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)

Exogenous arachidonic acid (AA) has been shown to induce the antioxidant manganese superoxide dismutase gene by reactive oxygen species (ROS) derived from AA metabolism and the participation of the p38 mitogen-activated protein kinase (MAPK) pathway in human HepG2 hepatoma cells. The goal of this study was to investigate the effect of AA on the activation of the two redox-sensitive transcription factors AP-1 and NF-kappaB in HepG2 cells. Using electrophoretic mobility shift assays, DNA-binding activities of AP-1 and NF-kappaB were markedly increased in AA-treated HepG2 cells. The c-Jun and c-Fos proteins were identified as components of the AA-induced AP-1 complex and their levels were increased. AA-activated NF-kappaB complex was constituted as a p50 homodimer resulting in a nuclear translocation for this protein only. Moreover, no degradation of IkappaBalpha was observed. These results were contrasted to the interleukin-1beta-activated p50/p65 complex used as a positive control. Using 5,8,11,14-eicosatetraynoic acid and inhibitors of AA metabolism, AP-1 and NF-kappaB activation required the lipoxygenase/cytochrome P450 monooxygenase pathways. In addition, antioxidants inhibited the AA-induced AP-1 and NF-kappaB activation, suggesting a role of ROS released from the AA metabolism. In reporter gene assays, AA induced the transcriptional activity of AP-1 but not that of NF-kappaB. Further investigations showed that the AA-induced transcriptional activity of AP-1 was regulated by protein kinase C and p38 MAPK pathways. These results suggest that the functional AP-1 activated by AA and coupled to that of p38 MAPK pathway may play an important role in response to ROS induced by AA metabolism in HepG2 cells without the involvement of the NF-kappaB pathway.
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PMID:Arachidonic acid activates a functional AP-1 and an inactive NF-kappaB complex in human HepG2 hepatoma cells. 1295 56

Flavonoids are natural polyphenolic compounds that have anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we investigated the effects of several flavonoids on nuclear factor-kappa B (NF-kappa B) activation by using luciferase reporter gene assay. Among the flavonoids examined, luteolin showed the most potent inhibition on lipopolysaccharide (LPS)-stimulated NF-kappa B transcriptional activity in Rat-1 fibroblasts. Luteolin did not inhibit either I kappa B alpha degradation or NF-kappa B nuclear translocation, DNA binding or phosphorylation by LPS. However, luteolin prevented LPS-stimulated interaction between the p65 subunit of NF-kappa B and the transcriptional coactivator CBP. In addition, a specific PKA inhibitor that blocked the phosphorylation of CREB and c-Jun by luteolin partially reversed the inhibitory effect of luteolin on NF-kappa B.CBP complex formation and NF-kappa B transcriptional activity by LPS. These data imply that inhibition of NF-kappa B transcriptional activity by luteolin may occur through competition with transcription factors for coactivator that is available in limited amounts. Taken together, this study provides a molecular basis for the understanding of the anti-inflammatory effects of luteolin.
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PMID:Luteolin inhibits the nuclear factor-kappa B transcriptional activity in Rat-1 fibroblasts. 1296 82

Ultrafine (Uf) particles are a component of particulate air pollution suggested to be responsible for the health effects associated with elevations of this pollutant. We have previously suggested that Uf particles, through the induction of oxidative stress, may induce inflammation in the lung, thus exacerbating preexisting illness in susceptible individuals. Alveolar macrophages are considered to play a key role in particlemediated inflammation and lung disease. The effect of Uf particles on rat alveolar macrophages and human blood monocytes was investigated with reference to the roles of calcium and reactive oxygen species (ROS). TNF-alpha protein release, intracellular calcium concentration, TNF-alpha mRNA expression, and transcription factor activation were studied as end points after treatment of rat alveolar macrophages or peripheral blood monocytes. The calcium channel blocker verapamil, the intracellular calcium chelator BAPTA-AM, the calmodulin inhibitor W-7, and the antioxidants Trolox and Nacystelin (NAL) were included in combination with Uf particles. Verapamil reduced intracellular calcium concentration in rat alveolar macrophages on stimulation with Uf particles. This effect was also apparent with transcription factor AP-1 activation. All antagonists and antioxidants reduced Uf-stimulated nuclear localization of the p50 and p65 subunits of NF-kappaB in human monocytes. Verapamil, BAPTA-AM, and NAL reduced Uf-stimulated TNF-alpha protein release, whereas only verapamil reduced Uf-stimulated mRNA expression in rat alveolar macrophages. In human monocytes, verapamil, Trolox, BAPTA-AM, and W-7 reduced Uf-stimulated TNF-alpha protein release. These findings suggest that Uf particles may exert proinflammatory effects by modulating intracellular calcium concentrations, activation of transcription factors, and cytokine production through a ROS-mediated mechanism.
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PMID:Calcium and ROS-mediated activation of transcription factors and TNF-alpha cytokine gene expression in macrophages exposed to ultrafine particles. 1455 62

