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)

Activation of mast cells by aggregation of their IgE receptors induces rapid and transient synthesis of cyclooxygenase-2 (COX-2). In this study we investigated (i) the cis-acting response elements and transcription factors active at the COX-2 promoter and (ii) the signal transduction pathways mediating COX-2 induction following aggregation of mast cell IgE receptors. Transient transfection assays with COX-2 promoter/luciferase constructs suggest that a consensus cyclic AMP response element is essential for induced COX-2 expression. Cotransfection studies with plasmids expressing c-Jun, dominant negative Ras, dominant negative c-Jun NH(2)-terminal kinase, and dominant negative MEKK1 demonstrate that activation of the Ras/MEKK1/c-Jun NH(2)-terminal kinase/c-Jun pathway is required for COX-2 promoter-mediated luciferase expression. Attenuation of COX-2 promoter activity by dominant negative constructs for Raf-1, ERK1, and ERK2 suggests that the Ras/Raf-1/extracellular signal-regulated kinase pathway is also necessary for COX-2 induction. Although mutating the two NF-IL6 sites individually did not affect COX-2 promoter activity, mutating both NF-IL6 sites substantially inhibits COX-2 promoter activity. Moreover, overexpression of wild type CCAAT/enhancer-binding protein-beta (C/EBPbeta) augments COX-2 promoter activity in activated mast cells and cotransfection of a dominant negative C/EBPbeta construct completely blocks COX-2 promoter/luciferase expression. Our data suggest that in activated mast cells, a Ras/MEKK1/c-Jun NH(2)-terminal kinase signal transduction pathway activating c-Jun, a Ras/Raf-1/extracellular signal-regulated kinase pathway, and activated C/EBPbeta facilitate COX-2 induction via the cyclic AMP response element and NF-IL6 sites of the COX-2 promoter.
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PMID:Transcriptional regulation of the cyclooxygenase-2 gene in activated mast cells. 1065 93

Glucocorticoid drugs suppress tumor necrosis factor-alpha (TNF-alpha) synthesis by activated monocyte/macrophages, contributing to an anti-inflammatory action in vivo. In lipopolysaccharide (LPS)-activated human monocytic THP-1 cells, glucocorticoids acted primarily on the TNF-alpha promoter to suppress a burst of transcriptional activity that occurred between 90 min and 3 h after LPS exposure. LPS increased nuclear c-Jun/ATF-2, NF-kappaB(1)/Rel-A, and Rel-A/C-Rel transcription factor complexes, which bound specifically to oligonucleotide sequences from the -106 to -88 base pair (bp) region of the promoter. The glucocorticoid, dexamethasone, suppressed nuclear binding activity of these complexes prior to and during the critical phase of TNF-alpha transcription. Site-directed mutagenesis in TNF-alpha promoter-luciferase reporter constructs showed that the adjacent c-Jun/ATF-2 (-106 to -99 bp) and NF-kappaB (-97 to -88 bp) binding sites each contributed to the LPS-stimulated expression. Mutating both sites largely prevented dexamethasone from suppressing TNF-alpha promoter-luciferase reporters. LPS exposure also increased nuclear Egr-1 and PU.1 abundance. The Egr-1/Sp1 (-172 to -161 bp) binding sites and the PU.1-binding Ets site (-116 to -110 bp) each contributed to the LPS-stimulated expression but not to glucocorticoid response. Dexamethasone suppressed the abundance of the c-Fos/c-Jun complex in THP-1 cell nuclei, but there was no direct evidence for c-Fos/c-Jun transactivation through sites in the -172 to -52 bp region. Small contributions to glucocorticoid response were attributable to promoter sequences outside the -172 to -88 bp region and to sequences in the TNF-alpha 3'-untranslated region. We conclude that glucocorticoids suppress LPS-stimulated secretion of TNF-alpha from human monocytic cells largely through antagonizing transactivation by c-Jun/ATF-2 and NF-kappaB complexes at binding sites in the -106 to -88 bp region of the TNF-alpha promoter.
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PMID:Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter. 1074 79

