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)

Manipulation of the glutathione status of an embryo during organogenesis leads to abnormal development, as well as increasing the susceptibility of the embryo to insult by either xenobiotic or endogenous electrophiles. The glutathione S-transferases are a family of drug-metabolizing enzymes that catalyze the conjugation of reactive chemicals with glutathione, playing an important role in protecting cells against attack. The purpose of this study was to investigate the presence and regulation of one glutathione S-transferase, glutathione S-transferase P, a homodimer of the Yp subunit, in the conceptus during organogenesis. Northern blot analysis of the RNA isolated from rat embryos and their yolk sacs on days 10, 11 and 12 of gestation revealed a single Yp transcript. Steady-state concentrations of the Yp mRNA in embryos did not change with either gestational age or culture for 24 hr (day 11 in vitro) or 45 hr (day 12 in vitro). In contrast, concentrations of this transcript in yolk sac increased 3-fold from day 10 to 12 of gestation and a further 3-fold with culture (day 12 in vivo compared with in vitro). Transcription of the rat Yp subunit gene in cell lines is induced by treatment with phorbol esters. However, the addition of 12-O-tetradecanoylphorbol-13-acetate (TPA, 50 or 100 nM) to embryos in culture had no effect on the steady-state concentrations of the Yp transcript. Thus, the glutathione S-transferase Yp message is subject to tissue- and development-specific regulation in the conceptus during organogenesis. Moreover, culture of the embryos resulted in a further up-regulation of the steady-state concentrations of the Yp transcript in yolk sac. Western blot analysis demonstrated that a single immunoreactive Yp subunit band of 26 kDa was found in both embryos and yolk sacs. Neither age nor culture appeared to affect the concentrations of immunoreactive Yp subunit in the yolk sac. Thus, glutathione S-transferase Yp mRNA is translated in the conceptus during organogenesis. The apparent differences between the relative amounts of the message and immunoreactive protein in yolk sac suggest that this subunit may be subject to post-transcriptional as well as transcriptional regulation in this tissue. Immunohistochemical analysis of embryos cultured for 45 hr (day 12 in vitro) revealed that the Yp reaction product was localized over the hepatic primordia, mesonephric ducts, otocyst, yolk sac and ectoplacental cone.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of the Yp subunit of glutathione S-transferase P in rat embryos and yolk sacs during organogenesis. 801 Sep 87

The nm23-H1 gene is regarded as a human homologue of the mouse nm23 gene, which was expressed in a non-metastatic subline of mouse melanoma K-1735. The expression levels of nm23-H1 mRNA and the levels of protein during induced differentiation of human leukemia cell lines were analysed. mRNA levels of the megakaryoblastic leukemia line MEG-01, which were induced to differentiate into megakaryocyte by TPA, decreased rapidly from 2 days after the start of treatment and became almost undetectable at day 4. Similar down-regulation of nm23-H1 mRNA was also observed in the induced differentiation of the promyelocytic leukemia line HL-60 by TPA, or DMSO into monocyte-macrophage lineage or granulocytes, respectively. The amount of Nm23-H1 protein was analysed by Western immuno-blot analysis using mouse antiserum raised against a recombinant fusion protein with glutathione S-transferase. The amount of Nm23-H1 protein also decreased during the induced differentiation of these leukemia cell lines. On the other hand, in the differentiation of the erythroleukemia line K562 by hemin, levels of both mRNA and protein of Nm23-H1 elevated transiently, then reduced to the original level. When MEG-01 and K562 were stably transfected with nm23-H1 cDNA, MEG-01 transfectants showed reduced sensitivity to the induction of differentiation, whereas K562 transfectants were better induced to synthesize hemoglobin than controls. These findings suggest the possibility that Nm23-H1 protein plays an important role to maintain the proliferation of immature leukemic cells in MEG-01 and HL-60, but it may also play a role in the early stage of K562 differentiation, possibly in the different manner.
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PMID:Alteration of nm23 gene expression during the induced differentiation of human leukemia cell lines. 805 9

