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)

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

We previously reported that injury-induced medial vascular smooth muscle cell (VSMC) proliferation and neointima formation in carotid arteries of inducible nitric oxide synthase knockout (iNOS KO) mice were significantly reduced compared with wild type (WT). However, the molecular pathway underlying such differences is not known. In this in vitro study, we discovered that the AP-1/Ref-1/thioredoxin signaling pathway is altered in aortic VSMC from iNOS KO mice, which leads to reduced growth response when compared with aortic VSMC from WT mice. After equal initial seeding, the cell number after 7 days in serum medium was less in iNOS KO cells compared with WT VSMC (1.2 +/- 0.6 x 10(5) vs 3.2 +/- 1.1 x 10(5); p < 0.05). Significantly more iNOS KO cells remained in the G0/G1 phase compared with WT cells after 24-h serum treatment (82.6 +/- 13.7% vs 62.3 +/- 14.6%; p < 0.05) by cell-cycle analysis. Nuclear PCNA expression was also less in the iNOS KO cells, which was not affected by exogenous NO or superoxide. Superoxide generation after 24-h serum stimulation was less in the iNOS KO cells compared with WT cells. After 30-min serum stimulation, AP-1 DNA binding was reduced and a lack of increase in nuclear c-Jun protein was observed in iNOS KO VSMC. RT-PCR analysis confirmed a lack of inducible c-Jun mRNA after serum stimulation in the KO cells. In addition, KO cells had less nuclear reducing factor-1 (Ref-1) and serum-inducible thioredoxin protein expression. Reduced proliferative response of iNOS KO VSMC to serum treatment is associated with altered AP-1 /Ref-1 /thioredoxin pathway activation.
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PMID:Altered AP-1/Ref-1 redox pathway and reduced proliferative response in iNOS-deficient vascular smooth muscle cells. 1567 81

The p53 protein is redox-sensitive in vitro but in vivo effectors of this sensitivity are not known. In yeasts deficient for thioredoxin (Trx) reductase (TRR), p53 accumulates in an inactive, oxidized form, suggesting a role for TRR-Trx in controlling p53. In mammalian cells, p53 binds to redox factor-1 (APE/Ref-1), an enzyme containing an abasic endonuclease domain involved in base excision repair, and a thiol reductase domain recycled by Trx and involved in regulating the transcription factor AP-1. To evaluate the role of TRR and APE/Ref-1 in p53 regulation, we have abrogated their expression using RNA interference in cell lines expressing wild-type p53. Inhibition of TRR resulted in accumulation of oxidized Trx and increased levels and DNA-binding activity of p53, with no phosphorylation of Ser15 or Ser20. In contrast, inhibition of APE/Ref-1 accelerated p53 protein turnover, resulting in a decrease in p53 levels and activity. However, inhibition of either TRR or APE/Ref-1 did not prevent activation and accumulation of p53 in response to DNA-damage by doxorubicin. When both factors were inhibited, basal levels of p53 were restored. These results suggest that TRR-Trx and APE/Ref-1 cooperate in the control of basal p53 activity, but not in its induction by DNA-damage.
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PMID:Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity. 1582 42

It has been demonstrated that growth factors quiescin Q6 family was created by the fusion of the sulfhydryl oxidase fragment of the yeast essential for respiration and vegetative growth (ERV)1 prototype [an orthologue of hepatopoietin (HPO)] and thioredoxin (TRX)/disulfide isomerase domain during evolution. In this paper, our results demonstrated that two components of this composite protein, i.e., HPO and TRX, were involved in the same signal transduction and interacted physically in eukaryocyte. When HPO and TRX were cotransfected into COS7 cells, the activity of activator protein-1 (AP-1) and NF-kappaB was evidently enhanced compared with the transfection with HPO or TRX alone, at the same time, the phosphorylation of c-Jun was increased. They were colocalized in the cells. By Co-IP and GST pull-down experiments, we found that HPO could physically interact with TRX, which was also confirmed by yeast two-hybrid assay. By further investigation, we found both HPO and TRX were sensitive to cellular oxidative state. HPO dimer is in its natural state and could be reduced by dithiothreitol (DTT) in vitro and in vivo. Under the treatment of oxidants such as H(2)O(2) and diamide, the amount of HPO monomer was decreased significantly and assembled into dimer, and the free thiol in TRX was oxidized. HPO could transfer oxidizing equivalents to TRX via direct thiol-disulfide exchange in vitro, the redox state of TRX was also affected by HPO in vivo. Taken together, it was implicated that the oxidizing equivalents might flow from HPO to TRX and then to substrate protein by the dimerization of HPO, and its interaction with TRX finally activates the redox-sensitive transcription factor, suggesting a new redox signal pathway conducted by thiol-disulfide transformation in eukaryocytic cytoplasm.
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PMID:Direct association of hepatopoietin with thioredoxin constitutes a redox signal transduction in activation of AP-1/NF-kappaB. 1589 71

