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)

We investigated the effects of D1 dopamine receptor stimulation on the activation of mitogen-activated protein kinases (MAPKs) in SK-N-MC human neuroblastoma cells. We found that the D1 dopamine receptor agonist SKF38393 induced similar time- and dose-related activation of p38 MAPK and c-Jun amino-terminal kinase (JNK), whereas extracellular signal-regulated kinase activity was not affected by D1 dopamine receptor stimulation. Maximal stimulation of p38 MAPK and JNK was observed after a 15-min incubation with 100 microM SKF38393. In contrast, 10 microM quinpirole, a D2 dopamine receptor agonist, did not activate p38 MAPK or JNK. Treatment of cells with 10 muM SCH23390, a D1 dopamine receptor antagonist, significantly inhibited the activation of both kinases by SKF38393. These results indicate that activation of the p38 MAPK and JNK signaling pathways is mediated by dopamine D1 receptors in SK-N-MC neuroblastoma cells. Furthermore, dibutyryl-cAMP mimicked SKF38393-mediated stimulation of p38 MAPK and JNK. Inhibition of protein kinase A by 1 microM H-89 or 10 microM adenosine 3', 5'-cyclic monophosphothioate (Rp-isomer, triethylammonium salt) markedly attenuated the activation of p38 MAPK and JNK. Conversely, the selective protein kinase C inhibitor calphostin C did not block D1 dopamine receptor-stimulated activation of p38 MAPK and JNK. These results demonstrate, for the first time, that the Gs-coupled D1 dopamine receptor activates the p38 MAPK and JNK signaling pathways by a protein kinase A-dependent mechanism.
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PMID:D1 dopamine receptor agonists mediate activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. 973 Sep 3

The aim of this study was to analyze the effects of osmotic shock and secretagogues such as ATP and 12-O-tetradecanoylphorbol 13-acetate (TPA) on various intracellular signaling pathways in primary cultures of alveolar type II cells and examine their potential role in regulating events such as secretion and apoptosis in these cells. Sorbitol-induced osmotic stress caused the sustained release of [3H]phosphatidylcholine ([3H]PC) from primary cultures of rat alveolar type II cells prelabeled with [3H]choline chloride. This release was not dependent on protein kinase C because downregulation of the major protein kinase C isoforms (alpha, betaII, delta, and eta) expressed in alveolar type II cells had no effect on [3H]PC secretion. Sorbitol, as well as the known secretagogues TPA and ATP, activated extracellular signal-regulated kinase. Although an inhibitor of the extracellular signal-regulated kinase cascade, PD-98059, blocked this activation, it had no effect on the release of [3H]PC. Sorbitol and ultraviolet C radiation, but not TPA or ATP, were also found to activate both p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase. Furthermore, both sorbitol and ultraviolet C radiation induced apoptosis in alveolar type II cells as demonstrated by Hoechst 33258 staining of the condensed nuclei, the generation of DNA ladders, and the activation of caspases. The data indicate that multiple signaling pathways are activated by traditional secretagogues such as TPA and ATP and by cellular stresses such as osmotic shock and that these may be involved in regulating secretory and apoptotic events in alveolar type II cells.
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PMID:Osmotic stress induces both secretion and apoptosis in rat alveolar type II cells. 975 98

