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:2.3.1.28 (chloramphenicol acetyltransferase)
5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p34tax protein [p38tax, p34, p38(XBL), XBL-I] of bovine leukaemia virus (BLV) activates transcription from the BLV long terminal repeat (LTR) promoter. To analyse the functional properties of this protein, inframe insertions and internal deletions were systematically introduced in a plasmid-encoded copy of the p34tax gene. The abilities of wild-type and mutant genes to activate gene expression from the LTR promoter linked to the chloramphenicol acetyltransferase gene and to inhibit trans-activation by the wild-type protein were studied. The trans-activating activity of 14 of the 18 mutants tested was completely abolished, but four mutants each containing a lesion in the internal portion of the polypeptide retained activity. Taken together, these results suggest the presence of an internal region of the polypeptide where structural integrity is less strictly required for the functional activity of this protein. Among the mutants incompetent in the transactivation assay, only two with mutations in the N-terminal region of the polypeptide inhibited transactivation by the wild-type protein in a dose-dependent manner. These results facilitate understanding of the physiological function of the tax protein family.
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PMID:Construction and functional characterization of mutants of the bovine leukaemia virus trans-activator protein p34tax. 165 59

Several reports have shown that bicyclic imidazoles, specific inhibitors of the p38 mitogen-activated protein kinase (MAPK), block cytokine synthesis at the translational level. In this study, we examined the role of p38 MAPK in the regulation of the IL-1beta cytokine gene in monocytic cell lines using the bicyclic imidazole SB203580. Addition of SB203580 30 min before stimulation of monocytes with LPS inhibited IL-1beta protein and steady state message in a dose-dependent manner in both RAW264.7 and J774 cell lines. The loss of IL-1beta message was due mainly to inhibition of transcription, since nuclear run-off analysis showed an approximately 80% decrease in specific IL-1 RNA synthesis. In contrast, SB203580 had no effect on the synthesis of TNF-alpha message. LPS-stimulated p38 MAPK activity in the RAW264.7 cells was blocked by SB203580, as measured by the inhibition of MAPKAP2 kinase activity, a downstream target of the p38 MAPK. CCAATT/enhancer binding protein (C/EBP)/NFIL-6-driven chloramphenicol acetyltransferase (CAT) reporter activity was sensitive to SB203580, indicating that C/EBP/NFIL-6 transcription factor(s) are also targets of p38 MAPK. In contrast, transfected CAT constructs containing NF-kappaB elements were only partially inhibited (approximately 35%) at the highest concentration of SB203580 after LPS stimulation. As measured by EMSA, LPS-stimulated NF-kappaB activation was not affected by SB203580. Overall, the results demonstrate, for the first time, a role for p38 MAPK in IL-1beta transcription by acting through C/EBP/NFIL-6 transcription factors.
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PMID:The role of p38 mitogen-activated protein kinase in IL-1 beta transcription. 1022 13

Signal transduction pathways convey signals generated at the cell surface into the cell nucleus in order to initiate a program of gene expression that is characteristic for particular stimuli. Here we present evidence that infection by herpes simplex virus type 1 activated the two terminal kinases, cJUN N-terminal kinase (JNK) and p38, of stress-activated signal transduction kinase cascades. By using a solid-phase kinase assay, a phospho-specific antibody, and extracts prepared from a variety of infected cell types, we determined that activation of both kinases began 3 to 4 h postinfection (p.i.) and remained elevated out to 14 h p.i. Through the use of UV-irradiated or antibody-neutralized wild-type virus and the temperature-sensitive mutant tsB7, the high level of JNK activation was shown to be dependent on viral gene expression. Activation of JNK following infection by vi13, an ICP4 mutant virus that does not express early or late genes, suggested that only virus entry and immediate-early gene expression were necessary for JNK activation. The activation of JNK and p38 correlated with increased chloramphenicol acetyltransferase (CAT) activity in reporter assays dependent upon the activity of cJUN and ATF2 trans-activation domains. Increased CAT activity dependent on TRE and CRE promoter sites was also observed in response to herpes simplex virus infection. The activities of ERK and ERK-dependent transcription factors were unchanged or depressed following infection, showing that activation of JNK and p38 was a specific event. Finally, the activation of JNK was important for the efficiency of viral replication. The yield of virus in NIH 3T3 cells stably expressing JIP-1, an inhibitor of JNK translocation to the nucleus, was reduced 70% compared to that of control cells, in single-step growth experiments.
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PMID:Activation of cJUN N-terminal kinase by herpes simplex virus type 1 enhances viral replication. 1048 93

