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)

Soluble staphylococcal peptidoglycan (sPGN) is an inducer of cytokine secretion and may activate macrophages through the CD14 lipopolysaccharide (LPS) receptor. To elucidate sPGN-activated signal transduction pathways, stimulation of mitogen-activated protein (MAP) kinases by sPGN was studied in mouse RAW264.7 macrophages. sPGN strongly activated extracellular signal-regulated kinase (ERK) 1 and ERK2, moderately activated c-Jun NH2 terminal kinase (JNK), and weakly activated p38 MAP kinase, in contrast to LPS, which strongly activated all of these kinases, and phorbol 12,13-dibutyrate (PDB), which strongly activated ERK1 and ERK2 but did not activate p38 or JNK. sPGN- and LPS-induced activation of ERK1 and ERK2, unlike PDB-induced activation, was sensitive to inhibition by herbimycin A and insensitive to inhibition by increased intracellular cAMP. These results demonstrate differential activation of MAP kinases by sPGN, similar but not identical activation of signal transduction pathways by sPGN and LPS, and different mechanisms of MAP kinase activation by bacterial stimulants and phorbol esters.
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PMID:Differential activation of extracellular signal-regulated kinase (ERK) 1, ERK2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases by bacterial peptidoglycan. 884 16

Membrane depolarization of NG108 cells gives rapid (< 5 min) activation of Ca2+/calmodulin-dependent protein kinase IV (CaM-KIV), as well as activation of c-Jun N-terminal kinase (JNK). To investigate whether the Ca2+-dependent activation of mitogen-activated protein kinases (ERK, JNK, and p38) might be mediated by the CaM kinase cascade, we have transfected PC12 cells, which lack CaM-KIV, with constitutively active mutants of CaM kinase kinase and/or CaM-KIV (CaM-KKc and CaM-KIVc, respectively). In the absence of depolarization, CaM-KKc transfection had no effect on Elk-dependent transcription of a luciferase reporter gene, whereas CaM-KIVc alone or in combination with CaM-KKc gave 7- to 10-fold and 60- to 80-fold stimulations, respectively, which were blocked by mitogen-activated protein (MAP) kinase phosphatase cotransfection. When epitope-tagged constructs of MAP kinases were co-transfected with CaM-KKc plus CaM-KIVc, the immunoprecipitated MAP kinases were activated 2-fold (ERK-2) and 7- to 10-fold (JNK-1 and p38). The JNK and p38 pathways were further investigated using specific c-Jun or ATF2-dependent transcriptional assays. We found that c-Jun/ATF2-dependent transcriptions were enhanced 7- to 10-fold by CaM-KIVc and 20- to 30-fold by CaM-KKc plus CaM-KIVc. In the case of the Jun-dependent transcription, this effect was not due to direct phosphorylation of c-Jun by activated CaM-KIV, since transcription was blocked by a dominant-negative JNK and by two MAP kinase phosphatases. Mutation of the phosphorylation site (Thr196) in CaM-KIV, which mediates its activation by CaM-KIV kinase, prevented activation of Elk-1, c-Jun, and ATF2 by the CaM kinase cascade. These results establish a new Ca2+-dependent mechanism for regulating MAP kinase pathways and resultant transcription.
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PMID:Regulation of mitogen-activated protein kinases by a calcium/calmodulin-dependent protein kinase cascade. 885 61

