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)

Cytomegalovirus (CMV) infection is nonpermissive or persistent in many lymphoid and myeloid cell types but can be activated in differentiated macrophages. We have shown elsewhere that both the major immediate-early gene (MIE) and lytic cycle infectious progeny virus expression can be induced in otherwise nonpermissive monocyte-like U-937 cell cultures infected with either human CMV (HCMV) or simian CMV (SCMV) by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Two multicopy basal enhancer motifs within the SCMV MIE enhancer, namely, 11 copies of the 16-bp cyclic AMP response element (CRE) and 3 copies of novel 17-bp serum response factor (SRF) binding sites referred to as the SNE (SRF/NFkappaB-like element), as well as four classical NFkappaB sites within the HCMV version, contribute to TPA responsiveness in transient assays in monocyte and T-cell types. The SCMV SNE sites contain potential overlapping core recognition binding motifs for SRF, Rel/NFkappaB, ETS, and YY1 class transcription factors but fail to respond to either serum or tumor necrosis factor alpha. Therefore, to evaluate the mechanism of TPA responsiveness of the SNE motifs and of a related 16-bp SEE (SRF/ETS element) motif found in the HCMV and chimpanzee CMV MIE enhancers, we have examined the functional responses and protein binding properties of multimerized wild-type and mutant elements added upstream to the SCMV MIE or simian virus 40 minimal promoter regions in the U-937, K-562, HL-60, THP-1, and Jurkat cell lines. Unlike classical NFkappaB sites, neither the SNE nor the SEE motif responded to phosphatase inhibition by okadaic acid. However, the TPA responsiveness of both CMV elements proved to involve synergistic interactions between the core SRF binding site (CCATATATGG) and the adjacent inverted ETS binding motifs (TTCC), which correlated directly with formation of a bound tripartite complex containing both the cellular SRF and ELK-1 proteins. This protein complex was more abundant in U-937, K-562, and HeLa cell extracts than in Raji, HF, BALB/c 3T3, or HL-60 cells, but the binding activity was altered only twofold after TPA treatment. A 40-fold stimulation of chloramphenicol acetyltransferase activity mediated by four tandem repeats of the SNE could be induced within 2 h (and up to 250-fold within 6 h) after addition of TPA in DNA-transfected U-937 cells, indicating that the stimulation appeared likely to be a true protein kinase C-mediated signal transduction event rather than a differentiation response. Slight differences in the sequence of the core SRF binding site compared with that of the classical c-Fos promoter serum response element, together with differences in the spacing between the SRF and ETS motifs, appear to account for the inability of the SCMV SNEs to respond to serum induction.
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PMID:Synergistic interactions between overlapping binding sites for the serum response factor and ELK-1 proteins mediate both basal enhancement and phorbol ester responsiveness of primate cytomegalovirus major immediate-early promoters in monocyte and T-lymphocyte cell types. 897 Sep 84

Caffeic acid phenethyl ester (CAPE) is a phenolic antioxidant derived from the propolis of honeybee hives. CAPE was shown to inhibit the formation of intracellular hydrogen peroxide and oxidized bases in DNA of 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated HeLa cells and was also found to induce a redox change that correlated with differential growth effects in transformed cells but not the nontumorigenic parental ones. Mediated via the electrophile or human antioxidant response element (hARE), induction of the expression of NAD(P)H quinone oxidoreductase (NQO1) and glutathione S-transferase Ya subunit genes by certain phenolic antioxidants has been correlated with the chemopreventive properties of these agents. Here, we determined by Northern analysis that CAPE treatment of hepatoma cells stimulates NQO1 gene expression in cultured human hepatoma cells (HepG2), and we characterized the effects of CAPE treatment on the expression of a reporter gene either containing or lacking the hARE or carrying a mutant version of this element in rodent hepatoma (Hepa-1) transfectants. A dose-dependent transactivation of human hARE-mediated chloramphenicol acetyltransferase (cat) gene expression was observed upon treatments of the Hepa-1 transfectants with TPA, a known inducer, as well as with CAPE. The combined treatments resulted in an apparent additive stimulation of the reporter expression. To learn whether this activation of cat gene expression was effected by protein kinase C in CAPE-treated cells, a comparison was made of cat gene activity after addition of calphostin, a protein kinase C inhibitor. Calphostin reduced the cat gene induction by TPA but not by CAPE, suggesting that stimulation of gene expression in this system by these agents proceeds via distinct mechanisms. Band-shift experiments to examine binding of transactivator proteins from nuclear extracts of treated and untreated cells to a hARE DNA probe showed that TPA exposure increased the binding level. In contrast, binding of factors to this probe was inhibited after either in vivo treatment of cells with CAPE or in vitro addition of this compound to the nuclear extract. In view of the clear stimulation by CAPE of gene expression mediated by hARE, possible explanations of this result are discussed.
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PMID:Caffeic acid phenethyl ester stimulates human antioxidant response element-mediated expression of the NAD(P)H:quinone oxidoreductase (NQO1) gene. 901 71