The cAMP response element (CRE) binding protein (CREB) is emerging as a key regulatory factor of gene transcription in B lymphocytes; however, the postreceptor pathways that regulate CREB activity and CRE-dependent gene transcription remain largely undefined. We investigated B cell Ag receptor (BCR)-mediated phosphorylation and activation of CREB in the surface IgM+ CH31 B cell lymphoma, which undergoes Ag-dependent cell death. The activity of p38 mitogen-activated protein kinase (MAPK) was increased in response to BCR ligation. Phosphorylation of CREB on serine 133, a modification that positively regulates its trans-activation, was concomitantly increased. Inhibition of p38 MAPK by pretreating CH31 B cells with the highly specific bicyclic imidazole inhibitor, SB203580, reduced BCR-induced CREB phosphorylation. BCR cross-linking also led to increased MAPK-activated protein kinase-2 activity, an enzyme that lies immediately downstream from p38 MAPK; MAPK-activated protein kinase-2 immune complexes phosphorylated a peptide substrate containing the CREB serine 133 phosphoacceptor motif. Given the role of CREB in regulating junB gene expression in mature B lymphocytes, we examined whether p38 MAPK activity was necessary for CRE-dependent junB transcription in CH31 B cells. BCR ligation led to increased junB mRNA levels, which were significantly reduced in CH31 B cells pretreated with SB203580. Activation of a CRE-dependent junB promoter/chloramphenicol acetyltransferase (CAT) reporter gene by the BCR was also blocked by SB203580. Similarly, inhibition of p38 MAPK in surface IgM+ WEHI-231 B cell lymphomas resulted in reduced BCR-induced junB mRNA expression and junB promoter activation. The results implicate a p38 MAPK pathway in BCR-mediated CREB phosphorylation and junB transcriptional activation in B cell lymphomas.
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PMID:Identification of a membrane Ig-induced p38 mitogen-activated protein kinase module that regulates cAMP response element binding protein phosphorylation and transcriptional activation in CH31 B cell lymphomas. 1067 65

In the present study, the mechanism by which dexamethasone (DEX) inhibited IL-1beta gene expression in bacterial lipopolysaccharide (LPS)-activated RAW 264.7 cells was investigated. The decrease in LPS-induced IL-1beta mRNA expression was demonstrated by quantitative reverse transcription polymerase chain reaction (RT-PCR). Since the promoter in IL-1beta gene contains binding motifs for NF-kappaB/Rel, AP-1, NF-IL6, and CREB/ATF, which appear to be important in LPS-mediated IL-1beta induction, the effects of DEX on the activation of these transcription factors were examined. Treatment of DEX to RAW 264.7 cells induced a dose-related inhibition of NF-kappaB/Rel and AP-1 in chloramphenicol acetyltransferase activity, while neither NF-IL6 nor CREB/ATF activation was affected by DEX. Treatment of RAW 264.7 cells with DEX inhibited DNA binding of NF-kappaB/Rel and AP-1 proteins to their cognate DNA sites as measured by electrophoretic mobility shift assay (EMSA). DEX treatment caused a significant reduction in nuclear c-rel, p65, and p50 protein contents, and these decreases were paralleled by the accumulation of cytoplasmic c-rel, p65, and p50. DEX treatment of RAW 264.7 cells did not inhibit the nuclear translocation of c-jun and c-fos. We found that the inhibition of IL-1beta production by DEX is not related to p38, which is important in the IL-1beta induction. These results suggest that DEX may inhibit IL-1beta gene expression by a mechanism involving the blocking of LPS-induced NF-kappaB/Rel and AP-1 activation.
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PMID:Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. 1093 15