Mitogen-activated protein (MAP) kinases are activated by osmotic stress in a variety of cells, but their function and regulation in renal tubules is poorly understood. The present study was designed to examine the osmotic regulation of MAP kinases in the medullary thick ascending limb (MTAL) of the rat and to determine their possible role in the hyperosmotic inhibition of HCO-3 absorption in this segment. Tissues from the inner stripe of the outer medulla and microdissected MTALs were incubated at 37 degreesC in control (290 mosmol/kgH2O) or hyperosmotic (300 mM added mannitol) solution for 15 min. Activities of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase were then measured using immune complex assays. Hyperosmolality increased p38 MAP kinase activity (2.3-fold) and ERK activity (2.0-fold) but had no effect on JNK activity (1.1-fold). Exposure to hyperosmolality for various times showed that the activation of p38 MAP kinase was rapid (</=5 min) and was sustained for up to 60 min, whereas the activation of ERK was transient (ERK activity peaked at 15 min, then declined to basal levels at 30 min). Pretreatment with the MAP kinase kinase inhibitor PD98059 (15 microM) blocked the hyperosmotic activation of p38 MAP kinase and ERK but did not prevent hyperosmotic inhibition of HCO-3 absorption. These results show that hyperosmolality differentially activates p38 MAP kinase and ERK in the MTAL. In contrast, we found no evidence for involvement of JNK in the early response to hyperosmotic stress. Eliminating the activation of p38 MAP kinase and ERK does not prevent hyperosmotic inhibition of HCO-3 absorption, suggesting that hyperosmolality inhibits apical membrane Na+/H+ exchange (NHE3) activity via a signaling pathway distinct from these MAP kinase pathways.
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PMID:Hypertonicity activates MAP kinases and inhibits HCO-3 absorption via distinct pathways in thick ascending limb. 975 19

c-Jun NH2-terminal kinases (JNKs) are protein kinases that are activated by a wide variety of extracellular signals. This study investigated the expression and regulation of JNKs in isolated gastric canine parietal cells. Western blot analysis of cell lysates from highly purified (>95%) parietal cells with an antibody recognizing JNK1 and to a lesser degree JNK2 revealed the presence of two bands of 46 and 54 kDa, respectively. JNK1 activity was quantitated by immunoprecipitation and in-gel kinase assays. Of the different agents tested, carbachol was the most potent inducer of JNK1 activity, whereas histamine and epidermal growth factor induced weaker responses. The proinflammatory cytokine tumor necrosis factor-alpha stimulated JNK1 but had no effect on extracellular signal-regulated kinase (ERK2) induction, suggesting that activation of JNK1 might represent an important event in mediation of the inflammatory response in the stomach. The action of carbachol was dose (0.1-100 microM) and time dependent, with a maximal stimulatory effect (fourfold) detected after 30 min of incubation and sustained for 2 h. Addition of the specific protein kinase C (PKC) inhibitor GF109203X did not affect the stimulatory action of carbachol. The intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-AM inhibited carbachol induction of JNK1 activity by 60%. Thapsigargin (1 microM), an intracellular Ca2+-rising agent, induced JNK1 activity more than threefold. Carbachol activation of JNK1 resulted in induction of c-Jun (protein) transcriptional activity and in stimulation of parietal cell mRNA content of c-jun. In conclusion, our data indicate that carbachol induces JNK activity in gastric parietal cells via intracellular Ca2+-dependent, PKC-independent pathways, leading to induction of c-jun gene expression via phosphorylation and transcriptional activation of c-Jun.
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PMID:Regulation of c-Jun NH2-terminal kinases in isolated canine gastric parietal cells. 975 5

Ligand binding to vascular endothelial cell growth factor (VEGF) receptors activates the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK). Possible cross-communication of ERK and JNK effecting endothelial cell (EC) actions of VEGF is poorly understood. Incubation of EC with PD 98059, a specific mitogen-activated protein kinase kinase inhibitor, or transfection with Y185F, a dominant negative ERK2, strongly inhibited VEGF-activated JNK. JNK was also activated by ERK2 expression in the absence of VEGF, inhibited 82% by co-transfection with dominant negative SEK-1, indicating upstream activation of JNK by ERK. VEGF-stimulated JNK activity was also reversed by dominant negative SEK-1. Other EC growth factors exhibited similar cross-activation of JNK through ERK. VEGF stimulated the nuclear incorporation of thymidine, reversed 89% by PD 98059 and 72% by Y185F. Dominant negative SEK-1 or JNK-1 also significantly reduced VEGF-stimulated thymidine incorporation. Expression of wild type Jip-1, which prevents JNK nuclear translocation, inhibited VEGF-induced EC proliferation by 75%. VEGF stimulated both cyclin D1 synthesis and Cdk4 kinase activity, inhibited by PD 98059 and dominant negative JNK-1. Important events for VEGF-induced G1/S progression and cell proliferation are enhanced through a novel ERK to JNK cross-activation and subsequent JNK action.
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PMID:Extracellular signal-regulated protein kinase/Jun kinase cross-talk underlies vascular endothelial cell growth factor-induced endothelial cell proliferation. 975 15

