Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia (low-oxygen tension) is an important physiological stress that influences responses to a wide range of pathologies, including stroke, infarction, and tumorigenesis. Prolonged or chronic hypoxia stimulates expression of the stress-inducible transcription factor gene c-jun and transient activation of protein kinase and phosphatase activities that regulate c-Jun/AP-1 activity. Here we describe evidence obtained by using wild-type and HIF-1 alpha nullizygous mouse embryonic fibroblasts (mEFs) that the induction of c-jun mRNA expression and c-Jun phosphorylation by prolonged hypoxia are completely dependent on the presence of the oxygen-regulated transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha). In contrast, transient hypoxia induced c-jun expression in both types of mEFs, showing that the early or rapid induction of this gene is independent of HIF-1 alpha. These findings indicate that the c-jun gene has a biphasic response to hypoxia consisting of inductions that depend on the degree or duration of exposure. To more completely define the relationship between prolonged hypoxia and c-Jun phosphorylation, we used mEFs from mice containing inactivating mutations of critical phosphorylation sites in the c-Jun N-terminal region (serines 63 and 73 or threonines 91 and 93). Exposure of these mEFs to prolonged hypoxia demonstrated an absolute requirement for N-terminal sites for HIF-1 alpha-dependent phosphorylation of c-Jun. Taken together, these findings suggest that c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in pathophysiological microenvironments.
 ...
PMID:The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. 1190 46

Glutathione (GSH) is a ubiquitous antioxidant in lung epithelial cells and lung lining fluid. Transforming growth factor beta1 (TGF-beta1) is a pleiotropic cytokine involved in cellular proliferation and differentiation. The level of TGF-beta1 is elevated in many chronic inflammatory lung disorders associated with oxidant/antioxidant imbalance. In this study, we show that TGF-beta1 depletes GSH by down-regulating expression of the enzyme responsible for its formation, gamma-glutamylcysteine synthetase (gamma-GCS) and induces reactive oxygen species production in type II alveolar epithelial cells (A549). To investigate the molecular mechanisms of inhibition of glutathione synthesis, we employed reporters containing fragments from the promoter region of the gamma-GCS heavy subunit (h), the gene that encodes the catalytic subunit of gamma-GCS. We found that TGF-beta1 reduced the expression of the long gamma-GCSh construct (-3802/GCSh-5'-Luc), suggesting that an antioxidant response element (ARE) may be responsible for mediating the TGF-beta1 effect. Interestingly, the electrophoretic mobility shift assay revealed that the DNA binding activity of both activator protein-1 (AP-1) and ARE was increased in TGF-beta1-treated epithelial cells. The gamma-GCSh ARE contains a perfect AP-1 site embedded within it, and mutation of this internal AP-1 sequence, but not the surrounding ARE, prevented DNA binding. Further studies revealed that c-Jun and Fra-1 dimers, members of the AP-1 family previously shown to exert a negative effect on phase II gene expression, bound to the ARE sequence. We propose a novel mechanism of gamma-GCSh down-regulation by TGF-beta1 that involves the binding of c-Jun and Fra-1 dimers to the distal promoter. The findings of this study provide important information, which may be used for the modulation of glutathione biosynthesis in inflammation.
 ...
PMID:Molecular mechanism of transforming growth factor (TGF)-beta1-induced glutathione depletion in alveolar epithelial cells. Involvement of AP-1/ARE and Fra-1. 1191 97

Exposure to irradiation leads to detrimental changes in several cell types. In this study we assessed the changes induced in hippocampus by exposure of rats to whole body irradiation; the findings reveal that irradiation leads to apoptotic cell death in hippocampus, and as a consequence, long term potentiation in perforant path-granule cell synapses is markedly impaired. The evidence is consistent with the view that irradiation induced an increase in reactive oxygen species and that this leads to stimulation of the stress-activated protein kinase, JNK, and activation of the transcription factor, c-Jun. Consequent upon activation of JNK, a cascade of cell signaling events was stimulated that ultimately resulted in apoptosis, as suggested by parallel increases in cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end labeling staining. Treatment of rats with eicosapentaenoic acid inhibited the irradiation-induced increase in reactive oxygen species production and the subsequent cellular signaling events, suggesting that oxidative stress triggered apoptotic cell death in the hippocampus of rats exposed to irradiation. Significantly, when the compromise in cell viability induced by irradiation was prevented by eicosapentaenoic acid, long term potentiation was sustained in a manner similar to that in the sham-treated control group.
 ...
PMID:Neuroprotective effect of eicosapentaenoic acid in hippocampus of rats exposed to gamma-irradiation. 1191 18