The effects of EGF, TPA, UV radiation, okadaic acid and anisomycin on ERK and JNK/SAPK MAP kinase cascades have been compared with their ability to elicit histone H3/HMG-14 phosphorylation and induce c-fos and c-jun in C3H 10T1/2 cells. EGF and UV radiation activate both ERKs and JNK/SAPKs but to markedly different extents; EGF activates ERKs more strongly than JNK/SAPKs, whereas UV radiation activates JNK/SAPKs much more strongly than ERKs. Anisomycin and okadaic acid activate JNK/SAPKs but not ERKs, and conversely, TPA activates ERKs but not JNK/SAPKs. Nevertheless, all these agents elicit phosphorylation of ribosomal and pre-ribosomal S6, histone H3 and HMG-14, and the induction of c-fos and c-jun, showing that neither cascade is absolutely essential for these responses. We then analysed the relationship between ERKs, JNK/SAPKs and the transcription factors Elk-1 and c-Jun, implicated in controlling c-fos and c-jun, respectively. JNK/SAPKs bind to GST-cJun1-79, and ERKs, particularly ERK-2, to GST-Elk1(307-428); there is no cross-specificity of binding. Further, GST-Elk1(307-428) binds preferentially to active rather than inactive ERK-2. In vitro, JNK/SAPKs phosphorylate both GST-cJun1-79 and GST-Elk1(307-428), whereas ERKs phosphorylate GST-Elk1(307-428) but not GST-cJun1-79. Thus, neither ERKs nor JNK/SAPKs are absolutely essential for nuclear signalling and c-fos and c-jun induction. The data suggest either that activation of a single MAP kinase subtype is sufficient to elicit a complete nuclear response, or that other uncharacterised routes exist.
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PMID:Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction. 858 71

Rat glutathione transferase P (GST-P) is expressed at low levels in the normal liver but becomes highly expressed in hyperplastic nodules and in hepatocellular carcinomas during chemical hepatocarcinogenesis. To understand the regulation mechanisms of this gene, we have characterized the 5'-flanking region and have found that GST-P gene is regulated by at least two elements: one is a strong enhancer and the other is a silencer. GST-P enhancer I (GPEI), located at -2.5 Kb, consists of two TPA-responsive element (TRE)-like sequences that are palindromically oriented with 3 bp in between. It is well known that TRE is activated by two nuclear oncogenes, c-Jun and c-Fos. Although GPEI is trans-activated by these oncogenes, it is also active in F9 embryonal carcinoma cells that lack c-Jun protein, suggesting that it can function with some trans-activator other than AP-1 (c-Jun/c-Fos heterodimer). Indeed, another protein is identified from the F9 nuclear extract. We have also identified a silencer element at 300 bp upstream from the cap site. There are several cis-elements in this region and at least three trans-acting factors bind to these elements. We purified SF-A (silencer factor A) which binds to several regions in this silencer, and determined the partial amino acid sequence. Interestingly, SF-A seemed to be a related protein to NF1 (nuclear factor 1) which is an activator for the transcription and DNA replication. Another factor SF-B (silencer factor B) has been cloned and found to be the same as LIP (liver inhibitory protein) which is a competitor for LAP (liver activator protein), both are from the same gene designated as C/EBP beta. By transfection analysis using GAL4 DNA binding domain we found LIP is not only a competitor but a direct repressor. In the normal liver, another C/EBP family member, C/EBP alpha also acts as a negative regulator, and this expression decreases during hepatocarcinogenesis, resulting in the loss of silencer function. We carried out the carcinogenesis experiments using transgenic rats harboring a chloramphenicol acetyltransferase (CAT) reporter gene with -2900 to + 59 of the GST-P gene. Liver foci and nodules produced by chemical carcinogens were found to express high levels CAT activity by both CAT assay and immunohistochemical study, while normal liver cells did not express any CAT activity. These results demonstrate that the GST-P gene is trans-activated locus-independently during rat hepatocarcinogenesis. Moreover, the similar results were obtained using transgenic rats carrying GPEI-CAT, indicating that GPEI is an important cis-element for activation of GST-P gene during hepatocarcinogenesis.
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PMID:[Regulation mechanism of specific expression of tumor marker gene during carcinogenesis]. 883 Dec 56