Two subgroups of mitogen-activated protein kinases, c-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), are thought to be involved in cultured cardiac myocyte hypertrophy and gene expression. To examine the in vivo activation of these kinases, we measured cardiac JNK and ERK activities in conscious rats subjected to acute or chronic angiotensin II (Ang II) infusion, by using in-gel kinase methods. About 50 mm Hg rise in blood pressure by Ang II (1000 ng . kg-1 . min-1) infusion caused larger activation of left ventricular JNK than ERK, via the AT1 receptor. In spite of short duration (about 30 minutes) of maximal blood pressure elevation by Ang II, JNK sustained the peak value (more than 5-fold increase) from 15 minutes up to at least 3 hours. Similar activation of JNK was seen in the right ventricle. Thus, cardiac JNK activation by Ang II seems to be in part mediated by its direct action via the AT1 receptor. The dose-response relationships for Ang II-induced rises in blood pressure and cardiac JNK and ERK activation indicated that cardiac JNK or ERK was not activated by a mild increase in blood pressure and that cardiac JNK was activated by Ang II-mediated hypertension in a more sensitive manner than ERK. Cardiac hypertrophy, induced by chronic Ang II infusion, was preceded by JNK activation without ERK activation. Furthermore, gel mobility shift analysis showed that cardiac JNK activation was followed by increased activator protein-1 DNA binding activity due to c-Fos and c-Jun. These results provided the first evidence for the preferential activation of cardiac JNK in Ang II-induced hypertension and suggested that JNK might play some role in Ang II-induced cardiac hypertrophic response in vivo. However, further study is needed to elucidate the role of JNK in cardiac hypertrophy in vivo.
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PMID:Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated kinase in angiotensin II-mediated hypertension. 975 46

Mitogen-activated protein (MAP) kinase family members, including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase ( JNK), and p38 MAP kinase, have been implicated in coupling the B cell antigen receptor (BCR) to transcriptional responses. However, the mechanisms that lead to the activation of these MAP kinase family members have been poorly elucidated. Here we demonstrate that the BCR-induced ERK activation is reduced by loss of Grb2 or expression of a dominant-negative form of Ras, RasN17, whereas this response is not affected by loss of Shc. The inhibition of the ERK response was also observed in phospholipase C (PLC)-gamma2-deficient DT40 B cells, and expression of RasN17 in the PLC-gamma2-deficient cells completely abrogated the ERK activation. The PLC-gamma2 dependency of ERK activation was most likely due to protein kinase C (PKC) activation rather than calcium mobilization, since loss of inositol 1,4,5-trisphosphate receptors did not affect ERK activation. Similar to cooperation of Ras with PKC activation in ERK response, both PLC-gamma2-dependent signal and GTPase are required for BCR-induced JNK and p38 responses. JNK response is dependent on Rac1 and calcium mobilization, whereas p38 response requires Rac1 and PKC activation.
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PMID:Involvement of guanosine triphosphatases and phospholipase C-gamma2 in extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase activation by the B cell antigen receptor. 976 8

The signal transduction pathways activated by tumor necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) that lead to priming of polymorphonuclear leukocytes (PMNs) are unknown. The hypotheses that these cytokines stimulate multiple mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs), and p38 MAPK, and that these MAPKs participate in priming of human PMNs were examined. TNF-alpha stimulated a dose-dependent increase in ERK and p38 MAPK activities that was maximal at 10 min. JNKs were not stimulated by TNF-alpha or GM-CSF. GM-CSF stimulated ERK activity comparable to that of TNF-alpha, but GM-CSF was a less potent stimulus of p38 MAPK activity. The tyrosine kinase inhibitor, genistein, inhibited ERK and p38 MAPK stimulation by both cytokines. The phosphatidylinositol 3-kinase inhibitor, wortmannin, attenuated stimulation of ERKs and p38 MAPK by GM-CSF, but not TNF-alpha. GM-CSF, but not TNF-alpha, stimulated wortmannin-sensitive activation of Raf-1. TNF-alpha and GM-CSF priming of superoxide release stimulated by N-formyl-methionyl-leucyl-phenylalanine was significantly attenuated by the MEK inhibitor, PD098059, and the p38 MAPK inhibitor, SB203580. Incubation with both MAPK inhibitors produced an additive effect. Our data suggest that TNF-alpha and GM-CSF activate ERKs and p38 MAPK by different signal transduction pathways. Both ERK and p38 MAPK cascades contribute to the ability of TNF-alpha and GM-CSF to prime the respiratory burst response in human PMNs.
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PMID:Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-alpha and GM-CSF. 976 35

