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)

We have shown previously that overexpression of p-170 glycoprotein-mediated multidrug resistance plays only a minor role in conferring chemoresistance to human melanoma cells. In addition to membrane transporters like p-170, metabolizing enzyme systems have been implicated in altered drug sensitivity. Recently, glutathione and associated enzymes have been associated with resistance to alkylating substances, particularly in gastrointestinal and gynecologic cancers. In this study, we investigated whether increased levels of glutathione and related enzymes may play a role in chemoresistance in melanoma. Levels of glutathione, glutathione S-transferase (GST), glutathione reductase, and gamma-glutamyl transpeptidase were analyzed in melanoma and non-melanoma cell lines. In addition, 18 melanoma metastases derived from skin and lymph nodes were examined. Levels of gamma-glutamyl transpeptidase were statistically different in cells derived from melanocytic tumors compared with non-melanoma cell lines and normal cells. In addition, GST levels in metastases derived from skin or lymph nodes were significantly lower than those in permanent cell lines. However, levels of glutathione and related enzymes in metastases and cell lines fluctuated over a wide range, up to 40-fold, regardless of treatment status or origin of metastases. In a second part of the study, the expression of GST isoenzymes alpha, mu, and pi was studied by immunohistology in 10 benign nevi, 29 primary melanomas, and 39 melanoma metastases before and during chemotherapy. Expression of GST isoenzymes was increased with tumor progression, and GST pi was the strongest isoform expressed. However, no correlation was found between GST levels by immunohistochemistry and the course of tumor progression, between GST levels in metastases obtained before or during chemotherapy, or between GST levels and clinical response. These data suggest that alterations in glutathione metabolism and the expression of GST do not play a major role in resistance to chemotherapeutic drugs in melanoma.
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PMID:Glutathione and related enzymes in tumor progression and metastases of human melanoma. 761 63

The herpes simplex virus 1 UL10 gene encodes a hydrophobic membrane protein dispensable for viral replication in cell culture (J.D. Baines and B. Roizman, J. Virol. 65:938-944, 1991). We report the following. (i) A fusion protein consisting of glutathione S-transferase fused to the C-terminal 93 amino acids of the UL10 protein was used to produce a rabbit polyclonal antiserum. The antiserum reacted with infected-cell proteins which formed in denaturing polyacrylamide gels a sharp band (apparent M(r) of 50,000) and a very broad band (M(r) of 53,000 to 63,000). These bands were not formed by lysates of UL10- virus or by lysates of infected cells boiled in the presence of sodium dodecyl sulfate before electrophoresis. (ii) The proteins forming both bands were labeled by [3H]glucosamine, indicating that they were glycosylated. (iii) The UL10 protein in cells treated with tunicamycin formed a single band (apparent M(r) of 47,000) reactive with the anti-UL10 antibody, indicating that the 47,000-M(r) protein was a precursor of N-glycosylated, more slowly migrating forms of UL10. Treatment of the immunoprecipitate with endoglycosidase H increased the electrophoretic mobility of the 50,000-M(r) species to that of the 47,000-M(r) species, indicating that the 50,000-M(r) species contained high-mannose polysaccharide chains, whereas the proteins forming the 53,000- to 63,000-M(r) bands contained mature chains inasmuch as they were resistant to digestion by the enzyme. (iv) The UL10 protein of R7221 carrying a 20-amino-acid epitope formed only one band with an M(r) of 53,000. This band was sensitive to endoglycosidase H, suggesting that the epitope inserted in the R7221 UL10 protein may have interfered with glycosylation. (v) The UL10 protein does not contain a cleavable signal sequence inasmuch as the first UL10 methionine codon was reflected in the 50,000-M(r) protein. (vi) The UL10 protein is present in virions and plasma membranes of unfixed cells that were reacted with the polyclonal rabbit antibody. In accordance with the current nomenclature, the UL10 protein is designated glycoprotein M.
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PMID:The UL10 gene of herpes simplex virus 1 encodes a novel viral glycoprotein, gM, which is present in the virion and in the plasma membrane of infected cells. 767 47