The extracellular matrix protein osteopontin (OPN) interacts with a number of integrins, namely alphavbeta1, alphavbeta3, alphavbeta5, alpha9beta1, alpha8beta1, and alpha4beta1. We have investigated the interaction of alpha5beta1 integrin with OPN using K562 cells, which only express alpha5beta1. alpha5beta1 is in a low activation state in this cell line, but can be stimulated to a higher activation state by the phorbol ester TPA. Treating K562 wild-type cells (K562-WT) with TPA stimulated an interaction between alpha5beta1 and OPN. No interaction was seen in the absence of TPA. alpha5beta1 selectively interacted with a GST fusion protein of the N-terminal fragment of OPN (aa17-168), which is generated in vivo by thrombin cleavage of OPN. Expression of the alpha4 integrin in K562 cells (K562-alpha4beta1) stimulated alpha5beta1-dependent binding to aa17-168 in the absence of TPA, suggesting that alpha4beta1 activates alpha5beta1 in K562 cells. Adhesion via alpha5beta1 is mediated by the Arg-Gly-Asp (RGD) motif of OPN, as mutating this sequence to Arg-Ala-Asp (RAD) blocked binding of both cell types. These data demonstrate that thrombin cleavage regulates the adhesive properties of OPN and that alpha5beta1 integrin can interact with thrombin-cleaved osteopontin when in a high activation state.
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PMID:A regulated interaction between alpha5beta1 integrin and osteopontin. 1067 66

In the mouse study, topical application of green tea polyphenols (GTP) significantly inhibited TPA-induced increasing of epidermal ornithine decarboxylase (ODC) and increased the activities of several antioxidant enzymes (CAT, GR and GST). In another in vitro study, when GTP was incubated with TPA and mice polymorphonuclear leukocytes (PMNs), TPA induced hydrogen peroxide formation was markedly suppressed with a dose-dependent relationship. The results suggest that the antioxidative effect of GTP may play an important role in inhibiting tumor promotion.
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PMID:[The antioxidative mechanisms of tea polyphenols in inhibiting tumor promotion by TPA]. 1068 39

In recent years, considerable emphasis has been placed on identifying new cancer chemopreventive agents, which could be useful for the human population. Tephrosia purpurea has been shown to possess significant activity against hepatotoxicity, pharmacological and physiological disorders. Earlier we showed that Tephrosia purpurea inhibits benzoyl peroxide-mediated cutaneous oxidative stress and toxicity. In the present study, we therefore assessed the effect of Tephrosia purpurea on 12-O-tetradecanoyl phorbal-13-acetate (TPA; a well-known phorbol ester) induced cutaneous oxidative stress and toxicity in murine skin. The pre-treatment of Swiss albino mice with Tephrosia purpurea prior to application of croton oil (phorbol ester) resulted in a dose-dependent inhibition of cutaneous carcinogenesis. Skin tumor initiation was achieved by a single topical application of 7,12-dimethyl benz(a)anthracene (DMBA) (25 microg per animal per 0.2 ml acetone) to mice. Ten days later tumor promotion was started by twice weekly topical application of croton oil (0.5% per animal per 0.2 ml acetone, v /v). Topical application of Tephrosia purpurea 1 h prior to each application of croton oil (phorbol ester) resulted in a significant protection against cutaneous carcinogenesis in a dose-dependent manner. The animals pre-treated with Tephrosia purpurea showed a decrease in both tumor incidence and tumor yield as compared to the croton oil (phorbol ester)-treated control group. In addition, a significant reduction in TPA-mediated induction in cutaneous ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation was also observed in animals pre-treated with a topical application of Tephrosia purpurea. The effect of topical application of Tephrosia purpurea on TPA-mediated depletion in the level of enzymatic and non-enzymatic molecules in skin was also evaluated and it was observed that topical application of Tephrosia purpurea prior to TPA resulted in the significant recovery of TPA-mediated depletion in the level of these molecules, namely glutathione, glutathione S-transferase, glutathione reductase and catalase. From these data we suggest that Tephrosia purpurea can abrogate the tumor-promoting effect of croton oil (phorbol ester) in murine skin.
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PMID:Tephrosia purpurea alleviates phorbol ester-induced tumor promotion response in murine skin. 1124 14

