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: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

12-O-Tetradecanoylphorbol-13-acetate (TPA) is widely used as a tumor promoter with organotropy in skin and esophagus. TPA-induced, organ-specific tumor promotion is not correlated with the distribution of its receptor, protein kinase C (PKC). Using five administration methods (painting, drinking, gavage feeding, i.p. injection, and i.v. injection), we analyzed TPA-stimulated activator protein-1 (AP-1) activity in various organs (liver, kidney, brain, lung, spleen, heart, stomach, colon, esophagus, and skin) from transgenic mice expressing the AP-1 luciferase reporter gene. Topical application of TPA by painting the skin on the back of mice raised AP-1 activity 122.6-fold, and the highest peak of AP-1 activity was at 12 h after administration of TPA. Drinking water containing TPA caused a 25.8-fold induction of AP-1 activity in the skin, whereas gavage feeding with TPA caused a 34.2-fold induction of AP-1 in the skin. Intraperitoneal or i.v. injection of TPA induced a 49.56-fold or 20.4-fold increase in AP-1 activity in the skin, respectively. The highest peaks of AP-1 activity in the skin were at 12 h after drinking, feeding, or injection of TPA. More interesting, in the esophagus, i.p. injection of TPA raised AP-1 activity 13.9-fold, drinking TPA raised AP-1 activity 8.4-fold, and painting with TPA caused a 2.4-fold induction of AP-1 activity. In the colon, i.p. injection of TPA raised AP-1 activity 3.9-fold, drinking TPA induced a 1.2-fold increase in AP-1 activity, but painting with TPA had no effect. AP-1 activity in other organs was not detectable after administration of TPA by painting, drinking, or injection. Phosphorylation of extracellular signal-regulated kinases in the skin increased at 12 h after painting, drinking, or i.p. injection of TPA. In addition, phosphorylation of p38 kinase was raised slightly after TPA administration, but phosphorylation of c-Jun NH(2)-terminal kinases was not detected at any time point after TPA administration. Similar changes in MAP kinases were also seen in the esophagus after TPA administration. These results indicate that the skin is the most sensitive organ to TPA induction of AP-1 activity. The data suggest that the organ-specific, tumor-promoting effect of TPA may be through AP-1 activation and phosphorylation of ERKs and p38 kinase.
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PMID:Organ-specific activation of activator protein-1 in transgenic mice by 12-o-tetradecanoylphorbol-13-acetate with different administration methods. 1135 30

The tumor suppressor, p53, has been shown to transcriptionally activate or silence a number of target genes. As an activator, p53 relies on its specific consensus sequence within the promoter. It is not clear whether p53 requires a specific DNA binding site in its action as a gene repressor. This report demonstrates that the human BKB1R gene is a p53 target. Expression of p53 in transiently transfected SV40-transformed IMR90 cells strongly suppressed luciferase reporter activity driven by a 1.8 kb BKB1R promoter as well as its minigene. These down-regulations were p53 dose-dependent. p53 reduced both basal and induced promoter activities of the minigene. Expression of p53 abolished the inducibility of the minigene. Induction of endogenous p53 expression by etoposide also inhibited promoter activity and minigene inducibility. Replacing the region containing both the putative p53 binding site and the TATA-box with a basal adenovirus promoter in the 1.8 kb promoter construct did not prevent p53 from inhibiting BKB1R promoter activity. Thus suppression by p53 is not mediated by competition with the TATA-binding protein and is not through interaction with the putative p53-binding site. p53 also does not appear to suppress BKB1R gene expression through interaction with c-Jun which functions in the inducibility of this gene [Yang et al., 2001].
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PMID:p53 down-regulates human bradykinin B1 receptor gene expression. 1140 Jan 61