B cell antigen receptor (BCR)-induced apoptosis in the WEHI-231 B lymphoma cell line can be prevented by engaging CD40. We have used this cell line to investigate the role of mitogen-activated protein (MAP) kinases in integrating BCR and CD40 signaling. Each of the three types of MAP kinases, the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and p38, phosphorylates a distinct set of transcription factors. Thus, activating different combinations of MAP kinases could lead to distinct biological responses. We found that BCR engagement in WEHI-231 cells caused a 15- to 20-fold activation of ERK2 and a 2- to 3-fold stimulation of ERK1. CD40 did not activate either of these kinases, nor did it affect BCR-induced ERK activation. In contrast, CD40 engagement caused a 50- to 70-fold increase in JNK activity. BCR cross-linking caused a modest (4- to 8-fold) increase in JNK activity by itself and also potentiated CD40-induced JNK activation. Finally, CD40 caused strong activation of the p38 kinase as well as MAPKAP kinase-2, a downstream target of p38. BCR engagement caused only weak activation of the p38 pathway. In summary, the BCR strongly activates ERK2 and weakly activates ERK1, JNK, and p38, while CD40 markedly stimulates the JNK and p38 kinases. Thus, activation of only ERK2 correlates with apoptosis in WEHI-231 cells, whereas full activation of all three MAP kinase pathways correlates with cell survival. The role of MAP kinases in regulating these responses remains to be tested.
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PMID:Differential activation of the ERK, JNK, and p38 mitogen-activated protein kinases by CD40 and the B cell antigen receptor. 887 35

Hemodynamic forces play a key role in inducing atherosclerosis-implicated gene expression in vascular endothelial cells. To elucidate the signal transduction pathway leading to such gene expression, we studied the effects of fluid shearing on the activities of upstream signaling molecules. Fluid shearing (shear stress, 12 dynes/cm2 [1 dyne = 10(-5)N]) induced a transient and rapid activation of p21ras and preferentially activated c-Jun NH2 terminal kinases (JNK1 and JNK2) over extracellular signal-regulated kinases (ERK-1 and ERK-2). Cotransfection of RasN17, a dominant negative mutant of Ha-Ras, attenuated the shear-activated JNK and luciferase reporters driven by 12-O-tetradecanoylphorbol-13-acetate-responsive elements. JNK(K-R) and MEKK(K-M), the respective catalytically inactive mutants of JNK1 and MEKK, also partially inhibited the shear-induced luciferase reporters. In contrast, Raf301, ERK(K71R), and ERK(K52R), the dominant negative mutants of Raf-1, ERK-1, and ERK-2, respectively, had little effect on the activities of these reporters. The activation of JNK was also correlated with increased c-Jun transcriptional activity, which was attenuated by a negative mutant of Son of sevenless. Thus, mechanical stimulation exerted by fluid shearing activates primarily the Ras-MEKK-JNK pathway in inducing endothelial gene expression.
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PMID:The Ras-JNK pathway is involved in shear-induced gene expression. 888 24

Previous studies suggested that tyrosine kinase activation is an important signal transduction event in the IL-1 response of chondrocytes. The present study identifies the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK)-1 and ERK-2 as major tyrosine phosphorylated proteins in IL-1 stimulated chondrocytes. Kinase assays on immunoprecipitates with myelin basic protein as substrate showed that ERK-1 and ERK-2 activation was detectable within 5 min after IL-1 stimulation and decreased to baseline within 60 min. Analysis of other members of the MAP kinase family showed that chondrocytes also express c-Jun NH2 terminal kinase (JNK)-1, JNK-2, and p38 proteins. These kinases were time-dependently activated by IL-1. Among other chondrocyte activators tested, only TNF activated all three of the MAP kinase subgroups. JNK and p38 were not activated by any of the other cytokines and growth factors tested. However, ERK was also activated by PDGF, IGF-1, and IL-6. Phorbol 12-myristate 13-acetate, calcium ionophore, and cAMP analogues only increased ERK activity but had no significant effects on JNK or p38. These results suggest differential activation of MAP kinase subgroups by extracellular stimuli. ERK is activated in response to qualitatively diverse extracellular stimuli and various second messenger agonists. In contrast, JNK and p38 are only activated by IL-1 or TNF, suggesting that these kinases participate in the induction of the catabolic program in cartilage.
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PMID:Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes. 894 62