We investigated the inhibitory effects of intracellular cyclic adenosine monophosphate (cAMP) levels in regulating class 3 aldehyde dehydrogenase (aldh3) gene expression using cultures of primary rat hepatocytes and transient transfection experiments with HepG2 cells. In addition to regulation by an Ah receptor-dependent mechanism, expression of many members of the Ah gene battery have been shown to be negatively regulated. As was seen for the cytochrome P450 (cyp1A1) gene, aldh3 is transcriptionally inducible by polycyclic aromatic hydrocarbons (PAH), and this induction involving function of the arylhydrocarbon (Ah) receptor is inhibited by the protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine di-HCl (H7) and staurosporine. However, PAH induction of ALDH-3 activity, protein, and mRNA was potentiated 2-4-fold by addition of the protein kinase A (PKA) inhibitors, N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide di-HCl (H8) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide HCl (HA1004). These PKA inhibitors had no effect on the PAH induction of the cyp1A1. Protein kinase A activity of cultured hepatocytes was specifically inhibited by H8 and HA1004 in a concentration-dependent manner, but not by H7, and there was an inverse correlation observed between potentiation of PAH-induced aldh3 gene expression and inhibition of specific PKA activity by the PKA inhibitors. The cAMP analog dibutyryl cAMP, the adenylate cyclase activator forskolin, and the protein phosphatase 1 and 2A inhibitor okadaic acid all dramatically inhibited both PAH induction and H8 potentiation of PAH induction of aldh3 expression but had no effect on induction of cyp1A1 expression in cultured hepatocytes. Both basal and PAH-dependent expression of a chloramphenicol acetyltransferase expression plasmid containing approximately 3.5 kilobase pairs of the 5'-flanking region of aldh3 (pALDH3.5CAT) were enhanced 3-4-fold by the PKA inhibitor H8 but not by the PKC inhibitor H7 (>20 microM). cAMP analogs, activators of PKA activity, or protein phosphatase inhibitors diminished expression of the reporter gene in a manner identical to the native gene in cultured rat hepatocytes. Using deletion analysis of the pALDH3.5CAT construct, we demonstrated the existence of a negative regulatory region in the 5'-flanking region between -1057 and -991 base pairs which appears to be responsible for the cAMP-dependent regulation of this gene under both basal and PAH-induced conditions. At least two apparently independent mechanisms which involve protein phosphorylation regulate aldh3 expression. One involves function of the Ah receptor which requires PKC protein phosphorylation to positively regulate both aldh3 and cyp1A1 gene expression and the other a cAMP-responsive process which allows PKA activity to negatively regulate expression of aldh3 under either basal or inducible conditions.
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PMID:cAMP-dependent negative regulation of rat aldehyde dehydrogenase class 3 gene expression. 901 60