The role of H2O2 as a second messenger in signal transduction pathways is well established. We show here that the NADPH oxidase-dependent production of O2*(-) and H2O2 or respiratory burst in alveolar macrophages (AM) (NR8383 cells) is required for ADP-stimulated c-Jun phosphorylation and the activation of JNK1/2, MKK4 (but not MKK7) and apoptosis signal-regulating kinase-1 (ASK1). ASK1 binds only to the reduced form of thioredoxin (Trx). ADP induced the dissociation of ASK1/Trx complex and thus resulted in ASK1 activation, as assessed by phosphorylation at Thr845, which was enhanced after treatment with aurothioglucose (ATG), an inhibitor of Trx reductase. While dissociation of the complex implies Trx oxidation, protein electrophoretic mobility shift assay detected oxidation of Trx only after bolus H2O2 but not after ADP stimulation. These results demonstrate that the ADP-stimulated respiratory burst activated the ASK1-MKK4-JNK1/c-Jun signaling pathway in AM and suggest that transient and localized oxidation of Trx by the NADPH oxidase-mediated generation of H2O2 may play a critical role in ASK1 activation and the inflammatory response.
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PMID:The ADP-stimulated NADPH oxidase activates the ASK-1/MKK4/JNK pathway in alveolar macrophages. 1701 65

This study is the first to investigate the anticancer effect of isoobtusilactone A (IOA) in two human breast cancer cell lines, MCF-7 and MDA-MB-231. IOA exhibited effective cell growth inhibition by inducing cancer cells to undergo G(2)-M phase arrest and apoptosis. Further investigation revealed that IOA's inhibition of cell growth was also evident in a nude mice model. Cell cycle blockade was associated with increased levels of p21 and reduced amounts of cyclin B1, cyclin A, cdc2, and cdc25C. IOA also enhanced the levels of inactivated phosphorylated cdc2 and cdc25C. IOA triggered the mitochondrial apoptotic pathway, as indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that the generation of reactive oxygen species (ROS) is a critical mediator in IOA-induced cell growth inhibition. Enhancement of ROS by IOA activated apoptosis signal-regulating kinase 1 (ASK1) resulted in the increased activation of c-Jun NH(2)-terminal kinase and p38. Antioxidants EUK8 and N-acetyl cystenine significantly decreased apoptosis by inhibiting the ASK1 dephosphorylation at Ser(967) and subsequently increased the interaction of ASK1 with thioredoxin or 14-3-3 proteins. Moreover, blocking ASK1 by small interfering RNA inhibition completely suppressed IOA-induced apoptosis. Taken together, these results imply a critical role for ROS and ASK1 in IOA's anticancer activity.
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PMID:Isoobtusilactone A induces cell cycle arrest and apoptosis through reactive oxygen species/apoptosis signal-regulating kinase 1 signaling pathway in human breast cancer cells. 1767 Dec 11

Macrophage-derived reactive oxygen species contribute to the initiation and development of atherosclerosis. The cellular balance between oxidative and reductive states depends on the endogenous antioxidant capacity, with the thioredoxin-1 (Trx-1) system playing a major role. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is expressed by human macrophages and exhibits anti-inflammatory properties. Here we show that the selective PPARalpha activator GW647 significantly increased the Trx-1 mRNA and protein expression in human macrophages as determined by quantitative polymerase chain reaction and Western immunoblotting. Consistently, the Trx-1 activity was significantly increased by PPARalpha activation. By contrast, PPARalpha activation led to the down-regulation of vitamin D(3) up-regulated protein 1 (VDUP-1), the physiological inhibitor of Trx-1. Analysis of the Trx-1 and VDUP-1 promoters with gene reporter assays, mutational analysis, gel shift assays and chromatin immunoprecipitation analyses revealed the presence of a functional response element specific for PPARalpha in the Trx-1 promoter and the presence of a functional activator protein 1 (AP-1) site in the VDUP-1 promoter. The interference of PPARalpha/retinoid X receptor alpha with the AP-1 transcription factor elements c-Jun/c-Fos resulted in the inhibition of AP-1 binding and down-regulation of the VDUP-1 gene expression. Finally, PPARalpha activation reduced the lidocaine-induced caspase-3 activity and apoptosis, which might be due to the VDUP-1-mediated regulation of the Bax/Bcl-2 ratio. Together these data indicate that stimulation of PPARalpha in human macrophages might reduce arterial inflammation through differential regulation of the Trx-1 and VDUP-1 gene expression.
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PMID:Thioredoxin-1 and its natural inhibitor, vitamin D3 up-regulated protein 1, are differentially regulated by PPARalpha in human macrophages. 1884 38