The bradykinin B1 receptor (BKB1R) gene is expressed in selected tissues such as lung and kidney. In these tissues it is expressed at a very low level until induced by inflammatory mediators. Our aim has been to understand the mechanism of this regulatory process. A human BKB1R minigene was constructed. It contained a 1.8 kb promoter, the entire exon I, 1.5 kb of intron I, the entire exon II and intron II, and the luciferase gene as a reporter. Transient transfection of the minigene into SV40-transformed IMR90 cells (IMRSV) resulted in a promoter activity which was activated by the mediators, lipopolysaccharide and (LPS) desArg(10)-kallidin. In contrast, these mediators did not induce the activity of the 1.8 kb promoter construct alone. Thus, motifs exclusive of the promoter such as 5'-UTR and/or intron regions are required for mediator-induced expression of this gene. Promoter activities of both the minigene and the 1.8 kb promoter construct were enhanced in a dose-dependent manner upon cotransfection with c-Jun. Furthermore, cotransfecting c-Jun with the minigene achieved the maximal promoter activity with no further increase in response to mediators. Conversely, the induction of the minigene promoter activity by mediators was abolished upon cotransfection with a dominant negative mutant of c-Jun. Other experiments suggest that multiple AP-1 sites are interactive with the c-Jun upregulation of this gene. Taken together, these results point to c-Jun as a key intermediary in the activation of the expression of this gene by mediators. However, participation of motifs outside of the promoter are necessary to obtain this inducible expression.
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PMID:Mediator caused induction of a human bradykinin B1 receptor minigene: participation of c-Jun in the process. 1140 Jan 73

Endothelial dysfunction is a major atherogenic proinflammatory event. LDL causes the activation and phenotypic changes of cultured vascular endothelial cells (ECs). We previously reported that LDL activates c-Jun and AP-1 in ECs. In this study, we demonstrated that p38-ATF-2 is activated by LDL in human ECs and that this activation is mediated by Ras. When ECs are incubated with LDL in pathophysiological concentrations, the p38-mediated ATF-2 phosphorylation and ATF-2 transactivation are increased in a time- and dose-dependent manner. To elucidate the upstream mechanism in LDL-activated p38 in ECs, we demonstrate that LDL increases Ras translocation from the cytoplasm to the cellular membrane, with concurrent increases in Ras binding activity to GST-Raf-1. Overexpression of RasN17, a dominant negative mutant of Ras, attenuates the LDL-induced increases in (1) phosphorylation of ATF-2, (2) phosphorylation of c-Jun, (3) AP-1 binding, and (4) AP-1-driven luciferase activity. To study the effect of p38 in the regulation of an LDL targeting gene, we show that a specific p38 inhibitor attenuates LDL-induced E-selectin at the mRNA level. Thus, LDL activates both p38 and JNK signaling pathways through Ras activation, and furthermore, these events may play an important role in LDL-induced endothelial activation.
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PMID:LDL-activated p38 in endothelial cells is mediated by Ras. 1145 45

Overexpression of the multidrug resistance protein, MRP1, confers resistance to multiple natural product-type chemotherapeutics. MRP1 amplification is observed in some multidrug-resistant cell lines, while in others, increased transcription occurs in the absence of gene amplification. To investigate mechanisms influencing MRP1 transcription, three small cell lung cancer cell lines were examined: drug sensitive H69 cells with two apparently normal MRP1 alleles, highly resistant H69AR cells in which MRP1 is amplified and low level resistant H69PR cells that contain only one MRP1 allele. Deoxyribonuclease I footprinting and gel mobility shift assays were undertaken using nuclear extracts from the three cell lines and a 1 kb region encompassing the 5' flanking region of MRP1. Thirteen protein binding sites were identified of which six were sequence specific. Differences in levels of protein binding occurred with a putative antioxidant response element (ARE)/AP-1 binding site at -511 to -477. Levels of protein binding to this site were 2.5- to 3.0-fold higher in H69AR nuclear extracts versus extracts from H69 or H69PR cells. The AP-1 sequence is required for binding and c-Jun and JunD were identified as components of the protein complex. The ARE/AP-1 element functioned as a transcriptional enhancer but did not mediate induction of a luciferase reporter gene upon beta-naphthoflavone treatment.
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PMID:Identification of DNA-protein interactions in the 5' flanking and 5' untranslated regions of the human multidrug resistance protein (MRP1) gene: evaluation of a putative antioxidant response element/AP-1 binding site. 1146 49