Transcription of the mouse vas deferens protein (MVDP) gene, a member of the aldo-keto reductase superfamily, is stimulated by androgens via the androgen responsive element (ARE) located in the proximal promoter (-111 to -97). We investigated interaction between androgens and the protein kinase C (PKC) signalling pathway. Transcriptional regulation was determined by analysis of chloramphenicol acetyltransferase (CAT). T47D cells were transiently transfected with 5' flanking MVDP DNA promoter sequences (-1804 to +41; -510 to +41 and -121 to +41) fused to the reporter (CAT) gene. Androgen-induced transcriptional activity can be enhanced from 6 (1.8 and 0.5 kb MVDP-CAT constructs) to 18 fold (0.16 kb MVDP-CAT construct), in a time and dose-dependent manner, by the PKC activator 12-o-tetradecanoylphorbol-13 acetate (TPA). A mutation in the proximal ARE abolished both androgen and TPA-dependent gene enhancement. TPA influenced minimally MMTV promoter in T47D cells and MVDP promoter in CV1 cells suggesting that the effects of the PKC activator are probably promoter and cell-specific. In contrast, activation of protein kinase A (PKA) via addition of dibutyryl-cAMP (db-cAMP) reduced androgen induction of the MVDP gene.
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PMID:Protein kinase C pathway potentiates androgen-mediated gene expression of the mouse vas deferens specific aldose reductase-like protein (MVDP). 902 27

Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian cancers. Although the primary target of paclitaxel is microtubules, its efficacy exceeds that of conventional microtubule-disrupting agents, suggesting that it may have additional cellular effects. Previously, we demonstrated that paclitaxel can induce interleukin-8 (IL-8) gene expression at the transcriptional level in subsets of human ovarian cancer lines. In this as well as the previous report, we present evidence that this ability is not linked to the lipopolysaccharide pathway of IL-8 gene induction. The present study identifies the cis-acting elements and trans-acting factors involved in this induction by transfecting DNA constructs containing the 5'-flanking region of the IL-8 gene linked to the chloramphenicol acetyltransferase reporter gene into paclitaxel-responsive and nonresponsive ovarian cancer cells (responsiveness refers to the IL-8 response). Paclitaxel only activated the IL-8 promoter in responsive cells. The AP-1 and NF-kappaB binding sites in the IL-8 promoter are required for activation by paclitaxel; in contrast, a C/EBP site required for IL-8 promoter activation in other cell types is not involved. Gel shift assays demonstrate that paclitaxel causes a marked increase in protein binding to the NF-kappaB and AP-1 consensus binding sequences in the paclitaxel-responsive ovarian cells, but not the nonresponsive cells. The induction of NF-kappaB and AP-1 binding is reduced by the addition of protein kinase C inhibitors and cyclic AMP effector, respectively. These results demonstrate a molecular mechanism for cell-specific paclitaxel-induced IL-8 gene expression which may have clinical relevance.
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PMID:Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in the interleukin-8 promoter. 927 87

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin-6 (IL-6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL-6 promoter fused (-1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast-like osteosarcoma SaOS-2 cells. We compared the effects of PTH on IL-6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, interleukin-1 alpha (IL-1 alpha), prostaglandin E-2 (PGE-2), RS-66271 (a parathyroid hormone-related peptide analog), and platelet-derived growth factor-BB (PDGF-BB). Analyses of cell clones showed that IL-6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001-100 nM) for 12 h stimulated CAT expression in a dose-dependent manner (200-500% of control). Treatment with IL-1 alpha was more potent than PTH in inducing transcription of the IL-6 promoter (900-1,000%). Activation of the cAMP-PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS-66271, previously shown to have PTH-like effects, induced a comparable level of IL-6 promoter expression. When examined together, PTH+RS-66271 effects were comparable to PTH effects alone. Exposure to PGE-2, PMA, PDGF-BB, or A23187 for 12 h did not significantly alter IL-6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS-66271, and IL-1 alpha stimulate IL-6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL-6 expression.
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PMID:Parathyroid hormone (1-34)-mediated interleukin-6 induction. 932 32