The stress-activated protein kinase JNK plays an important role in the stability and activities of key regulatory proteins, including c-Jun, ATF2, and p53. To better understand mechanisms underlying the regulation of JNK activities, we studied the effect of expression of the amino-terminal JNK fragment (N-JNK; amino acids 1-206) on the stability and activities of JNK substrates under nonstressed growth conditions, as well as after exposure to hydrogen peroxide. Mouse fibroblasts that express N-JNK under tetracycline-off (tet-off) inducible promoter exhibited elevated expression of c-Jun, ATF2, and p53 upon tetracycline removal. This increased coincided with elevated transcriptional activities of p53, but not of c-Jun or ATF2, as reflected in luciferase activities of p21(Waf1/Cip1)-Luc, AP1-Luc, and Jun2-Luc, respectively. Expression of N-JNK in cells that were treated with H(2)O(2) impaired transcriptional output as reflected in a delayed and lower level of c-Jun-, limited ATF2-, and reduced p53-transcriptional activities. N-JNK elicited an increase in H(2)O(2)-induced cell death, which is p53-dependent, because it was not seen in p53 null cells yet could be observed upon coexpression of p53 and N-JNK. The ability to alter the activity of ATF2, c-Jun, and p53 and the degree of stress-induced cell death by a JNK-derived fragment identifies new means to elucidate the nature of JNK regulation and to alter the cellular response to stress.
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PMID:Amino-terminal-derived JNK fragment alters expression and activity of c-Jun, ATF2, and p53 and increases H2O2-induced cell death. 1074 85

Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-kappaB and c-Jun NH(2)-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in IL-17-induced NF-kappaB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IkappaB kinases (IKKs) and JNK. Consequently, IL-17-induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17-induced NF-kappaB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses.
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PMID:Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. 1074 40

Regulation of the mitogen-activated protein kinase (MAPK) family by gonadotropin-releasing hormone (GnRH) in the gonadotrope cell line LbetaT2 was investigated. Treatment with gonadotropin-releasing hormone agonist (GnRHa) activates extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK). Activation of ERK by GnRHa occurred within 5 min, and declined thereafter, whereas activation of JNK by GnRHa occurred with a different time frame, i.e. it was detectable at 5 min, reached a plateau at 30 min, and declined thereafter. GnRHa-induced ERK activation was dependent on protein kinase C or extracellular and intracellular Ca(2+), whereas GnRHa-induced JNK activation was not dependent on protein kinase C or on extracellular or intracellular Ca(2+). To determine whether a mitogen-activated protein kinase family cascade regulates rat luteinizing hormone beta (LHbeta) promoter activity, we transfected the rat LHbeta (-156 to +7)-luciferase construct into LbetaT2 cells. GnRH activated the rat LHbeta promoter activity in a time-dependent manner. Neither treatment with a mitogen-activated protein kinase/ERK kinase (MEK) inhibitor, PD98059, nor cotransfection with a catalytically inactive form of a mitogen-activated protein kinase construct inhibited the induction of the rat LHbeta promoter by GnRH. Furthermore, cotransfection with a dominant negative Ets had no effect on the response of the rat LHbeta promoter to GnRH. On the other hand, cotransfection with either dominant negative JNK or dominant negative c-Jun significantly inhibited the induction of the rat LHbeta promoter by GnRH. In addition, GnRH did not induce either the rat LHbeta promoter activity in LbetaT2 cells transfected stably with dominant negative c-Jun. These results suggest that GnRHa differentially activates ERK and JNK, and a JNK cascade is necessary to elicit the rat LHbeta promoter activity in a c-Jun-dependent mechanism in LbetaT2 cells.
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PMID:Activation of the luteinizing hormone beta promoter by gonadotropin-releasing hormone requires c-Jun NH2-terminal protein kinase. 1078 26

