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)

Transient global ischemia caused by 5 min of cardiac arrest induced delayed neuronal cell death (apoptosis) in the CA1 region of the rat hippocampus. To characterize the molecular mechanisms that regulate apoptosis in vivo, the contributions to cell death of mitogen-activated protein kinase family members were examined in the hippocampal region after brain ischemia-reperfusion. Ischemia-reperfusion led to a strong activation of the JNK/SAPK (c-Jun NH2-terminal protein kinase/stress activated protein kinase), ERK (extracellular signal-regulated kinase), and p38 enzymes. These results with other previous studies suggest that the activation of JNK/SAPK in accordance with p38 contributes to the induction of apoptosis in CA1 neurons.
 ...
PMID:Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. 1007 72

In the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity. Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins. The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes. Transient overexpression of inactive mutants of either Raf-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059, we demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B. Interestingly, it was shown that NF-kappa B-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction with c-Jun protein. We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent activation of NF-kappa B transcriptional capacity. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun.
 ...
PMID:Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes. 1020 34

Cisplatin treatment activates multiple signal transduction pathways, which can lead to several cellular responses including cell cycle arrest, DNA repair, survival, or apoptosis. We investigated the response of the mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun-N-terminal kinase 1 (JNK1), and p38, to cisplatin treatment in the ovarian carcinoma cell line SK-OV-3. Cisplatin caused a late and prolonged induction in a dose-dependent manner of both ERK1/2 and JNK1 activity. ERK1/2 and JNK1 activities continued to increase in magnitude up to 24 h following initiation of cisplatin treatment. In contrast, cisplatin treatment had no effect on p38 activity. Transplatin failed to induce either ERK1/2 or JNK1 at 24 h, which suggests that the activation of these kinases was dependent on cisplatin-specific DNA damage. Treatment with cycloheximide resulted in inhibition of cisplatin-induced ERK1/2 activation, demonstrating that ERK1/2 activity induced by cisplatin was dependent on de novo protein synthesis. Furthermore, inhibition of cisplatin-induced ERK1/2 activity by PD 98059 caused enhanced cisplatin cytotoxicity. Similar enhanced cytotoxic effects of cisplatin were also observed following treatment with PD 98059 in the ovarian carcinoma cell line UCI 101. These observations indicate that ERK1/2 activation induced by cisplatin partially protects cells from cisplatin cytotoxicity. Continued investigation into the mechanism by which the ERK pathway and other signal transduction pathways modulate the response to cisplatin may be helpful in the development of new strategies for improving the therapeutic use of platinum drugs.
 ...
PMID:Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. 1035 33

The AP-1 transcription factor, which is composed of various combinations of Fos and Jun proteins, is believed to be a key participant in molecular processes that guide activity-dependent changes in gene expression. In this study, we investigated the activity of different MAP kinases that have been implicated in AP-1 activation. We examined the activities of ERK, JNK/SAPK, and p38 MAPK along with their nuclear targets (Elk-1 and c-Jun) in rat visual cortex after light stimulation. The transcription factor Elk-1 (a possible regulator of c-fos expression) was found to be transiently modified by phosphorylation when visual stimulation was applied after a period of dark rearing. In vitro kinase assay with Elk-1 as substrate showed that light stimulation activated MAPK/ERK in visual cortex but not frontal cortex. Furthermore, ERK activation was temporally matched to onset of Elk-1 phosphorylation. The activity of JNK1 (c-Jun N-terminal kinase 1) was elevated at 2-6 h after visual exposure and was also temporally correlated to increase of endogenous P-c-Jun levels and its appearance within the AP-1 DNA-binding complex. The activities of p38 MAP kinases did not change significantly. These results demonstrate the differential engagement of MAPK signaling pathways following sensory stimulation and their relative effects upon AP-1 expression in the intact brain.
 ...
PMID:Rapid phosphorylation of Elk-1 transcription factor and activation of MAP kinase signal transduction pathways in response to visual stimulation. 1038 26