The clinical abuse of methamphetamine (METH) is a major concern because it can cause long-lasting neurodegenerative effects in humans. Current concepts of the molecular mechanisms underlying these complications have centered on the formation of reactive oxygen species. Herein, we provide cDNA microarray evidence that METH administration caused the induction of c-Jun and of other members involved in the pathway leading to c-Jun activation [stress-activated protein kinase/Jun N-terminal kinase (JNK3), Crk-associated substrate-Cas and c-Src] after environmental stresses or cytokine stimulation. Reverse transcription-polymerase chain reaction analysis confirmed these increases and also showed that the expression of JNK1 and JNK3 but not JNK2 was also increased in the METH-treated mice. Western blot analysis showed that METH increased the expression of c-Jun phosphorylated at serine-63 and serine-73 residues. Other upstream members of the JNK pathway, including phosphorylated JNKs, mitogen-activated protein kinase kinase 4, mitogen-activated protein kinase kinase 7, Crk II, Cas, and c-Src were also increased at the protein level. These values returned to baseline by 1 week after drug treatment. These results are discussed in terms of their support for a possible role of the activation of the JNK/Jun pathway in the pathophysiological effects of METH.
 ...
PMID:Methamphetamine causes coordinate regulation of Src, Cas, Crk, and the Jun N-terminal kinase-Jun pathway. 1196 Nov 30

Reactive oxygen species have been implicated in the activation of signal transduction pathways. However, extracellular addition of oxidants such as hydrogen peroxide (H2O2) often requires concentrations that cannot be readily achieved under physiological conditions to activate biological responses such as apoptosis. Explanations for this discrepancy have included increased metabolism of H2O2 in the extracellular environment and compartmentalization within the cell. We have addressed this issue experimentally by examining the induction of apoptosis of endothelial cells induced by exogenous addition of H2O2 and by a redox cycling agent, 2,3-dimethoxy-1,4-naphthoquinone, that generates H2O2 in cells. Here we show that low nanomolar steady-state concentrations (0.1-0.5 nmol x min(-1) x 10(6) cells) of H2O2 generated intracellularly activate c-Jun N terminal kinase and initiate apoptosis in endothelial cells. A comparison with bolus hydrogen peroxide suggests that the low rate of intracellular formation of this reactive oxygen species results in a similar profile of activation for both c-Jun N terminal kinase and the initiation of apoptosis. However, a detailed analysis reveals important differences in both the duration and profile for activation of these signaling pathways.
 ...
PMID:Activation of c-Jun N-terminal kinase and apoptosis in endothelial cells mediated by endogenous generation of hydrogen peroxide. 1203 58

Cellular response to oxidative stress is a complex process that is often connected to cell cycle regulation. The present study examines the effect of H(2)O(2) on cell cycle regulation and involvement of reactive oxygen species (ROS) in these H(2)O(2)-induced responses in a p53-deficient human lung carcinoma cell line, H1299. Treatment of the cells with H(2)O(2) caused a G2/M phase arrest. Among the redox-sensitive transcription factors, NF-kappaB and AP-1, we found that only AP-1 was activated by 200 microM H(2)O(2) in human lung cells. Furthermore, electrophoretic mobility shift assays revealed that H(2)O(2) enhanced the DNA binding of AP-1 to a putative AP-1 binding element (TGAGGAA) in the p21(WAF1/CIP1) promoter region (between -2203 and -2197 nucleotides upstream of the transcription initiation site). An increase in c-Jun phosphorylation by ERK was also found to accompany the increased AP-1 activity as detected by Western blot. PD98059, a specific inhibitor of MEK, diminished H(2)O(2)-induced phosphorylation of c-Jun and DNA binding activity of AP-1, decreased expression of p21(WAF1/CIP1), and released the cells from G2/M arrest. Taken together, these results revealed a novel AP-1 binding site in the promoter region of p21(WAF1/CIP1) and a possible cell cycle regulation mechanism mediated by activation of a redox-dependent ERK signaling pathway.
 ...
PMID:H(2)O(2)-induced AP-1 activation and its effect on p21(WAF1/CIP1)-mediated G2/M arrest in a p53-deficient human lung cancer cell. 1205 10

Reactive oxygen species released during the respiratory burst are known to participate in cell signaling. Here we demonstrate that hydrogen peroxide produced by the respiratory burst activates AP-1 binding. Stimulation of the macrophage cell line NR8383 with respiratory burst agonists ADP and C5a increased AP-1 binding activity. Importantly, this increase in binding was blocked by catalase, confirming mediation by endogenous H(2)O(2). Moreover, exogenously added H(2)O(2) mimicked the agonists, and also activated AP-1. Antibodies revealed that the activated AP-1 complex is composed predominantly of c-Fos/c-Jun heterodimers. Treatment of the cells with ADP, C5a and H(2)O(2) (100 microM) all increased the phosphorylation of c-Jun. c-Fos protein was increased in cells treated with C5a or high dose (200 microM) H(2)O(2), but not in cells treated with ADP. The MEK inhibitor, PD98059, partially blocked the C5a-mediated increase in AP-1 binding. A novel membrane-permeable peptide inhibitor of JNK, JNKi, also inhibited AP-1 activation. Together these data suggest that C5a-mediated AP-1 activation requires both the activation of the ERK and JNK pathways, whereas activation of the JNK pathway is sufficient to increase AP-1 binding with ADP. Thus, AP-1 activation joins the list of pathways for which the respiratory burst signals downstream events in the macrophage.
 ...
PMID:AP-1 activation through endogenous H(2)O(2) generation by alveolar macrophages. 1205 68