Macrophage inflammatory protein-2 (MIP-2) is a mouse C-X-C chemokine that plays an important role in the recruitment of neutrophils. Transcription of the MIP-2 gene is rapidly induced by lipopolysaccharide (LPS) stimulation in cells of macrophage lineage. We show here that the MIP-2 promoter is transcriptionally activated in a macrophage cell line RAW 264.7 by LPS through a sequence located between -450 and -54 and this region contains two copies of activator protein-1 (AP-1) and one copy of nuclear factor-kappaB (NF-kappaB) binding site. A MIP-2 promoter-reporter was activated by ectopical expression of NF-kappaB p65 or c-Jun transcription factors. Inhibition of NF-kappaB nuclear localization by co-expression of a mutant IkappaBalpha protein (IkappaBalpha super repressor, IkappaBalphaSR) blocked LPS-induced transcription from a MIP-2 promoter-reporter construct, showing that NF-kappaB activation is required for MIP-2 gene expression in the LPS-signaling pathway. By deletion analysis of the MIP-2 promoter region, we show that NF-kappaB and c-Jun binding sites are essential for LPS-induced MIP-2 gene expression. Using transient transfection, NF-kappaB and c-Jun transcription factors were found to synergistically activate the MIP-2 promoter. In summary, our data suggest that both NF-kappaB and c-Jun contribute to LPS-induced mouse MIP-2 gene expression in RAW 264.7 cells.
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PMID:NF-kappaB and c-Jun-dependent regulation of macrophage inflammatory protein-2 gene expression in response to lipopolysaccharide in RAW 264.7 cells. 1459 66

EBV latent infection is associated with the development of lymphoid and epithelial malignancies such as nasopharyngeal carcinoma (NPC). The EBV latent membrane protein 1 (LMP1) acts as a constitutively active tumor necrosis factor receptor and activates cellular signaling pathways such as c-Jun-NH(2)-terminal kinase, cdc42, Akt, and nuclear factor (NF)-kappaB. In epithelial cells, two regions of LMP1 induce specific forms of NF-kappaB. COOH-terminal activating region 2 only activates p52/p65 dimers, whereas COOH-terminal activating region 1 activates p50/p50, p50/p52, and p52/p65 dimers and also uniquely up-regulates the epidermal growth factor receptor (EGFR) at the mRNA level. Deregulation of specific NF-kappaB members is associated with the development of many cancers. In this study, the status of NF-kappaB activation was investigated in NPC to determine which NF-kappaB dimers may contribute to the development of NPC. Electrophoretic mobility shift assay, immunoblot, ELISA, and immunohistochemistry data demonstrate that in NPC, NF-kappaB p50 homodimers are specifically activated, and this activation is not dependent on LMP1 expression. Coimmunoprecipitation assays indicate that homodimers are bound to the transcriptional coactivator Bcl-3, and chromatin immunoprecipitation indicates that this complex is bound to NF-kappaB consensus motifs within the egfr promoter in NPC. The discrete yet striking NF-kappaB p50 activation in NPC suggests that p50/p50 homodimers may be important factors in the development of NPC and may contribute to oncogenesis through transcriptional up-regulation of target genes through their interaction with Bcl-3.
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PMID:Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma. 1467 88