Induction of antioxidant proteins like thioredoxin (Trx) and heat shock protein 90 alpha (HSP90 alpha) is a crucial step in the cellular response to oxidative stress. Here, we report the impact of environmental stress on Trx and HSP90 alpha expressions in freshly isolated hepatocytes of Mugil cephalus living in either a contaminated (Test; Ennore) or uncontaminated (Control; Kovalam) estuary. Modulation in the activities of signal transduction molecules like apoptosis signal-regulating kinase 1 (ASK1) and c-Jun NH(2)-terminal kinase 1/2 (JNK1/2) were also investigated to understand their functional role under natural stressed condition. The expression pattern of the proteins was determined by immunoblotting and the relationship between the proteins was identified by regression analysis. Test fish hepatocytes demonstrated significant upregulation (P<0.05) in the levels of Trx and HSP90 alpha and insignificant inductions in the expression pattern of ASK1 and JNK1/2 than control fish hepatocytes. These findings provide direct evidence that Trx and HSP90 alpha induction in fish hepatocytes under stress may aid cell survival by negatively regulating ASK1 expression and thereby functionally antagonizing the apoptotic role of JNK1/2 in natural aquatic systems.
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PMID:Thioredoxin and HSP90 alpha modulate ASK1-JNK1/2 signaling in stressed hepatocytes of Mugil cephalus. 1986 Nov 73

c-Jun NH(2)-terminal kinase (JNK) and p38 kinase are key regulators of cardiac hypertrophy and apoptosis during pathological stress, but their role in regulating ion channels in the diseased heart is unclear. Thus, we compared the kinase profile and electrophysiological phenotype of the rat ventricle 6-8 weeks after myocardial infarction (MI). Molecular analyses showed that JNK and p38 activities were markedly increased in post-MI hearts, while parallel voltage-clamp studies in ventricular myocytes revealed a characteristic downregulation of transient outward K(+) current (I(to)) density. When post-MI myocytes were treated with JNK or p38 inhibitors, I(to) density increased to control levels. Upregulation of I(to) was also elicited by insulin-like growth factor-1, which decreased JNK/p38 activity in post-MI hearts, and these changes were blocked by the thioredoxin (Trx) reductase inhibitor auranofin. Consistent with activation of JNK-p38 signaling, binding of apoptosis signal-regulating kinase-1 with Trx1 was also markedly decreased post-MI, and was reversed by insulin-like growth factor-1 in an auranofin-sensitive manner. We conclude that expression of ventricular K(+) channels is redox regulated and that chronic impairment of the Trx system in the post-MI heart contributes to I(to) remodeling through sustained activation of apoptosis signal-regulating kinase-1-JNK-p38 signaling. The cardiac Trx system may thus be a novel therapeutic target to reverse or prevent ventricular arrhythmias in the failing heart.
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PMID:Role of apoptosis signal-regulating kinase-1-c-Jun NH2-terminal kinase-p38 signaling in voltage-gated K+ channel remodeling of the failing heart: regulation by thioredoxin. 2051 94

Beta-amyloid (Abeta) peptide, the hallmark of Alzheimer's disease (AD), invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. In this study, salidroside (Sald), an active compound isolated from a traditional Chinese medicinal plant, Rhodiola rosea L., was investigated to assess its protective effects and the underlying mechanisms against Abeta-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Abeta(25-35)-induced neuronal toxicity was characterized by the decrease of cell viability, the release of lactate dehydrogenase (LDH), morphological alterations, neuronal DNA condensation, and the cleavage of poly(ADP-ribose) polymerase (PARP) by activated caspase-3. Pretreatment with salidroside markedly attenuated Abeta(25-35)-induced loss of cell viability and apoptosis in a dose-dependent manner. The mechanisms of salidroside protected neurons from oxidative stress included the induction of antioxidant enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), and peroxiredoxin-I (PrxI); the downregulation of pro-apoptotic protein Bax and the upregulation of anti-apoptotic protein Bcl-X(L). Furthermore, salidroside dose-dependently restored Abeta(25-35)-induced loss of mitochondrial membrane potential (MMP) as well as suppressed the elevation of intracellular reactive oxygen species (ROS) level. It was also observed that Abeta(25-35) stimulated the phosphorylation of mitogen-activated protein (MAP) kinases, including c-Jun NH(2)-terminal kinase (JNK) and p38 MAP kinase, but not extracellular signal-regulated kinase1/2 (ERK1/2). Salidroside inhibited Abeta(25-35)-induced phosphorylation of JNK and p38 MAP kinase, but not ERK1/2. These results suggest that salidroside has protective effects against Abeta(25-35)-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.
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PMID:Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. 2061 44


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