In the present study, we have examined the insulin-signaling pathways involved in myogenesis in mouse C2C12 skeletal muscle cell line, a cellular system that expresses high number of high affinity insulin receptors. Insulin (50 nM) rapidly (5 min) stimulated beta-chain insulin receptor, activated the phosphatidylinositol (PI) 3-kinase/Akt/p70S6-kinase signaling pathway, as well as phosphorylated both p44/p42- and p38-mitogen-activated protein kinases (MAPKs). Preconfluent cells were differentiated in a serum-free medium in response to 50 nM insulin for 72 h, as revealed by the formation of multinucleated myotubes and the induction of the creatine kinase activity. This differentiation process was also monitored by the inhibition of the PCNA content and induction of the cell cycle inhibitor p21. Furthermore, insulin induced nuclear factor-kappaB (NF-kappaB) DNA binding activity and down-regulated activating protein-1 (AP-1) DNA binding activity throughout the differentiation process. The use of specific inhibitors of the insulin-signaling pathways indicated that myogenesis was precluded by treatment for 72 h with LY294002 (an inhibitor of PI 3-kinase), rapamycin (a p70S6-kinase blocker), and SB203580 or PD169316 (p38-MAPK inhibitors). These inhibitors abolished insulin induction of NF-kappaB DNA binding activity and kappaB-chloramphenicol acetyltransferase (CAT) promoter activity, maintaining expressed cytosolic IkappaB-alpha protein, and increased AP-1 DNA binding activity and TRE-CAT promoter activity. These data suggest that insulin induces myogenesis in C2C12 through PI 3-kinase/ p70S6-kinase and p38-MAPK pathways, the signaling through p44/p42-MAPK being inhibited.
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PMID:Insulin produces myogenesis in C2C12 myoblasts by induction of NF-kappaB and downregulation of AP-1 activities. 1114 17

By use of cDNA array technology we have screened 588 genes to determine the effect of autocrine production of human growth hormone (hGH) on gene expression in human mammary carcinoma cells. We have used a previously described cellular model to study autocrine hGH function in which the hGH gene or a translation-deficient hGH gene was stably transfected into MCF-7 cells. Fifty two of the screened genes were regulated, either positively () or negatively (), by autocrine production of hGH. We have now characterized the role of one of the up-regulated genes, chop (gadd153), in the effect of autocrine production of hGH on mammary carcinoma cell number. The effect of autocrine production of hGH on the level of CHOP mRNA was exerted at the transcriptional level as autocrine hGH increased chloramphenicol acetyltransferase production from a reporter plasmid containing a 1-kilobase pair fragment of the chop promoter. The autocrine hGH-stimulated increase in CHOP mRNA also resulted in an increase in CHOP protein. As a consequence, autocrine hGH stimulation of CHOP-mediated transcriptional activation was increased. Stable transfection of human CHOP cDNA into mammary carcinoma cells demonstrated that CHOP functioned not as a mediator of hGH-stimulated mitogenesis but rather enhanced the protection from apoptosis afforded by hGH in a p38 MAPK-dependent manner. Thus transcriptional up-regulation of chop is one mechanism by which hGH regulates mammary carcinoma cell number.
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PMID:Autocrine human growth hormone (hGH) regulation of human mammary carcinoma cell gene expression. Identification of CHOP as a mediator of hGH-stimulated human mammary carcinoma cell survival. 1129 45