Because transcription factors NF-kappaB and activator protein-1 (AP-1) are known to regulate gene expression, we have analyzed the role of acetaldehyde in the activation of NF-kappaB and AP-1 in HepG2 cells. Binding activity and transactivation of NF-kappaB and AP-1 were determined by gel retardation assays and transfection of a luciferase reporter construct controlled by kappaB and AP-1 binding sites, respectively. Acetaldehyde enhanced the DNA binding of NF-kappaB and AP-1 by 1 and 4 h, respectively, increasing the kappaB- and AP-1-dependent luciferase expression. Supershift assays revealed the presence of NF-kappaB heterodimers p65/p50 and p50/p52, whereas nuclear c-Jun levels correlated with the DNA binding of AP-1. The enhanced binding of NF-kappaB to DNA by acetaldehyde in intact cells was accompanied by the proteolytic degradation of IkappaB-alpha. However, the addition of acetaldehyde to cytostolic extracts from untreated Hep G2 cells did not affect the DNA binding of AP-1 but activated the NF-kappaB heterodimer p65/p50 in the absence of IkappaB-alpha degradation. Preincubation of HepG2 cells with protein kinase C inhibitors abolished the enhanced DNA binding of NF-kappaB and AP-1 caused by acetaldehyde. Hence, these findings uncover a previously unrecognized role for acetaldehyde in the activation of NF-kappaB and AP-1, which may be of relevance in the alcohol-induced liver disease.
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PMID:Enhanced DNA binding and activation of transcription factors NF-kappa B and AP-1 by acetaldehyde in HEPG2 cells. 1079 56

PGs play a functional role in the early stage of Gram-negative bacterial infections, because this prostanoid is produced rapidly by epithelial cells after a bacterial infection. CD14, one of the LPS receptors, is a key molecule in triggering the response to bacterial LPS in association with a Toll-like molecule. Therefore, in this study, we investigated the effect of PG on CD14 expression in mouse macrophages. PGE1, PGE2, and PGA1 among the PGs tested strongly stimulated the expression of the CD14 gene in the cells. The stimulatory action also was observed by Western blot analysis. cAMP-elevating agents stimulated expression of CD14 gene as well. Protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), but not protein kinase C inhibitor 3-(1-[3-(dimethylamino)propyl]-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-py rrole-2,5-dione (GF109203X), abolished the stimulated expression of CD14. A run-on assay showed that PGE2 stimulated the CD14 gene expression at the transcriptional level via protein kinase A. PGE2 also stimulated activation of AP-1, a heterodimer of c-Jun and c-Fos, because the prostanoid increased specific binding of nuclear proteins to the AP-1 consensus sequence and stimulated AP-1-promoted luciferase activity. PGE2-stimulated expression of CD14 was inhibited by antisense c-fos and c-jun oligonucleotides, but not by their sense oligonucleotides. Finally, PGE2 pretreatment synergistically stimulated LPS-induced expression of IL-1beta and IL-6 genes in mouse macrophages. Therefore, the present study demonstrates that PGE2 has the ability to stimulate AP-1-mediated expression of CD14 in mouse macrophages via cAMP-dependent protein kinase A.
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PMID:Prostaglandin E2 stimulates AP-1-mediated CD14 expression in mouse macrophages via cyclic AMP-dependent protein kinase A. 1079 5

Involucrin is a major protein of the cornified envelope of keratinocytes that provides much of the structural integrity of the skin. The gene expression of this differentiation marker is induced by elevated extracellular calcium in cultured human keratinocytes. A 3.7-kilobase fragment of this gene contains the necessary elements to drive a luciferase reporter in a calcium-dependent manner. We have sequenced the upstream region of the involucrin promoter and localized a calcium response element that contains an activating protein-1 (AP-1) site (TGAGTCA). Mutation of this site abolished the promoter activation by calcium. Compared with cells grown in 0.03 mm calcium, the binding activity of factors within nuclear extracts from keratinocytes for this AP-1 site was enhanced 3-fold in cells grown in 1.2 mm calcium. Immunoelectrophoretic mobility shift (supershift) assays identified JunD, Fra1, and Fra2 as the major factors that bind to the AP-1 element. Western analysis of the proteins in the nuclear extracts showed that the levels of c-Jun, JunB, JunD, FosB, and Fra2 increased and the levels of c-Fos and Fra1 decreased slightly with calcium treatment. The effect of calcium on the involucrin promoter was enhanced synergistically by phorbol 12-myristate 13-acetate (PMA) in a protein kinase-dependent manner. In conclusion, calcium-regulated involucrin gene expression is mediated at least in part by AP-1 transcription factors.
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PMID:Requirement of an AP-1 site in the calcium response region of the involucrin promoter. 1081 78