Wogonin (Wog), an active component of Scutellaria baicalensis, has antioxidant and anti-inflammatory properties. Monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, plays a crucial role in case of early inflammatory responses, including atherosclerosis. In this study, we investigated the effect of Wog on phorbol ester (PMA)-induced MCP-1 expression in human umbilical vein endothelial cells (ECs). The MCP-1 mRNA levels and MCP-1 release in Wog-treated ECs were measured. Wog inhibited PMA-induced MCP-1 mRNA levels and MCP-1 secretion in a dose-dependent manner. The inhibition of MCP-1 induction by Wog is a transcriptional event, as shown by Wog's significant reduction of both MCP-1 promoter and 4x 12-O-tetradecanoylphorbol-13-acetate response element-luciferase reporter activities. By electrophoretic mobility assay, Wog significantly reduced the AP-1 binding activity induced by PMA. Furthermore, the PMA-induced extracellular signal-regulated kinase 1/2 and c-Jun amino-terminal kinase activities that contributed to AP-1 activity and MCP-1 gene induction were obviously attenuated after pretreating ECs with Wog. The decrease of MCP-1 secretion by Wog pretreatment led to a reduction of monocyte adhesion to ECs. Taken together, our results demonstrate that Wog inhibits MCP-1 induction in ECs; this inhibition is mediated by reducing AP-1 transcriptional activity via the attenuation of ERK1/2 and JNK signal transduction pathways. We conclude that Wog has the potential therapeutic development for use in anti-inflammatory and vascular disorders.
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PMID:Chinese herbal remedy wogonin inhibits monocyte chemotactic protein-1 gene expression in human endothelial cells. 1150 81

Inhalation of nickel dust has been associated with an increased incidence of pulmonary fibrosis. Nickel may promote fibrosis by transcriptionally activating plasminogen activator inhibitor (PAI)-1 and inhibiting fibrinolysis. The current studies examined whether nickel stimulated the PAI-1 promoter though an oxidant-sensitive activator protein (AP)-1 signaling pathway. Addition of nickel to BEAS-2B human airway epithelial cells stimulated intracellular oxidation, induced c-Jun and c-Fos mRNA levels, increased phospho- and total c-Jun protein levels, and elevated PAI-1 mRNA levels over a 24-h time course. Pretreatment of the cells with antioxidants did not affect increased c-Jun protein or PAI-1 mRNA levels. Expression of the dominant negative inhibitor of AP-1, TAM67, prevented nickel-stimulated AP-1 DNA binding, AP-1-luciferase reporter construct activity, and PAI-1 mRNA levels. Overexpression of c-Jun, however, failed to induce the AP-1 luciferase reporter construct or PAI-1 mRNA levels. These data indicated that nickel activated AP-1 through an oxidant-independent pathway and that basal AP-1 is necessary for nickel-induced expression of PAI-1.
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PMID:AP-1-dependent induction of plasminogen activator inhibitor-1 by nickel does not require reactive oxygen. 1150 88

Activation of brain natriuretic peptide (BNP) gene promoter activity represents one of the earliest and most reliable markers of ventricular cardiac myocyte hypertrophy. We recently demonstrated that mechanical strain increases immunoreactive BNP secretion, steady-state BNP mRNA levels and BNP gene transcriptional activity in neonatal rat myocyte cultures. We have also shown that strain-dependent BNP gene transcription is critically dependent on the functional integrity of a number of integrins (specfically beta1, beta3, and alpha(v)beta5 integrins) present on the surface of cardiac myocytes. When used alone, each of these antibodies resulted in a significant reduction in strain-dependent activation of a transfected hBNP-luciferase reporter and inhibition of a number of signaling pathways that have been linked to stimulation of this reporter (e.g., extracellular signal regulated kinase and c-Jun amino terminal kinase). The present study shows that combinations of these antibodies resulted in further reductions in hBNP gene promoter activity and inhibition of the relevant signaling cascades. These studies provide further support for the importance of integrin-matrix interactions in promoting strain-dependent changes in cardiac myocyte gene transcription.
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PMID:Signaling mechanisms underlying strain-dependent brain natriuretic peptide gene transcription. 1155 72