Two glutathione S-transferase fusion proteins containing 44 (p1503) and 75 (p1509) amino acid residues of the rubella virus E1 glycoprotein were expressed in Escherichia coli with the aim of producing a recombinant rubella virus antigen for use in serological assays. p1503 contained three neutralizing and hemagglutinating epitopes (G. M. Terry, L. M. Ho-Terry, P. Londesborough, and K. R. Rees, Arch. Virol. 98:189-197, 1988); p1509 contained the putative neutralization domain described by Mitchell et al. (L. A. Mitchell, T. Zhang, M. Ho, D. Decarie, A. Tingle, M. Zrein, and M. Lacroix, J. Clin. Microbiol. 30:1841-1847, 1992) in addition to the three epitopes present in p1503. Both fusion proteins were soluble and affinity purified on glutathione-Sepharose 4B. In Western blots (immunoblots), p1503 and p1509 reacted with human sera containing rubella virus-specific immunoglobulin G. When used as antigens in indirect enzyme immunoassays to detect rubella virus-specific immunoglobulin G, p1503 correctly identified the rubella virus antibody status of 43 (76.8%) and p1509 correctly identified that of 48 (85.7%) of 56 serum samples received for routine rubella virus antibody screening. The results obtained with p1509 compare well with those obtained with a latex agglutination assay.
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PMID:Use of rubella virus E1 fusion proteins for detection of rubella virus antibodies. 771 76

The Epstein-Barr virus (EBV) open reading frame BDLF3 is predicted to code for a glycoprotein on the basis that it contains sequences with signal peptide and transdomain characteristics and nine potential N-linked glycosylation sites. No sequential or positional homologues of BDLF3 have been located in other herpesviruses. A bacterial glutathione S-transferase (GST)-BDLF3 fusion protein was used to demonstrate that over one-third of EBV-immune human sera tested recognized the fusion protein but not GST alone on Western blots. The fusion protein was used to raise polyclonal sera in rabbits. A BDLF3 recombinant baculovirus was constructed using the full-length BDLF3 sequence (AcBDLF3). Rabbit anti-fusion protein sera and some human EBV-immune sera recognized products of approximately 30 and 55 kDa from AcBDLF3-infected insect cells by Western blotting. A peptide representing the carboxy-terminal amino acids 215-234 of the BDLF3 sequence was used to raise anti-peptide sera in rabbits. Anti-peptide serum detected a product by indirect immunofluorescence in acetone-fixed EBV-infected B cells from all cell lines tested. A diffuse band with a molecular mass of 100-150 kDa was detected by Western blot in B95-8 cell lysates, partially purified B95-8 virus and B95-8-infected cell membranes after probing with anti-BDLF3 peptide serum. This product was shown to be glycosylated after enzymatic deglycosylation of a B95-8 virus preparation using neuraminidase, O-glycosidase or N-glycosidase F. The BDLF3 protein products have no known function.
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PMID:The Epstein-Barr virus open reading frame BDLF3 codes for a 100-150 kDa glycoprotein. 778 67

The multidrug resistance-associated protein (MRP) is a 180- to 195-kDa glycoprotein associated with multidrug resistance of human tumor cells. MRP is mainly located in the plasma membrane and it confers resistance by exporting natural product drugs out of the cell. Here we demonstrate that overexpression of the MRP gene in human cancer cells increases the ATP-dependent glutathione S-conjugate carrier activity in plasma membrane vesicles isolated from these cells. The glutathione S-conjugate export carrier is known to mediate excretion of bivalent anionic conjugates from mammalian cells and is thought to play a role in the elimination of conjugated xenobiotics. Our results suggest that MRP can cause multidrug resistance by promoting the export of drug modification products from cells and they shed light on the reported link between drug resistance and cellular glutathione and glutathione S-transferase levels.
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PMID:Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. 780 67