Basic fibroblast growth factor (bFGF) stimulates collagenase-3 synthesis in fetal rat osteoblast-enriched (Ob) cells. In this study we examined the mechanism of collagenase-3 regulation in Ob cells. bFGF at 0.6 nM or more increased the transcriptional rate of collagenase-3 by 3- to 7-fold. bFGF at 0.6 nM increased the activity of collagenase-3 promoter-luciferase reporter deletion constructs from -721 to -53 nucleotides transiently transfected into Ob cells by 3- to 5-fold. The minimal bFGF response was retained within the -53 to +28 sequence. Mutational analysis revealed that the bFGF effect was mediated through an activator protein-1 (AP-1)-binding site located at -48 to -42 nucleotides in the promoter. bFGF stimulated the binding of nuclear factors to the collagenase AP-1 site by 3- to 4-fold, as determined by electrophoretic mobility shift assays. Supershift analysis of nuclear extracts revealed that bFGF stimulates the occupancy of AP-1 site by c-Jun, JunB, JunD, c-Fos, FosB, and Fra2. In conclusion, bFGF increases collagenase-3 gene transcription, an effect mediated through an AP-1 site, due to the induction or activation of Jun and Fos family transcription factors. The stimulation of collagenase-3 synthesis by bFGF may be critical in mediating the actions of this growth factor in bone remodeling.
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PMID:Basic fibroblast growth factor stimulates collagenase-3 promoter activity in osteoblasts through an activator protein-1-binding site. 1083 Mar 7

The tumor promoter phorbol 13-myristate 12-acetate (PMA), the best characterized protein kinase C agonist, frequently regulates gene expression via activation of Fos/Jun (AP-1) complexes. PMA rapidly and transiently induces prostaglandin G/H synthase-2 (PGHS-2) expression in murine osteoblastic MC3T3-E1 cells, but no functional AP-1 binding motifs in the 5'-flanking region have been identified. In MC3T3-E1 cells transfected with -371/+70 bp of the PGHS-2 gene fused to a luciferase reporter gene (Pluc), PMA stimulates luciferase activity up to eightfold. Computer analysis of the sequence of the PGHS-2 promoter region identified three potential AP-1 elements in the -371/+70 bp region, and deletion analysis suggested that the sequence 5'-aGAGTCA-3' at -69/-63 bp was most likely to mediate stimulation by PMA. Mutation of the putative AP-1 sequence reduces the ability of PMA to stimulate Pluc activity by 65%. On electrophoretic mobility shift analysis (EMSA), PMA induces binding to a PGHS-2 probe spanning this sequence, binding is blocked by an unlabeled AP-1 canonical sequence, and antibodies specific for c-Jun and c-Fos inhibit binding. Mutation of this AP-1 site also causes a small (22%) but significant reduction in the serum stimulation of Pluc activity in transiently transfected MC3T3-E1 cells. On EMSA, serum induces binding to a PGHS-2 probe spanning the AP-1 site, binding is blocked by an unlabeled AP-1 canonical sequence, and antibodies specific for c-Jun and c-Fos inhibit binding. Joint mutation of this AP-1 site and the nearby CRE site at -56/-52 bp, previously shown to mediate serum, v-src and PDGF induction of PGHS-2 in NIH-3T3 cells, blocks both PMA and serum induction of Pluc activity in MC3T3-E1 cells. Hence, the AP-1 and CRE binding sites are jointly but differentially involved in both the PMA and serum stimulation of PGHS-2 promoter activity.
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PMID:Identification of multiple cis-acting elements mediating the induction of prostaglandin G/H synthase-2 by phorbol ester in murine osteoblastic cells. 1084 15


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