GL331 is a novel podophyllotoxin-derived compound. In this study, GL331 induced human lung adenocarcinoma cell line CL1-5 growth arrest before death during the initial 24-h incubation period. We found that GL331 had no inhibitory effect on the expression of cyclins E, A, B1, CDK 4, and CDK 2; instead, its cell growth-inhibitory effect was partly attributable to an early down-regulation of cyclin D1 expression and in turn the reduction of retinoblastoma protein phosphorylation. GL331 enhanced the proteolysis of cyclin D1, and a proteasome inhibitor was able to block GL331-caused cyclin D1 reduction, suggesting that GL331-stimulated cyclin D1 degradation was through proteasomal processes. Additionally, GL331 reduced cellular cyclin D1 mRNA level down to 45% of control in 4 h and further to around 20% in 12 h. However, GL331 did not accelerate the disappearance of cyclin D1 mRNA under the condition of transcription blockage induced by actinomycin D. It was reported that a certain region in the 3'-untranslated region (UTR) of cyclin D1 mRNA mediated the mRNA degradation upon extracellular stresses. Herein, transient transfection studies demonstrated that the 3'-UTR insertion did not confer the susceptibility of luciferase reporter gene to the GL331 treatment. Together, these data suggested that GL331 did not decrease the stability of cyclin D1 mRNA. On the other hand, we found that GL331 specifically inhibited the cyclin D1 promoter-driven luciferase reporter activity. Western blot analyses showed that GL331 decreased the level of phosphorylated extracellular signal-regulated kinase (Erk), with no effect on p38 or c-Jun NH(2)-terminal kinase. Furthermore, GL331's inhibition of cyclin D1 promoter was attenuated by ectopic Erk-2 overexpression. These data suggested that GL331 inhibited cyclin D1 gene transcription via the Erk signaling pathway. In summary, we report that GL331 induced an early decline of cyclin D1 expression by dual mechanisms: 1) enhancement of protein turnover and 2) repression of Erk-mediated gene transcription.
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PMID:GL331 induces down-regulation of cyclin D1 expression via enhanced proteolysis and repressed transcription. 1156 39

Phospholipase A2 (PLA2) has been suggested in the pathogenesis of acute pancreatitis, in part through the PLA2-generated phospholipid by-products, most notably lysophosphatidylcholine (lyso-PC). The effects of lyso-PC on pancreatic acinar cells other than necrosis are poorly characterized. Recent studies have suggested a role of the activation of transcription factors such as nuclear factor kappa B (NF-kappaB) for the pathogenesis of acute pancreatitis. Here we examined the effects of lyso-PC on the activation of transcriptional factors in rat pancreatic AR42J cells. Lyso-PC induced apoptosis at concentrations > or = 10 microM. At 10 and 25 microM, lyso-PC increased the NF-kappaB- and activator protein-1 (AP-1)-specific DNA binding activity as determined by electrophoretic mobility shift assay. Lyso-PC also increased the transcriptional activity of NF-kappaB and AP-1 as assessed by luciferase assay. Lyso-PC increased the mRNA level of pancreatitis-associated protein-I and c-jun. Lyso-PC activated three classes of mitogen activated protein kinases: extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase/stress-activated protein kinase and p38 kinases. Activation of transcription factors by lyso-PC was not altered by a specific platelet activating factor receptor antagonist, TCV-309, suggesting that the activation was independent of the platelet activating factor receptor. These molecular events may suggest a novel role of lyso-PC for the modulation of acinar cell function.
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PMID:Lysophosphatidylcholine activates transcription factor NF-kappaB and AP-1 in AR42J cells. 1157 38


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