +1 reading frame, while so-called RNA editing generates a second population of mRNAs which express the V protein from the -1 reading frame which lies within and overlaps the larger P reading frame. While the P protein has been demonstrated to be an essential cofactor for the L protein in the formation of active transcriptase complexes, the functions of the V and C proteins remain unknown. In order to investigate these functions, we have expressed the MV P, V and C proteins as GST fusions in E. coli for affinity purification and use in an in vitro binding assay with other viral and cellular proteins. The P protein was found to interact with L, NP, and with itself. These interactions were mapped to the carboxy-terminal half of the protein which is absent in the V protein. In contrast, both the V and C proteins failed to interact with any other viral proteins, but were each found to interact specifically with one or more cellular proteins. Appropriate aspects of these results were confirmed in vivo using the yeast two-hybrid system. These observations suggest that the V and C proteins may be involved in modulation of the host cellular environment within MV-infected cells. Such activity would be distinct from their previously proposed role in the possible down-regulation of virus-specific RNA transcription and replication.
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PMID:Protein interactions entered into by the measles virus P, V, and C proteins. 857 62

The partially overlapping ORF P and ORF O are located within the domains of the herpes simplex virus 1 genome transcribed during latency. Earlier studies have shown that ORF P is repressed by infected cell protein 4 (ICP4), the major viral regulatory protein, binding to its cognate site at the transcription initiation site of ORF P. The ORF P protein binds to p32, a component of the ASF/SF2 alternate splicing factors; in cells infected with a recombinant virus in which ORF P was derepressed there was a significant decrease in the expression of products of key regulatory genes containing introns. We report that (i) the expression of ORF O is repressed during productive infection by the same mechanism as that determining the expression of ORF P; (ii) in cells infected at the nonpermissive temperature for ICP4, ORF O protein is made in significantly lower amounts than the ORF P protein; (iii) the results of insertion of a sequence encoding 20 amino acids between the putative initiator methionine codons of ORF O and ORF P suggest that ORF O initiates at the methionine codon of ORF P and that the synthesis of ORF O results from frameshift or editing of its RNA; and (iv) glutathione S-transferase-ORF O fusion protein bound specifically ICP4 and precluded its binding to its cognate site on DNA in vitro. These and earlier results indicate that ORF P and ORF O together have the capacity to reduce the synthesis or block the expression of regulatory proteins essential for viral replication in productive infection.
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PMID:The product of ORF O located within the domain of herpes simplex virus 1 genome transcribed during latent infection binds to and inhibits in vitro binding of infected cell protein 4 to its cognate DNA site. 929 19


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