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)

The classic sterol regulatory cis element (sre-1) in the LDL receptor promoter mediates sterol regulatory element binding protein (SREBP)-binding and the effects of insulin and platelet derived growth factor (PDGF). To elucidate whether SREBP-1a and SREBP-2 play a direct role in insulin and PDGF action, stable cell lines of HepG2 deficient in either SREBP-1 or SREBP-2 were used. Transfection of these cells with the wild-type promoter fragment of the low density lipoprotein (LDL) receptor gene showed that the effects of insulin and PDGF were significantly reduced in both, SREBP-1- as well as SREBP-2-deficient cells. Insulin and PDGF action could be reconstituted again in these deficient cell lines by reintroducing SREBP-1a or SREBP-2. Preincubation of cells with either the phosphatidylinositol (PI)-3 kinase inhibitor wortmannin or the mitogen-activated protein (MAP) kinase cascade inhibitor PD 98059 showed that the latter abolished the stimulatory effects of insulin and PDGF on LDL receptor promoter activity completely, whereas wortmannin had no effect. Overexpression of upstream activators of the MAP kinases, like MEKK1 or MEK1, stimulated LDL receptor promoter activity several fold in an sre-1 related manner. These effects could be enhanced by coexpression of the transcriptional active N-terminal domains of SREBP-1a and SREBP-2. Using the heterologous Gal-4 system, we could show that intracellular activation of the MAP kinase cascade by ectopic expression of MEKK1 or MEK1 has a direct stimulatory effect on the transcriptional activity of SREBP-1a and SREBP-2. Experimental evidence for a direct link between MAP kinases and SREBPs was obtained due to the MAP kinases ERK1 and ERK2 phosphorylating recombinant GST-fusion proteins of SREBP-1a and SREBP-2, in vitro. We conclude that SREBP-1a and SREBP-2 mediate different regulatory effects converging at sre-1 and that they appear to be linked to the MAP kinase cascade, possibly being direct substrates of ERK1 and ERK2.
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PMID:Sterol regulatory element binding proteins (SREBP)-1a and SREBP-2 are linked to the MAP-kinase cascade. 1062 7

Activation of ERK-1 and -2 by H(2)O(2) in a variety of cell types requires epidermal growth factor receptor (EGFR) phosphorylation. In this study, we investigated the activation of ERK by ONOO(-) in cultured rat lung myofibroblasts. Western blot analysis using anti-phospho-ERK antibodies along with an ERK kinase assay using the phosphorylated heat- and acid-stable protein (PHAS-1) substrate demonstrated that ERK activation peaked within 15 min after ONOO(-) treatment and was maximally activated with 100 micrometer ONOO(-). Activation of ERK by ONOO(-) and H(2)O(2) was blocked by the antioxidant N-acetyl-l-cysteine. Catalase blocked ERK activation by H(2)O(2), but not by ONOO(-), demonstrating that the effect of ONOO(-) was not due to the generation of H(2)O(2). Both H(2)O(2) and ONOO(-) induced phosphorylation of EGFR in Western blot experiments using an anti-phospho-EGFR antibody. However, the EGFR tyrosine kinase inhibitor AG1478 abolished ERK activation by H(2)O(2), but not by ONOO(-). Both H(2)O(2) and ONOO(-) activated Raf-1. However, the Raf inhibitor forskolin blocked ERK activation by H(2)O(2), but not by ONOO(-). The MEK inhibitor PD98059 inhibited ERK activation by both H(2)O(2) and ONOO(-). Moreover, ONOO(-) or H(2)O(2) caused a cytotoxic response of myofibroblasts that was prevented by preincubation with PD98059. In a cell-free kinase assay, ONOO(-) (but not H(2)O(2)) induced autophosphorylation and nitration of a glutathione S-transferase-MEK-1 fusion protein. Collectively, these data indicate that ONOO(-) activates EGFR and Raf-1, but these signaling intermediates are not required for ONOO(-)-induced ERK activation. However, MEK-1 activation is required for ONOO(-)-induced ERK activation in myofibroblasts. In contrast, H(2)O(2)-induced ERK activation is dependent on EGFR activation, which then leads to downstream Raf-1 and MEK-1 activation.
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PMID:Peroxynitrite targets the epidermal growth factor receptor, Raf-1, and MEK independently to activate MAPK. 1080 94

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
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PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