Interferon-tau (oIFNtau), the major secretory product of ovine conceptuses between days 13 and 21 (day 0=day of estrus) of pregnancy, is implicated in the process of maternal recognition of pregnancy. Culturing of day-14 and day-16 conceptus tissues in the presence of human granulocyte macrophage-colony stimulating factor (hGM-CSF) or interleukin-3 (IL-3) produces a marked increase in oIFNtau mRNA and protein expression. Since GM-CSF and IL-3 are localized at the luminal and glandular epithelia of the ovine endometrium, maternally derived GM-CSF and IL-3 may affect conceptus production of oIFNtau in a paracrine manner. However, the molecular mechanisms by which endometrial GM-CSF and IL-3 up-regulate oIFNtau production have not been defined. As an initial investigation of the signaling pathway regulating the GM-CSF induction of the oIFNtau gene, day-16 conceptuses were treated with an inducer, phorbol 12-myristate 13-acetate (PMA) and an inhibitor, calphostin C of the protein kinase C (PKC) pathway. Treatment with either 150 units/ml hGM-CSF (P<0.01) or 10 nM PMA (P<0.05) resulted in a significant increase in oIFNtau mRNA expression. Pretreatment of conceptuses with 1 microM PMA for 12 h to produce PKC-deficient tissues or treatment with 50 mM calphostin C abolished the hGM-CSF-induced increase in oIFNtau mRNA. An in vitro expression system was established for the analysis of oIFNtau gene regulatory sequences. The oIFNtau010 gene has been isolated previously and found to be the principal oIFNtau gene up-regulated during the preimplantation period. 5'-Flanking regions of the oIFNtau010 gene, 2 kb and 0.8 kb, were cloned into a basic chloramphenicol acetyltransferase reporter plasmid. These oIFNtau010 promoter constructs, along with expression controls, were transfected into human choriocarcinoma cells (JAR and JEG3) and their responsiveness to hGM-CSF and second messenger system activators including PMA, calcium ionophore (A23187) and 8-bromo-cAMP were characterized. The oIFNtau010 promoter constructs were up-regulated by hGM-CSF and PMA treatments (P<0.01). Combined treatment with PMA and A23187 prevented the promoter activation seen with PMA alone. The conceptus culture data, along with the results from the transfection experiments, suggest that the stimulatory effect of GM-CSF on oIFNtau is mediated through the PKC second messenger system.
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PMID:Enhancement of ovine trophoblast interferon by granulocyte macrophage-colony stimulating factor: possible involvement of protein kinase C. 934 4

The cytoplasmic regions of the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) bind and activate phospholipase C-gamma1 (PLC-gamma1) and other signaling proteins in response to ligand binding outside the cell. Receptor binding by PLC-gamma1 is a function of its SH2 domains and is required for growth factor-induced cell cycle progression into the S phase. Microinjection into MDCK epithelial cells and NIH 3T3 fibroblasts of a polypeptide corresponding to the noncatalytic SH2-SH2-SH3 domains of PLC-gamma1 (PLC-gamma1 SH2-SH2-SH3) blocked growth factor-induced S-phase entry. Treatment of cells with diacylglycerol (DAG) or DAG and microinjected inositol-1,4,5-triphosphate (IP3), the products of activated PLC-gamma1, did not stimulate cellular DNA synthesis by themselves but did suppress the inhibitory effects of the PLC-gamma1 SH2-SH2-SH3 polypeptide but not the cell cycle block imposed by inhibition of the adapter protein Grb2 or p21 Ras. Two c-fos serum response element (SRE)-chloramphenicol acetyltransferase (CAT) reporter plasmids, a wild-type version, wtSRE-CAT, and a mutant, pm18, were used to investigate the function of PLC-gamma1 in EGF- and PDGF-induced mitogenesis. wtSRE-CAT responds to both protein kinase C (PKC)-dependent and -independent signals, while the mutant, pm18, responds only to PKC-independent signals. Microinjection of the dominant-negative PLC-gamma1 SH2-SH2-SH3 polypeptide greatly reduced the responses of wtSRE-CAT to EGF stimulation in MDCK cells and to PDGF stimulation in NIH 3T3 cells but had no effect on the responses of mutant pm18. These results indicate that in addition to Grb2-mediated activation of Ras, PLC-gamma1-mediated DAG production is required for EGF- and PDGF-induced S-phase entry and gene expression, possibly through activation of PKC.
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PMID:Requirement for phospholipase C-gamma1 enzymatic activity in growth factor-induced mitogenesis. 941 5