The aim of this study was to test the hypothesis that oxidative stress induces apoptosis in the H9c2 cardiac muscle cell line, and that signaling via mitogen-activated protein kinase (MAPK) pathways is involved. Three forms of oxidative stress were utilized: the superoxide generator menadione; hydrogen peroxide; or simulated ischemia followed by reperfusion. Relatively low concentrations of menadione (10 micrometer) or H2O2 (250 micrometer) caused maximal DNA fragmentation and caspase activation, both markers for apoptotic cell death, and preferential activation of the c-Jun NH 2-terminal kinase (JNK) and p38 MAPK pathways. In contrast, higher concentrations of menadione or H 2O2 caused less DNA fragmentation, more necrotic cell death and preferential activation of the extracellular signal-regulated kinase (ERK) pathway. Simulated ischemia alone did not induce DNA fragmentation or caspase activation and activated only the p38 MAPK pathway. However, ischemia plus reperfusion resulted in DNA fragmentation, caspase activation, necrotic cell death and activation of all three MAPK pathways. Selective inhibition of the ERK or p38 MAPK pathways (by PD98059 or SB-203580, respectively) had no effect on the extent of oxidative stress-induced DNA fragmentation or caspase activation. In contrast, inhibition of the JNK pathway by transfection of a dominant negative mutant of JNK markedly reduced the extent of DNA fragmentation and caspase activation induced by oxidative stress. In conclusion, these data suggest that the JNK pathway plays an important role in signaling oxidative stress-induced apoptosis of H9c2 cardiac muscle cells.
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PMID:Oxidative stress induces DNA fragmentation and caspase activation via the c-Jun NH2-terminal kinase pathway in H9c2 cardiac muscle cells. 976 35

We investigated the involvement of mitogen-activated protein kinase (MAPK) signal transduction pathways in human endothelial cells in response to shear stress and alterations of these kinases in in vitro-propagated endothelial cells (ECs). Potent activation (10-fold) of extracellular signal-regulated kinase (ERK2), a member of the MAPK family, occurred within 10 min of shear stress (5 dynes/cm2), whereupon rapid inactivation ensued. Shear stress also induced activation of stress-activated protein kinase (SAPK) or c-Jun NH2-terminal protein kinase (JNK) in ECs. Suramin pretreatment completely inhibited shear stress stimulation of ERK2, but not SAPK/JNK, highlighting a role for growth factor receptors in ERK activation. Translocation of ERK2 from the cytoplasm to the nucleus was observed in shear-stressed endothelial cells. In addition, we compared activities of MAPKs in shear-stressed cells derived from passages 4 and 10 (older). The magnitude of ERK2 activation was significantly lower in aged ECs compared to those of passage 4, while SAPK/JNK was not altered in the in vitro aged ECs. A similar level of ERK2 activation was found in both young and older cells stimulated with phorbol-12-myristate-13-acetate (PMA), indicating an age-related alteration of the plasma membrane. Taken together, these findings suggest that MAP kinase activation may be crucial for the expression of many genes in ECs stimulated by shear stress, and that an alteration in MAPK activities could contribute to the age-related decline in proliferative capacity.
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PMID:Decline of shear stress-induced activation of extracellular signal-regulated kinases, but not stress-activated protein kinases, in in vitro propagated endothelial cells. 978 37


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