c-Jun N-terminal kinases (JNKs) participate in cellular responses to mitogenic stimuli, environmental stresses, and apoptotic agents. The mechanisms by which JNK integrates with other signaling pathways and regulates the diverse cellular events are unclear. We found JNK, but not p38-mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase 2, to be persistently activated in apoptosis induced by gamma radiation, UV-C, and anti-Fas treatment. Direct correlation was found between JNK activation and apoptosis induced by UV-C and gamma radiation; however, JNK induction and apoptosis induced by Fas signaling were not well correlated. Overexpression of activated JNK1 caused cell death in transfected cells, and the expression of a dominant-negative mutant of MAPK kinase 1 or JNK1 (but not a dominant-negative mutant of p38-MAPK or c-Raf) prevented the UV-C- and gamma radiation-induced cell death. The inductions of JNK in T-cell activation and apoptosis were distinguished by the different activation patterns, transient versus persistent, respectively. Co-treatment with a tyrosine phosphatase inhibitor (sodium orthovanadate) and T-cell activation signals (phorbol 12-myristate 13-acetate plus ionomycin) prolonged JNK induction, followed by T-cell apoptosis. Our data revealed the requirement of the JNK pathway in radiation-induced apoptosis and implicated the importance of the duration of JNK activation in determining the cell fates.
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PMID:The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. 894 38

Insulin increases the volume of isolated hepatocytes and cells in perfused livers, but effects of the hormone on the volume of fat or muscle cells have not been demonstrated. Exogenous amino acids may stimulate swelling of liver cells and induce insulin-like effects on hepatic protein metabolism; however, swelling of liver cells can be induced by some treatment that do not induce insulin-like metabolic responses. Exogenous amino acids also influence protein metabolism of fat and muscle cells, but no relationship with cell volume has been established and no corresponding effects on metabolism of carbohydrates or lipids have been observed. Three families of mitogen-activated protein kinases are activated after changes in extracellular osmolarity but they appear to play little or no role in the metabolic actions of insulin. Direct evidence against a metabolic role for the extracellular signal-regulated kinases ERK-1 and ERK-2 is discussed. The c-Jun N-terminal kinases (also called stress-activated protein kinases) and the mammalian homologs of the yeast Hog protein kinase are strongly activated by environmental stresses associated with catabolic metabolism. We conclude that cell volume and protein metabolism may be correlated in liver but there is no compelling evidence that the effects of insulin on metabolism of liver, fat, or muscle cells can be accounted for by changes in cell volume. The effects of insulin on cell volume may represent a discrete aspect of the complete physiological response rather than an obligatory intermediate step in metabolic signalling.
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PMID:Cell volume and the metabolic actions of insulin. 896 Mar 57

Urokinase-type plasminogen activator (uPA) expression is induced upon cytoskeletal reorganization (CSR) by a mechanism independent of protein kinase C and cAMP protein kinase in nontransformed renal epithelial (LLC-PK1) cells. This CSR-dependent uPA gene activation is mediated by an AP-1-recognizing element located 2 kilobases upstream of the transcription initiation site. The phosphorylation of c-Jun, a component of AP-1, is induced by CSR, which seems to increase both the activity and stability of c-Jun (Lee, J. S., von der Ahe, D., Kiefer, B., and Nagamine, Y. (1993) Nucleic Acids Res. 21, 3365-3372). It has been shown that c-Jun is phosphorylated by members of the mitogen-activated protein kinase family, i.e. ERKs and JNKs. ERKs are activated through a growth factor-coupled Ras/Raf-dependent signaling pathway, while JNKs are activated through a stress-induced signaling pathway. Although CSR induces both ERK-2 and JNK activity, JNK does not seem to be involved in the uPA gene induction because UV irradiation, which activates JNK as efficiently as CSR, does not activate the uPA promoter. Further analysis showed the involvement of SOS, Ras, and Raf-1 in the pathway induced by CSR. Our results suggest that cells sense changes in cell morphology using the cytoskeleton as a sensor and respond by activating the ERK-involving signaling pathway from within the cell.
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PMID:Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. 899 79