Invasion is an essential cellular response that plays an important role in a number of physiological and pathological processes. Matrix metalloproteinase (MMP) production and cell movement are diverse cellular responses integral to the process of invasion. The complexity of the invasive process suggests the necessity of coordinate activation of more than one signaling pathway in order to activate specific factors responsible for regulating these cellular responses. In this report, we demonstrate that cell movement and MMP-9 production are both directly dependent on the activation of endogenous ERK signaling in hepatocyte growth factor (HGF)-or epidermal growth factor (EGF)-stimulated human epidermal keratinocytes. The kinetic profiles of endogenous MEK and ERK activity suggest that prolonged activation of these signal transducers is an underlying mechanism involved in stimulating cell motility and MMP-9 production. In support of this finding, a transient MEK/ERK signal elicited by keratinocyte growth factor (KGF) or insulin-like growth factor-1 (IGF-1) fails to stimulate these invasion-related responses. Specific inhibition of MEK leads to suppression of ERK activation, marked reduction in steady-state levels of c-Fos, and inhibition of cell movement and MMP-9 production. This occurs despite continued activation of JNK and c-Jun signaling in the presence of MEK-specific inhibition. In contrast, when JNK activity is specifically inhibited in HGF-stimulated cells, AP-1 activity is suppressed but cell motility is not affected. This evidence suggests that while ERK and JNK activity are necessary for AP-1 activation, ERK but not JNK is sufficient in stimulating cell motility.
 ...
PMID:Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. 1039 97

Whole-cell [(32)P]-protein phosphorylation assays and two-dimensional gel electrophoresis (2-DGE) were applied to the analysis of the beta-adrenoceptor (betaAR)-linked signal transduction pathway. Rat C6 glioma cells were stimulated with isoproterenol and the protein lysates were resolved by 2-DGE. Two dimensional [(32)P]-phosphoprotein 'maps' were generated depicting the modulation of intracellular proteins after isoproterenol stimulation versus unstimulated cells. A total of 274 distinct phosphoprotein spots were detected, of which 200 were up-regulated, 69 were down-regulated, and 5 remained unchanged. An evaluation of isoproterenol's activity across several kinase pathways was performed using a computer-generated 2-DGE template incorporating the location and identification of individual signaling phosphoprotein intermediaries. The template served as a 'reference map' for drug treatment comparisons. We observed a significant increase in the phosphorylation states of several nuclear transcription factors, notably CREB-1, ATF-1, NFkappaB/IkappaBalpha and ELK-1, but not c-Jun. A parallel series of radioimmunoprecipitation studies confirmed our 2-DGE findings. Moreover, isoproterenol increased the phosphorylation state of PKC and of several MAPK-dependent pathway kinases which correlated with a significant increase in their endogenous kinase activity. Isoproterenol's effects on PKA, PKC and ERK-dependent activities were blocked by propranolol, a betaAR antagonist. In conclusion, an acute isoproterenol stimulus induced multiplex pathway modulation via the betaAR in the C6 glioma cell indicating that signaling pathway cross-talk is an essential feature for the regulation of cellular function. Moreover, the immediate advantages of the 2-DGE analytical approach were apparent, and further development of the protein database will provide a valuable tool to screen for broad-based drug-mediated signaling activities.
 ...
PMID:Probing for drug-induced multiplex signal transduction pathways using high resolution two-dimensional gel electrophoresis: application to beta-adrenoceptor stimulation in the rat C6 glioma cell. 1040 86

Cardiac myocytes contain functional estrogen receptors, however, the effect of estrogen on growth-related signaling pathways such as mitogen-activated protein kinases (MAPK) in the pathogenesis of cardiac disease is unclear. MAPKs are critically involved in regulatory signaling pathways which ultimately lead to cardiac hypertrophy. Here we show that 17beta-estradiol (E2) activates extracellular signal-regulated kinase (ERK1/2), c-Jun-NH2-terminal protein kinase (JNK) and p38 in rat cardiomyocytes in a distinctive pattern. As shown by immunoblot analysis and phosphorylation assays, E2 (10(-9) M) induced a rapid and transient activation of ERK1/2 and a rapid but sustained increase of JNK phosphorylation. In contrast, E2 had only a marginal effect on p38 activation. Furthermore, MAPK phosphatase expression was induced by E2 and E2-stimulated expression of endothelial and inducible NO synthase was inhibited by PD 98059, an inhibitor of the ERK pathway. These novel observations may help to explain the role of estrogen in gender-based differences found in cardiac disease.
 ...
PMID:Differential effects of 17beta-estradiol on mitogen-activated protein kinase pathways in rat cardiomyocytes. 1043 21