To investigate mechanisms of rat glutathione S-transferase P1 gene (rGSTP1) expression regulation during chemical carcinogenesis. we studied enhancer elements located in the region between -2.5 kb to -2.2 kb. The region was upstream from the start site of transcription and was divided into two major fragments, GPEI and GPEII. The GPEII fragment was further divided into two smaller fragments, GPEII- I and GPEII-2. Using a luciferase reporter system, we identified a strong enhancer of GPEI and a weak enhancer of GPEII in HeLa and a rat hepatoma cell line CBRH79 19 cell. The enhancer of GPEII was located within the GPEII-I region. Chemical stimulation by glycidyl methatylate (GMA) and phorbol 12-o-tetradecanoate 13-acetate (TPA) analysis revealed that induction of rGSTP1 expression was mainly through GPEI. Although H2O2 could enhance GPEII enhancer activity, the enhancement is not mediated by the NF-kappaB factor that bound the NF-kappaB site in GPEII. Using electrophoretic mobility shift assays (EMSA) and the UV cross-linking assays, we found that HeLa and CBRH7919 cells had proteins that specifically bound GPEI core sequence and a 64 kDa protein that interacted with GPEII-1. The cells from normal rat liver did not express the binding proteins. Therefore, the trans-acting factors seem to be closely related to GPEI, GPEII enhancer activities and may play an important role in high expression of rGSTPI gene.
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PMID:The effect of chemical carcinogenesis on rat glutathione S-transferase P1 gene transcriptional regulation. 1171 May 60

p68 RNA helicase has been implicated in a variety of processes, including rearrangement of RNA secondary structures, RNA splicing, gene transcription and tumor development, yet its mechanisms of action are not well understood. In this study, we show that p68 is predominantly localized to the cell nucleus, where it partially colocalizes with the transcriptional coactivator p300. Accordingly, p68 and p300, or the paralogous CREB-binding protein (CBP), coimmunoprecipitate. Similarly, p68 and RNA polymerase II (Pol II) are able to interact in vivo. GST pull-down assays confirmed these interactions in vitro, demonstrating that p68 can interact with several domains of CBP, while CBP/p300 bind to amino acids 176-388 of p68 and RNA Pol II binds to the N-terminal 80 amino acids of p68. Furthermore, p68 stimulates transcription mediated by the C-terminal transactivation domain of CBP. p68 is also able to stimulate TPA oncogene responsive unit (TORU) promoter activity, and p300 acts in synergy with p68. On the other hand, suppression of CBP/p300 function by the adenoviral protein E1A abolishes TORU promoter activation by p68. Altogether, our results suggest the existence of a multiprotein complex in which p68 RNA helicase, CBP/p300 and RNA Pol II jointly promote gene expression.
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PMID:Synergism between p68 RNA helicase and the transcriptional coactivators CBP and p300. 1252 17

We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 micromol) 24 hr before application of dimethylbenz[a]anthracene (0.2 micromol) markedly suppressed tumor incidence by 60% and the number of tumors by 80% per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83% as well as their diameter by 57%. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 micromol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-P1 and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome p450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29% to 86%, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways.
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PMID:Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice. 1512 79


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