Monocyte/macrophage infiltration to the subendothelial space of arterial wall is a critical initial step in atherogenesis, in which CC chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1) is thought to play a key role. This study investigated the effectiveness of phosphodiesterase inhibitors, including the nonselective pentoxifylline (PTX) and the selective type III (cilostamide) and type IV (denbufylline) inhibitors, on cytokine-induced CCL2/MCP-1 production in cultured rat vascular smooth muscle cells (VSMCs), and the signal transduction mechanisms whereby they act. Our results showed that tumor necrosis factor (TNF)-alpha induced a marked increase in CCL2/MCP-1 production in dose- and time-dependent manners. 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059), 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene (U0126) [both inhibitors of p42/44 mitogen-activated protein kinase (MAPK) kinase], and anthra[1hyphen]9-cd]pyrazol-6(2H)-one (SP600125) [an inhibitor of c-Jun NH(2)-terminal kinases (JNKs)] attenuated TNF-alpha-induced CCL2/MCP-1 production, without affecting I-kappaBalpha degradation or p65/nuclear factor-kappaB (NF-kappaB) nuclear translocation. PD98059 abolished TNF-alpha-activated p42/44 MAPK phosphorylation and c-Fos up-regulation, whereas SP600125 inhibited TNF-alpha-activated JNK and c-Jun phosphorylation. The NF-kappaB inhibitor carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132) attenuated TNF-alpha-induced CCL2/MCP-1 production in the presence of increased phospho-JNK and phospho-c-Jun levels. When SP600125 was added simultaneously, MG132 completely inhibited TNF-alpha-induced CCL2/MCP-1 production. Finally, the pretreatment of VSMCs with PTX or cilostamide, but not denbufylline, reduced TNF-alpha-induced CCL2/MCP-1 production, which was preceded by attenuation of p65/NF-kappaB nuclear translocation, p42/44 MAPK, and JNK-c-Jun phosphorylation, and c-Fos up-regulation. These data indicate that TNF-alpha-stimulated CCL2/MCP-1 production in rat VSMCs is dually regulated by activator protein-1 (AP-1) and NF-kappaB pathways, and inhibition of type III phosphodiesterase contributes substantially to the suppressive effect of PTX on CCL2/MCP-1 production via down-regulation of AP-1 and NF-kappaB signals.
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PMID:Dual regulation of tumor necrosis factor-alpha-induced CCL2/monocyte chemoattractant protein-1 expression in vascular smooth muscle cells by nuclear factor-kappaB and activator protein-1: modulation by type III phosphodiesterase inhibition. 1497 97

Changes in the components of the Jun N-terminal kinase (JNK) signalling pathway were investigated in human A549 lung carcinoma cells treated with sodium dichromate. Sodium dichromate (100 microM, 0-6h) failed to activate nuclear factor kappa B (NF-kappaB) as determined by a lack of nuclear translocation of p65 but resulted in Jun N-terminal kinase activation as assessed by phospho-Jun N-terminal kinase Western blotting in a dose-dependent (>25 microM) and time-dependent (>1h) manner. In addition, c-Jun, a downstream target of Jun N-terminal kinase signalling was also activated with a similar dose- and time-dependency at the level of both protein expression and degree of phosphorylation. In contrast, sodium dichromate treatment had no effect on levels of phospho-p38. Immunoprecipitation demonstrated that apoptosis signal regulating kinase-1 (ASK-1), an upstream activator of Jun N-terminal kinase was dissociated from its inhibitory partner thioredoxin (Trx) in response to sodium dichromate (100 microM, 4h) treatment. This treatment was also associated with a transient (2h) increase in cytosolic levels of thioredoxin but no nuclear translocation of thioredoxin was observed. In conclusion, sodium dichromate had a stimulatory effect on the Jun N-terminal kinase signalling pathway in A549 cells, resulting in activation of downstream effector molecules. We hypothesise that dissociation of apoptosis signal regulating kinase-1 from thioredoxin may be at least partially responsible for Jun N-terminal kinase activation.
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PMID:Activation of c-Jun N-terminal kinase in A549 lung carcinoma cells by sodium dichromate: role of dissociation of apoptosis signal regulating kinase-1 from its physiological inhibitor thioredoxin. 1500 21