Curcumin, the major component of the spice turmeric, is used as a coloring and flavoring additive in many foods and has attracted interest because of its anti-inflammatory and chemopreventive activities. However, this agent also inhibits the generation of reactive oxygen species (ROS) and the c-Jun NH(2)-terminal kinase (JNK) pathway, and because many chemotherapeutic drugs generate ROS and activate JNK in the course of inducing apoptosis, we considered the possibility that curcumin might antagonize their antitumor efficacy. Studies in tissue culture revealed that curcumin inhibited camptothecin-, mechlorethamine-, and doxorubicin-induced apoptosis of MCF-7, MDA-MB-231, and BT-474 human breast cancer cells by up to 70%. Inhibition of programmed cell death was time and concentration dependent, but occurred after relatively brief 3-h exposures, or at curcumin concentrations of 1 microM that have been documented in Phase I chemoprevention trials. Under these conditions, curcumin exhibited antioxidant properties and inhibited both JNK activation and mitochondrial release of cytochrome c in a concentration-dependent manner. Using an in vivo model of human breast cancer, dietary supplementation with curcumin was found to significantly inhibit cyclophosphamide-induced tumor regression. Such dietary supplementation was accompanied by a decrease in the activation of apoptosis by cyclophosphamide, as well as decreased JNK activation. These findings support the hypothesis that dietary curcumin can inhibit chemotherapy-induced apoptosis through inhibition of ROS generation and blockade of JNK function, and suggest that additional studies are needed to determine whether breast cancer patients undergoing chemotherapy should avoid curcumin supplementation, and possibly even limit their exposure to curcumin-containing foods.
 ...
PMID:Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. 1294 49

Permanent or temporary disruption of cerebral blood flow rapidly depletes brain regions of their limited energy reserves (glycogen, glucose, oxygen, ATP) leading to an energy crisis. Tissue damage occurs due to the energy crisis. The central part of the damage, the ischaemic "core" region is surrounded by zones of the shell-like penumbra. Necrotic, as well as apoptotic cell death could be identified in the penumbra. Going away from the ischaemic core different neurochemical processes are occurring by space and time. "Immediate early response" genes (c-fos, fos-B, c-Jun, krox 20, 24) are activated, heatshock proteins (hsp 70, 72, HSF, HSE, HIF), cytokines (TNF-alpha, IL-1 beta), inflammatory factors (COX), adhesion and glial factors (ICAM-1, ELAM-1, P-selectin), vasoactive factors (IL-6, -10, PAF), reactive oxigen radicals and connected factors (O2, OH, NO, NOS, SOD) are produced within minutes and hours. Cell deaths, necrosis and apoptosis due to the activation of calpains, caspases and nucleases occur in days. In parallel, growth factors and plasticity proteins (BDNF, NGF, TGF-beta, VEGF, PDGF, GAP-43) are activated as a basis of functional rehabilitation.
 ...
PMID:[Regulatory mechanisms in focal cerebral ischemia. New possibilities in neuroprotective therapy]. 1212 84

1: Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) is a selenoorganic compound exhibiting both glutathione peroxidase activity and antioxidant activity. Although it has been reported that ebselen is effective for oxidative stress-induced neuronal damage both in vivo and clinically, the precise mechanisms of the efficacy have not yet been elucidated. Thus, we hypothesized that ebselen may affect reactive oxygen species-induced mitogen-activated protein (MAP) kinase activation in cultured PC12 cells. 2: Our findings showed that hydrogen peroxide (H(2)O(2)) stimulated rapid and significant activation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 in PC12 cells, which is a model of catecholamine-containing neurons. 3: H(2)O(2)-induced JNK activation was inhibited by ebselen, whereas ERK1/2 and p38 activation by H(2)O(2) were not affected by ebselen. 4: Inhibition by ebselen of H(2)O(2)-induced hydroxyl radical generation in PC12 cells was observed using electron paramagnetic resonance measurements. Ebselen also inhibited H(2)O(2)-induced increases in DNA binding activity of activator protein-1 (AP-1), a downstream transcription factor of JNK, composed of the c-Jun homo/heterodimer. 5: Finally, pretreatment of cells with ebselen resulted in a significant recovery from cell death including apoptosis by H(2)O(2) in PC12 cells. 6 These findings suggest that ebselen attenuates oxidative stress-induced neuronal cell death through the inhibition of the JNK and AP-1 signalling pathway. Thus, inhibition of JNK by ebselen may imply its usefulness for treatment of ischaemic cerebral diseases relevant to neuronal cell death.
 ...
PMID:Ebselen attenuates oxidative stress-induced apoptosis via the inhibition of the c-Jun N-terminal kinase and activator protein-1 signalling pathway in PC12 cells. 1214 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>