IL-2, first identified as a T cell growth factor, has been proven to activate many cell types including polymorphonuclear neutrophils (PMN3). However, the mechanisms involved in PMN activation, especially the signaling pathways used by the IL-2R, are currently unknown. Here we demonstrate that IL-2 has the ability to induce protein tyrosine kinases in human PMN, and we provide the first evidence that lyn kinase is activated and physically associated with MAP kinase/ERK1. Co-immunoprecipitation experiments with anti-IL-2Rbeta and Western blotting with anti-p53/56lym revealed that lyn protein was present in IL-2R precipitates and that the association of lyn with IL-2Rbeta was markedly elevated by IL-2 stimulation. Furthermore the activity of lyn kinase, evaluated by an in vitro kinase assay with enolase as a substrate, increased following IL-2 stimulation. Another important finding was that, upon IL-2 activation, MAPK/ERK1 was also phosphorylated in PMN. A direct association between lyn and ERK1 was initially demonstrated by co-immunoprecipitation/Western blotting and then definitively proven by the use of a GST-ERK1 fusion protein. We showed that ERK1 binds lyn only in IL-2 stimulated PMN, but not in unstimulated PMN. These results suggest that IL-2 can promote the association of lyn protein tyrosine kinase with IL-2Rbeta as well as the direct binding of MAPK/ERK1 to lyn. The signaling pathway utilized by human PMN in response to IL-2 may thus involve the association of lyn with IL-2Rbeta and the activation process also triggers the recruitment and activation of a specific ERK.
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PMID:IL-2 induces the association of IL-2Rbeta, lyn, and MAP kinase ERK-1 in human neutrophils. 1113 Nov 53

Endothelins exert their biological effects through G protein-coupled receptors. However, the precise mechanism of downstream signaling and trafficking of the receptors is largely unknown. Here we report that the histone acetyltransferase Tip60 and the histone deacetylase HDAC7 interact with one of the ET receptors, ETA, as determined by yeast two-hybrid analysis, glutathione S-transferase pull-down assays, and co-immunoprecipitation from transfected COS-7 cells. In the absence of ET-1, Tip60 and HDAC7 were localized mainly in the cell nucleus while ETA was predominantly confined to the plasma membrane. Stimulation with ET-1 resulted in the internalization of ETA to the perinuclear compartment and simultaneously in the efflux of Tip60 and HDAC7 from the nucleus to the same perinuclear compartment where each protein co-localized with the receptor. Upon co-transfection with ETA into COS-7 cells, Tip60 strongly increased ET-1-induced ERK1/2 phosphorylation, whereas HDAC7 had no significant effect. We thus suggest that protein acetylase and deacetylase interact with ETA in a ligand-dependent fashion and may participate in ET signal transduction.
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PMID:Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling. 1126 86

p21-activated kinase (PAK) has been shown to be an upstream mediator of JNK in angiotensin II (AngII) signaling. Little is known regarding other signaling molecules involved in activation of PAK and JNK by AngII. Rho family GTPases Rac and Cdc42 have been shown to enhance PAK activity by binding to p21-binding domain of PAK (PAK-PBD). In vascular smooth muscle cells (VSMC) AngII stimulated Rac1 binding to GST-PAK-PBD fusion protein. Pretreatment of VSMC by genistein inhibited AngII-induced Rac1 activation, whereas Src inhibitor PP1 had no effect. Inhibition of protein kinase C by phorbol 12,13-dibutyrate pretreatment also decreased AngII-mediated activation of Rac1. The adaptor molecule Nck has been shown previously to mediate PAK activation by facilitating translocation of PAK to the plasma membrane. In VSMC AngII stimulated translocation of Nck and PAK to the membrane fraction. Overexpression of dominant-negative Nck in Chinese hamster ovary (CHO) cells, stably expressing the AngII type I receptor (CHO-AT1), inhibited both PAK and JNK activation by AngII, whereas it did not affect ERK1/2. Finally, dominant-negative Nck inhibited AngII-induced DNA synthesis in CHO-AT1 cells. Our data provide evidence for Rac1 and Nck as upstream mediators of PAK and JNK in AngII signaling and implicate JNK in AngII-induced growth responses.
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PMID:Angiotensin II-induced stimulation of p21-activated kinase and c-Jun NH2-terminal kinase is mediated by Rac1 and Nck. 1127 50