Four human breast cancer cell lines with or without estrogen and progesterone receptors were adapted to growth in the continuous presence of doxorubicin (Dox) at 10 (Zr-75-1), 15 (HTB-122), or 50 (MDA-MB-231 and Hs578T) ng/ml. The sublines of Zr-75-1, MDA-MB-231 and Hs578T showed 5-10-fold Dox resistance and also cross-resistance to vincristine (VCR) and etoposide (VP16). The sublines of Zr-75-1, MDA-MB-231 and Hs578T showed 5-10-fold Dox resistance and also cross-resistance to vincristine (VCR) and etoposide (VP16). The sublines maintained or slightly increased their cis-platinum (CDDP) sensitivity. The sublines of HTB-122 showed resistance only to VP16 combined with a paradoxical increased sensitivity to VCR. The phenotypic alteration in the sublines with respect to Dox sensitivity was maintained for at least two months in the absence of Dox. The glutathione depletor buthionine sulfoximine (BSO) and the calcium channel blocker verapamil (Ver) increased the Dox sensitivity slightly only in the MDA-MB-231 and Hs578T sublines, respectively. Ver also tended to protect some of the sublines from CDDP. The sublines of Zr-75-1 and Hs578T showed increased expression of the 170-kDa permeability glycoprotein (P-gp), whereas expression of a 85-kDa membrane protein determined by the MRK20 antibody was increased in the sublines of Zr-75-1, and HTB-122. Class pi glutathione transferase (GST) levels varied greatly between the cell lines but increased during Dox selection only in the subline of Zr-75-1. Class mu GST was detectable in the MDA-MB-231, Hs578T and HTB-122 cell lines, whereas class alpha GST was detectable in these sublines but undetectable in their parental cell lines. The Zr-75-1 subline showed a 5-fold increase in the class alpha concentration. Except for a correlation between increased P-gp expression and resistance to Dox, VCR and VP16, no obvious correlations between receptor status, increased P-gp expression, membrane proteins, GST levels and acquired drug resistance were found. Thus, except for a possible role for P-gp in multidrug-resistance, these findings indicate a pronounced mechanistic heterogeneity responsible for cytotoxic drug sensitivity also in cells with a common histologic origin and exposed to the same drug.
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PMID:Characterization of four doxorubicin adapted human breast cancer cell lines with respect to chemotherapeutic drug sensitivity, drug resistance associated membrane proteins and glutathione transferases. 790 62

One of the main problems in clinical oncology is an acquired cellular drug resistance. Special attention deserves the multidrug resistance phenomenon (MDR) involving tumors which become resistant to a wide spectrum of non-related drugs to which they have never been exposed. Several mechanisms responsible for this phenomenon have been described. Among them is the increased expression of the MDR1 gene which encodes the plasma membrane glycoprotein P-gp. This glycoprotein is an energy-dependant multidrug efflux pump of wide specificity. It seems to have a normal physiological function but in some tumors resistant to chemotherapy its expression is increased. In cell lines the increased expression of P-gp is correlated with a decreased accumulation and retention of drugs inside the cells. In addition to P-gp, at least two other mechanisms of multidrug resistance have been described: a decreased expression and changes in the catalytic activity of topoisomerase II enzyme, and changes in glutathione transferase levels. Through biochemical and molecular methods researchers continue to look for a correlation between non-responding tumors and changes in the known drug-resistance mechanisms. These studies suggest that several factors are involved in the cellular drug resistance observed in human tumors, and probably are interacting between them. In clinical practice, the need of controlling MDR phenomena has led to the creation of alternate therapeutic strategies.
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PMID:[Multiple drug resistance: a problem in cancer chemotherapy]. 790 10