Invasive and metastatic cells require protease expression for migration through the extracellular matrix. Metastatic NIH 3T3 fibroblasts transformed by different activated ras genes showed two different protease phenotypes, rasuPA+/CL- and rasCL+/uPA- (Zhang, J-Y., and Schultz, R. M. (1992) Cancer Research 52, 6682-6689). Phenotype rasuPA+/CL- is dependent on expression of the serine-type protease urokinase plasminogen activator (uPA) and the phenotype rasCL+/uPA- on the cystine-type protease cathepsin L (CL) for lung colonization in experimental metastasis. The existence of multiple invasive phenotypes on ras-isoform transformation implied the activation of alternative pathways downstream from Ras. We now show that c-Raf-1, extracellular signal-regulated protein kinase (ERK)-1, and ERK-2 are hyperphosphorylated, and the ERK activity is high in both the uPA- and CL-dependent ras-transformed invasive phenotypes. Levels of c-Jun and c-Jun NH2-terminal kinase (JNK) activity are also high in the uPA-dependent phenotype, but they are almost undetectable in the CL-dependent phenotype. The uPA Ras-response element is a PEA3/URTF element, and mobility shift assays show a strong PEA3/URTF protein band in the uPA-dependent phenotype. This band is competed by a consensus AP-1 DNA sequence and by antibodies to PEA3 and c-Jun. Thus, the uPA-invasive phenotype appears to require the activation of Ets/PEA3 and c-Jun transcription factors activated by the ERK and JNK pathways, while the CL-invasive phenotype appears to require ERK activity with suppression of JNK and c-Jun activities. These postulates are supported by the introduction of a dominant negative c-Jun, TAM67, into cells of phenotype rasuPA+/CL-, which down-regulated the high uPA mRNA levels characteristic of this phenotype to basal levels and up-regulated basal levels of CL mRNA to levels similar to those observed in cells of phenotype rasCL+/uPA-. We conclude that the JNK pathway acts as a switch between two distinct protease phenotypes that are redundant in their abilities to grow tumors and metastasize.
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PMID:Characterization of downstream Ras signals that induce alternative protease-dependent invasive phenotypes. 903 12

Under physiological conditions, activation of CD4+ T cells by major histocompatibility complex (MHC)antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule has also been shown to inhibit T cell proliferation and interleukin (IL)-2 production in human CD4+ T cells, in an MHC-independent way. We have previously shown that this inhibition was associated with a diminished binding activity of the IL-2 transcription factors NF-AT, NF-kappaB, and AP-1. AP-1 plays a key role in the regulation of IL-2 transcription, and ERK and JNK activities are necessary for regulating AP-1 at both the transcriptional and the post-transcriptional levels. We therefore studied, in human peripheral CD4+ T cells, the regulation of the activities of extracellular signal-regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK) by two CD4 ligands, gp160 the envelope glycoprotein of human immunodeficiency virus (HIV) and an anti-CD4 monoclonal antibody (mAb). Pre-incubation of CD4+ T lymphocytes in the presence of anti-CD4 mAb or gp160 inhibits the activation of JNK in response to phorbol 12-myristate 13-acetate and ionomycin. In the same conditions, phosphorylation and activation of ERK-2 were also inhibited. Inhibition of both JNK and ERK-2 activities are specific for binding of CD4 ligands to the CD4 molecule. They were not observed in CD8+ T lymphocytes. These results suggest that a specific inhibition of JNK and ERK-2 activities contributes to defective IL-2 production in T lymphocytes pre-incubated with CD4 ligands.
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PMID:gp160 of HIV or anti-CD4 monoclonal antibody ligation of CD4 induces inhibition of JNK and ERK-2 activities in human peripheral CD4+ T lymphocytes. 904 10


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