CCL5 (or RANTES (regulated upon activation, normal T cell expressed and secreted)) recruits T lymphocytes and monocytes. The source and regulation of CCL5 in pulmonary tuberculosis are unclear. Infection of the human alveolar epithelial cell line (A549) by Mycobacterium tuberculosis caused no CCL5 secretion and little monocyte secretion. Conditioned medium from tuberculosis-infected human monocytes (CoMTB) stimulated significant CCL5 secretion from A549 cells and from primary alveolar, but not upper airway, epithelial cells. Differential responsiveness of small airway and normal human bronchial epithelial cells to CoMTB but not to conditioned medium from unstimulated human monocytes was specific to CCL5 and not to CXCL8. CoMTB induced CCL5 mRNA accumulation in A549 cells and induced nuclear translocation of nuclear factor kappaB (NFkappaB) subunits p50, p65, and c-rel at 1 h; nuclear binding of activator protein (AP)-1 (c-Fos, FosB, and c-Jun) at 4-8 h; and binding of NF-interleukin (IL)-6 at 24 h. CCL5 promoter-reporter analysis using deletion and site-specific mutagenesis constructs demonstrated a key role for AP-1, NF-IL-6, and NFkappaB in driving CoMTB-induced promoter activity. The IL-1 receptor antagonist inhibited A549 and small airway epithelial cell CCL5 secretion, gene expression, and promoter activity. CoMTB contained IL-1beta, and recombinant IL-1beta reproduced CoMTB effects. Monocyte alveolar, but not upper airway, epithelial cell networks in pulmonary tuberculosis cause AP-1-, NF-IL-6-, and NFkappaB-dependent CCL5 secretion. IL-1beta is the critical regulator of tuberculosis-stimulated CCL5 secretion in the lung.
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PMID:Transcriptional mechanisms regulating alveolar epithelial cell-specific CCL5 secretion in pulmonary tuberculosis. 1511 56

Aplidin is an antitumor drug that induces apoptosis and activates EGFR, Src, JNK and p38MAPK. Here, we show that Aplidin induces c-JUN, JUN B, JUN D, c-FOS, FRA-1 and FOS B genes of the activator-protein (AP)-1 family, and also p65/RELA, a major component of nuclear factor-kappa B (NF-kappaB). Concordantly, Aplidin increases AP-1 and NF-kappaB activity. c-FOS induction depends on EGFR, Src and JNK/p38MAPK. In contrast, induction of c-JUN does not require EGFR activity and p65/RELA induction is only partially dependent on these kinases. We used several genetically deficient cells to identify the critical target of Aplidin. Mouse embryo fibroblasts (MEFs) deficient for src, yes and fyn, and those lacking all p38MAPK isoforms displayed normal Aplidin sensitivity (IC50=12 nM). In contrast, MEFs lacking jnk1 and jnk2, which do not express any JNK isoform, were much less sensitive (IC50>500 nM). Furthermore, cells lacking c-jun or expressing a c-Jun protein in which JNK targets Ser(63/73) were mutated (c-JunAA) showed intermediate sensitivity (IC50=60 nM). Additionally, Aplidin has higher cytotoxic activity against proliferating than quiescent cells, which is reflected in higher JNK activation. We conclude that phosphorylation by JNK of c-Jun and additional substrate(s) is crucial for Aplidin activity.
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PMID:JNK activation is critical for Aplidin-induced apoptosis. 1512 39

The human IL-6 promoter contains multiple regulatory elements such as those binding transcription factors belonging to the NF-kappaB (-75/-63), C/EBP (-158/-145 and -87/-76) and AP-1 (-283/-277) families. Herein, we report that ectopic expression of c-Jun, C/EBPdelta, and the p65 subunit of NF-kappaB synergistically activates an IL-6 promoter construct containing only a TATA box and a kappaB binding site. These results suggest that interactions among NF-kappaB, C/EBP, and AP-1, which are all activated by the most powerful physiological inducers of the IL-6 gene, namely TNF-alpha and IL-1, may be crucial for maximal activation of the IL-6 promoter in response to the two cytokines. Furthermore, we show that a mutated form of c-Jun lacking the transactivation domain (TAM-67) was a much stronger activator of the IL-6 promoter than c-Jun. In combination with p65 and/or C/EBPdelta, TAM-67 also synergistically activated the IL-6 promoter, while it inhibited TNF-alpha induced AP-1 activity directing an AP-1-responsive reporter plasmid. Lastly, electrophoretic mobility shift assay (EMSA) results strongly suggest the formation of complexes between p65, C/EBPdelta, and/or c-Jun or TAM-67 on the kappaB site, supporting the idea that the functional synergism is determined by a physical interaction. These data provide new insight into the molecular mechanisms regulating the formation of the transcription complex responsible for IL-6 promoter activation.
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PMID:Activation of the Interleukin-6 promoter by a dominant negative mutant of c-Jun. 1515 60


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