Neutrophil inhibitory factor (NIF) is a hookworm-derived glycoprotein ligand of the integrin CD11b/CD18 that inhibits human neutrophil function (Moyle, M., Foster, D. L., McGrath, D. E., Brown, S. M., Laroche, Y., De Meutter, J., Stanssens, P., Bogowitz, C. A., Fried, V. A., Ely, J. A., Soule, H. R., and Vlasuk, G. P. (1994) J. Biol. Chem. 269, 1008-10015). Here, we present evidence that recombinant NIF (rNIF) associates with the approximately 200-amino acid residue I domain of CD11b/CD18 and that this interaction is essential for inhibition of neutrophil function by NIF. First, radiolabeled rNIF binds to a recombinant glutathione S-transferase fusion protein that contains the CD11b I domain. This high affinity interaction has a partial dependence on divalent cations. The association of rNIF with the CD11b I domain is specific because 125I-rNIF does not bind either a glutathione S-transferase fusion protein that contains the I domain of the integrin CD11a/CD18 or recombinant glutathione S-transferase without the I domain. Second, the CD11b I domain fusion protein effectively competes with CD11b/CD18 on human neutrophils for 125I-rNIF binding. Third, the CD11b I domain fusion protein blocks the inhibition of certain neutrophil functions by rNIF, including adhesion of neutrophils to human endothelial cell monolayers and adhesion-dependent release of hydrogen peroxide from neutrophils. Specificity is demonstrated by the inability of the CD11a I domain fusion protein to block either rNIF binding to neutrophils or rNIF activity. Fourth, rNIF blocks the interaction between neutrophils and fibrinogen, a CD11b/CD18 ligand that is also thought to bind the I domain of CD11b. In contrast, rNIF does not appear to block the binding of factor X to CD11b/CD18 on neutrophils. These results suggest that CD11b/CD18 has multiple distinct binding sites for its cognate ligands, including, but not limited to, the I domain. NIF interferes with the binding of a subset of these CD11b/CD18 ligands in a highly selective manner.
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PMID:Functional interaction between the integrin antagonist neutrophil inhibitory factor and the I domain of CD11b/CD18. 792 63

By 1915 the very complex life cycles of all the major schistosomes of man had been completely worked out. The disease could be attacked by removing the adult worms with drugs, by eliminating the snail hosts by habitat modifications, and by the provision of safe water supplies. Effective drugs, e.g., trivalent antimonials, were introduced in 1918. In the 1920s copper sulphate was shown to be lethal to the aquatic vectors of S. mansoni and S. haematobium and lime was first used to attack the amphibious vectors of S. japonicum. In the search for antischistosome vaccines several protective antigens have been defined at the molecular level and are being evaluated in animal models. The characteristic decline in age-specific prevalence and intensity of infection seen in S. haematobium and S. mansoni endemic areas is largely due to the gradual development of acquired immunity. In the 1970s, work involving immunization with irradiation attenuated or heterologous, normal cercariae, using several different animal models demonstrated that short-lived larval infections could reliably induce significant levels of resistance to challenge infection with normal cercariae. The concomitant immunity premise led to the purification of the first such antigen, the 38 kDa S. mansoni surface glycoprotein GP38. Vaccination with KLH also protected rats against S. mansoni infection and elicited anti-GP38 antibodies which could passively protect rats; deglycosylation of KLH abolished these properties. S. mansoni GST was identified for protective antigens suitable for gene cloning. The protective efficacy of combined GST/KLH S. japonicum vaccines and the efficacy of recombinant-derived GSTs, and of S. japonicum paramyosin are being explored in sheep and bovines in China. Two irradiated vaccine dominant antigens have been cloned and sequenced, IVGS3 and IVRB4, which are now being tested in protection experiments in rodents prior to trials on large animals in China.
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PMID:Schistosomiasis vaccines: Farewell to the God of Plague? 793 21

DNA sequence analysis of the genome of the Smith strain of murine cytomegalovirus (MCMV) revealed an open reading frame (ORF) with amino acid sequence identity to glycoprotein L (gL) of other herpesviruses. The ORF is 822 bp in size and has the capacity to encode a protein of 274 amino acids. It has significant identity with the gL genes of human CMV and human herpesvirus 6. The coding sequence of the gL gene of MCMV strain K181 was also determined, and expressed in Escherichia coli as a fusion protein with glutathione S-transferase using the pGEX expression system. Two antibody-binding regions were identified on the basis of the reactivity of a series of truncated gL constructs with anti-MCMV antibodies. One was mapped to residues 1 to 38 and the other between residues 230 and 274. Polyclonal antibodies specific to gL were raised against the full-length gL fusion protein. The antisera were shown to react with a 46K protein present in purified virions by Western blotting. Treatment of purified virions with endoglycosidase-H or -F resulted in reductions in M(r) of the 46K species to 42K and 31K, respectively. The antisera did not exhibit any neutralizing activity in a plaque reduction assay.
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PMID:Identification, sequencing and expression of the glycoprotein L gene of murine cytomegalovirus. 796 34


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