Glutathione S-transferase P1-1 (GSTpi) is an abundant and ubiquitously expressed protein in normal and malignant mammalian tissues and possesses catalytic and ligand binding properties. Our present data suggest that the protein contributes to the regulation of cell proliferation. Mouse embryo fibroblasts (MEFs) isolated from mice with a GSTP1-1 [glutathione S-transferase P1-1 (isozyme in nonhepatic tissue)] null genotype (GSTpi(-/-)) doubled their population in 26.2 h versus 33.6 h for the wild type (GSTpi(+/+)). Retroviral transfection of GSTP1-1 into GSTpi(-/-) MEF cells slowed the doubling time to 30.4 h. Both early passage and immortalized MEF cells from GSTpi(-/-) animals expressed significantly elevated activity of extracellular signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferation pathways. In vivo, GSTpi(-/-) mice had higher basal levels of circulating white blood cells compared with GSTpi(+/+). Administration of a peptidomimetic inhibitor of GSTP1-1, TLK199, (gamma-glutamyl-S-(benzyl)cysteinyl-R-phenyl glycine diethyl ester), stimulated both lymphocyte production and bone marrow progenitor (colony-forming unit-granulocyte macrophage) proliferation, but only in GSTpi(+/+) and not in GSTpi(-/-) animals. Selection of a resistant clone of an HL60 tumor cell line through chronic exposure to TLK199 resulted in cells with elevated activities of c-Jun NH2 terminal kinase (JNK1) and ERK1/ERK2, and allowed the cells to proliferate under stress conditions that induced high levels of apoptosis in the wild type cells. The in vitro and in vivo data are consistent with the principle that GSTP1-1 influences cell proliferation.
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PMID:Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. 1140 60

RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. 1152 56

The Pax gene family encodes DNA-binding proteins that can both activate and repress transcription of specific target genes during embryonic development. Pax proteins are required for pattern formation and cell differentiation in a broad spectrum of developing tissues. Consistent with its expression in the intermediate mesoderm, the optic cup and stalk, and the otic vesicle, Pax2, a member of the Pax2/5/8 subfamily, is essential for the development of the renal epithelia, the optic cup, and the inner ear. In addition to a DNA binding domain, the Pax2 protein contains a carboxyl-terminal transactivation domain rich in serine, threonine, and tyrosine. In this report, we demonstrate that the Pax2 transactivation domain is phosphorylated by the c-Jun N-terminal kinase, but not the ERK1/2 or p38 MAP kinases and that phosphorylation is coincident with increased transactivation of a Pax2-dependent reporter gene. Activation of JNK by either upstream kinase MEKK1 or DLK or by expression of Wnt signaling proteins significantly enhances Pax2 phosphorylation in cells. In vitro kinase assays using immunoprecipitated JNK or constitutively active, recombinant JNK show phosphorylation of GST-Pax2 fusion proteins. In transfected cells, phosphorylation of Pax2 correlates with increased transactivation of a Pax2-dependent reporter gene, suggesting that serine/threonine phosphorylation of the transactivation domain is important for Pax2 activity. Pax2 can form a complex with the JNK scaffolding protein JIP1, and this interaction is enhanced by activation of the JNK signaling module with the upstream kinase DLK. The data demonstrate that Pax2 is a new target for the JNK signaling module and point to a novel mechanism for mediating Pax-dependent transcription regulation.
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PMID:Phosphorylation of Pax2 by the c-Jun N-terminal kinase and enhanced Pax2-dependent transcription activation. 1170 Mar 24

Butyrate, one of the major products of gut fermentation, is known to inhibit proliferation, induce apoptosis and differentiation, and increase phase II enzyme activities in tumor cells, whereas little information is available on protective effects in less-transformed colon cells. The aim of this study was to investigate whether the chemoprotective mechanism of glutathione S-transferase (GST) induction by butyrate could also play a role in earlier stages of colon carcinogenesis and whether chemoresistance of cells toward the endogenous genotoxic risk factor 4-hydroxy-2-nonenal (HNE) could be a consequence of butyrate treatment. As cell models, we used the human tumor cell lines HT29 and HT29 clone 19A, a differentiated subclone with properties resembling primary colon cells. We determined the expression of GSTP1 protein (enzyme-linked immunosorbent assay), the major GST in HT29, GSTP1 mRNA (Northern blotting), GST activity, intracellular glutathione, and total protein. The genotoxic impact of HNE (100-200 microM) was compared in butyrate-treated and nontreated cells using single-cell microgel electrophoresis. Our results show that GSTP1 mRNA, GSTP1 protein, GST activity, and total protein were increased (1.2- to 2.5-fold) and glutathione levels were maintained after 24-72 h of incubation with 4 mM butyrate. Moreover, a marked reduction of HNE-induced genotoxicity was caused by preincubation with butyrate. Butyrate also induced the phosphorylation of extracellular signal-regulated kinases (ERK1/2, Western blotting) after 5-30 min, which indicates a regulation of GST expression by this signal pathway. Most effects were greater in HT29 parent cells than in clone cells. In conclusion, butyrate enhances expression of GST and other proteins in both cell lines, which leads to an enhanced chemoprotection, reducing the impact of HNE genotoxicity. Thus butyrate could play a role in early and later stages of cancer prevention by reducing exposure to relevant risk factors.
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PMID:Butyrate induces glutathione S-transferase in human colon cells and protects from genetic damage by 4-hydroxy-2-nonenal. 1209 19


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