Low density lipoprotein (LDL) has been shown to perturb endothelial cells, with manifestations ranging from alterations in free radicals and arachidonate metabolism to stress fiber formation and monocyte recruitment. Some of these changes are regulated by LDL at the transcriptional level. Using mobility shift assays with consensus sequences for various transcription factors, we have detected an increase in activator protein 1 (AP-1), but not nuclear factor-kappaB (NF-kappaB), binding in human umbilical vein endothelial cells exposed to LDL. Following transfection, AP-1-driven chloramphenicol acetyltransferase and AP-1-driven-luciferase are upregulated by LDL. In contrast, there is no effect on NF-kappaB-driven chloramphenicol acetyltransferase. AP-1 increases in a biphasic fashion, with the first peak occurring 6 hours after and the second 48 hours after exposure to LDL. This AP-1 binding increase involves c-Jun, but not c-Fos, as shown by gel supershift, Northern hybridization, and Western blotting analyses. c-Jun mRNA levels are elevated by 9 hours after and remain so until at least 24 hours after exposure to LDL. c-Jun protein levels increase at 12 hours and continue to rise for 24 hours after exposure to LDL. Moreover, this LDL-increased AP-1 binding is suppressed by several protein kinase (PK) inhibitors: the PKC inhibitor calphostin C, the cAMP-dependent PK inhibitor H89, and the tyrosine PK inhibitors genistein and lavendustin A. This study demonstrates that (1) LDL is an endothelial agonist distinct from other cell stimulators, such as cytokines, endotoxin, and phorbol 12-myristate 13-acetate, because LDL appears to activate human umbilical vein endothelial cells predominantly through the transcription factor AP-1 and not NF-kappaB; and (2) LDL increases AP-1 via mechanisms involving multiple kinase activities and c-Jun transcription.
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PMID:LDL induces transcription factor activator protein-1 in human endothelial cells. 951 17

The purpose of this study was to analyze the mechanism of transcriptional activation of human chorionic gonadotropin-alpha (hCGalpha) gene by epidermal growth factor (EGF) in trophoblast cells. We stably transfected hCGalpha promoter-chloramphenicol acetyltransferase constructs into Rcho-1 trophoblast cells and monitored the promoter activities. -290-base pair hCGalpha promoter containing a tandem repeat of cAMP response element (CRE) was activated by EGF in a dose- and time-dependent manner. Deletion analysis of hCGalpha promoter suggested an involvement of CRE in EGF-induced hCGalpha transcriptional activation. Moreover, the hCGalpha promoter, of which both CREs were mutated, did not respond to EGF. These results indicate that EGF activates the hCGalpha gene transcription through CRE. Although EGF did not alter the amount of CRE-binding protein (CREB), EGF induced CREB phosphorylation. We next examined the mechanism of CREB phosphorylation by EGF. Protein kinase C inhibitors (H7, staurosporin, and chelerythrine) inhibited EGF-induced CREB phosphorylation, whereas either mitogen-activated protein kinase kinase-1 inhibitor (PD98059) or protein kinase A inhibitor (H8) showed no effect. Furthermore, H7 and staurosporin but not H8 inhibited hCGalpha promoter activation by EGF. In conclusion, EGF promotes hCGalpha gene transcription via the CRE region probably by phosphorylating CREB mainly through the protein kinase C pathway in trophoblast cells.
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PMID:Human chorionic gonadotropin-alpha gene is transcriptionally activated by epidermal growth factor through cAMP response element in trophoblast cells. 952 71


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