One of the characteristic responses of HT29 human colon adenocarcinoma cells to hypoxic stress is the induction of c-jun expression and binding to the activator-protein 1 (AP-1) element. To study the mechanism of c-jun activation during hypoxia, inhibitors of signaling pathways leading to the activation of AP-1 transcription factor were used. One of them, the benzoquinone ansamycin geldanamycin (GA) Mr-90,000 heat-shock protein (hsp90)-binding antibiotic, is known to disrupt signaling pathways by inducing destabilization of the enzyme complexes and degradation of signaling intermediates involving the proteasome. In our experiments, GA inhibited both basal and hypoxia-induced c-jun expression (IC50 = 75 nM). GA also abolished the hypoxia-induced increase in c-Jun NH2-terminal kinase (JNK1) catalytic activity and demonstrated an inhibitory effect on stress-activated protein kinase/ERK kinase-1 (SEK1); other participants in the mitogen-activated protein kinase and p38 signal transduction pathways were not affected to the same degree. GA treatment led to a decrease in the nuclear content of c-Jun but not that of c-Fos or of activating transcription factor 2. Functional consequences of these effects were suggested by the inhibition of AP-1 binding in hypoxic HT29 cells in the presence of GA. Pretreatment with the proteasome inhibitor lactacystin before the addition of GA resulted in the elevation of overall c-jun level, but it was unable to restore the hypoxia-induced c-jun expression. Our results demonstrate that GA acts as a highly potent inhibitor of hypoxia-induced c-jun expression, affecting the activation of JNK and of the AP-1 transcription factor. However, the effect of GA cannot be attributed solely to the inhibition of signaling through JNK, and additional mechanisms remain to be identified.
 ...
PMID:Effects of geldanamycin on signaling through activator-protein 1 in hypoxic HT29 human colon adenocarcinoma cells. 1046 87

Electroconvulsive shock (ECS), an effective treatment for psychiatric diseases, has been reported to induce immediate-early genes (IEGs) and to activate p42 and p44 MAPKs (ERK-1 and ERK-2) in rat brain. In this study, we examined the activation of the other members of MAPK family, c-Jun N-terminal protein kinase (JNK/SAPK) and p38. Following ECS, the phosphorylation of p38 was substantially increased in both hippocampus and cerebellum, but the increase of JNK phosphorylation was observed only in hippocampus. We also investigated the phosphorylation of their upstream kinases, SEK-1, MKK6 and MKK3. In both hippocampus and cerebellum, the phosphorylation of MKK6 showed closer correlation with p38 phosphorylation than that of MKK3. However, SEK-1, known as upstream kinase of JNK and p38 in vitro, corresponded with none of MAPKs. These results, with previous reports on the activation of ERK, indicate that ECS activates three MAPKs differentially in rat hippocampus and cerebellum, and suggest the possibility that unknown MAPKK may be involved in the activation of JNK in rat brain after ECS.
 ...
PMID:Differential activation of c-Jun N-terminal protein kinase and p38 in rat hippocampus and cerebellum after electroconvulsive shock. 1047 12

Asthma is frequently associated with abnormal airway smooth muscle (ASM) growth that may contribute to airway narrowing and hyperresponsiveness to contractile agents. Although numerous hormones and cytokines have been shown to induce human ASM (HASM) proliferation, the cellular and molecular mechanisms underlying HASM hyperplasia are largely unknown. Here we characterize the roles of the mitogen-activated protein kinase (MAPK) superfamily [p42/p44 MAPK, c-Jun amino-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38] in mediating hormone- and cytokine-induced HASM proliferation. Significant enhancement of [(3)H]thymidine incorporation in HASM cultures was observed only by treatment with agents (epidermal growth factor, platelet-derived growth factor, thrombin, and phorbol 12-myristate 13-acetate) that promoted a strong and sustained activation of p42/p44 MAPK. Significant activation of the JNK/SAPK and p38 pathways was only observed on stimulation with interleukin (IL)-1beta and tumor necrosis factor-alpha, agents that did not appreciably stimulate HASM proliferation. Two different inhibitors of MAPK/extracellular signal-regulated kinase kinase (MEK), PD-98059 and U-0126, inhibited mitogen-induced [3H]thymidine incorporation in a manner consistent with their ability to inhibit p42/p44 activation. Elk-1 and activator protein-1 reporter activation by mitogens was similarly inhibited by inhibition of MEK, suggesting a linkage between p42/p44 activation, transcription factor activation, and HASM proliferation. These findings establish a fundamental role for p42/p44 activation in regulating HASM proliferation and provide insight into species-specific differences observed among studies in ASM mitogenesis.
 ...
PMID:MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation. 1048 55


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