Oncostatin M (OSM) regulates expression of various genes in connective tissue (CT) cells, including tissue inhibitor of metalloproteinases-1 (TIMP-1). In mouse fibroblast cell lines MLg, NIH 3T3 and primary mouse lung fibroblasts (MLF), murine OSM (muOSM) stimulated high TIMP-1 mRNA expression in comparison to leukemia inhibitory factor (LIF), epidermal growth factor (EGF), interleukin (IL)-1beta and transforming growth factor (TGF)beta. In cell signaling, muOSM induced strong phosphorylation of extracellular-signal regulated protein kinase (Erk) 1/2, p38 and Akt in addition to phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3 and STAT5 within 15 min. LIF and TGFbeta had no such effects. EGF stimulated comparable or lower Erk1/2, p38 and Akt phosphorylation while IL-1beta induced p38 phosphorylation in the fibroblast cell lines. The Erk1/2 inhibitor PD98059 and the p38 inhibitor SB203580 inhibited TIMP-1 mRNA response to muOSM, whereas the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 enhanced the TIMP-1 mRNA response in NIH 3T3 and MLg cells. PD98059 and SB203580, but not LY294002, also inhibited fold induction of a chloramphenicol acetyltransferase (CAT) reporter gene driven by a minimal TIMP-1 promoter that contained a proximal activator protein-1 (AP-1) site. Co-transfection with JunB or c-Jun expression vector in NIH 3T3 cells caused marked transactivation of the TIMP-1 promoter/CAT reporter gene. muOSM caused a rapid increase of JunB and c-Jun protein in NIH 3T3 cells. PD98059 partially inhibited the increase of JunB, but not c-Jun, whereas SB203580 did not induce detectable changes in expression of either AP-1 factor in response to muOSM. These results demonstrate that Erk1/2 and p38 contribute to the elevation of muOSM induced TIMP-1 expression, but PI3K does not, and suggest that Erk1/2 does so by enhancing JunB expression.
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PMID:Mitogen-activated protein kinases Erk1/2 and p38 are required for maximal regulation of TIMP-1 by oncostatin M in murine fibroblasts. 1524 7

Mood stabilizers block some central effects induced by stress and glucocorticosteroids; however, little is known about interaction of these drugs with glucocorticoid receptor function. In the present study, we evaluated effects of lithium, valproate and carbamazepine on glucocorticoid receptor-mediated gene expression in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus (MMTV)-chloramphenicol acetyltransferase reporter plasmid (LMCAT cells). Treatment of LMCAT cells with lithium (1-4 mM), valproate (0.1-3 mM) and carbamazepine (30 and 100 microM) inhibited corticosterone-induced activity of reporter gene in a time- and concentration-dependent manner. Furthermore, it was found that valproate, but not two other antimanic drugs, decreased the glucocorticoid receptor level in cytosolic and nuclear fraction, and its inhibitory effect on glucocorticoid receptor-mediated transcriptional activity was attenuated by c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) inhibitor. Protein kinase B (PKB), glycogen synthase kinase (GSK), p38-MAPK and depletion of inositol were not shown to be involved in the mechanism of mood-stabilizer action on glucocorticoid receptor function under present experimental condition. In contrast to mood stabilizers, amphetamine (1-100 microM) had no effect on glucocorticoid receptor-mediated transcriptional activity. These findings corroborate the hypothesis that direct effects of antidepressants and mood stabilizers on glucocorticoid receptor function is an important mechanism, by which these drugs may inhibit some deleterious effects of stress and glucocorticoids on the central nervous system.
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PMID:Mood stabilizers inhibit glucocorticoid receptor function in LMCAT cells. 1524 58

Interleukin (IL)-13 is a novel lymphokine produced by activated Type 2 helper cells. In this study, we examined the target genes of IL-13 by the cDNA microarray analysis in human dermal fibroblasts. We focused on the human alpha2(I) collagen gene, which was one of the IL-13-induced genes by the microarray analysis. IL-13 induced type I collagen protein as well as mRNA in a dose-dependent manner. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the IL-13-mediated up-regulation of alpha2(I) collagen mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not block this up-regulation. In addition, IL-13 treatment induced the promoter activity of alpha2(I) collagen by nuclear run-on transcription assay and chloramphenicol acetyltransferase assay. IL-13-mediated transcriptional activation of alpha2(I) collagen gene or type I collagen protein up-regulation was inhibited by the treatment of fibroblasts with a selective phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or STAT6 antisense oligonucleotide, but not by PD98059, a specific inhibitor of MEK/ERK, or SB202190 or SB203580, specific inhibitors of p38 MAPK; IL-13 induced the phosphorylation of PI3K p85 regulatory subunit and STAT6. These results suggest that IL-13 may play a role in the regulation of extracellular matrix and indicate the possible therapeutic value of the blockade of IL-13 signaling pathways via PI3K and STAT6 in fibrosis.
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PMID:Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblasts. 1527 99


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