UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

A high concentration (50 micrograms/ml) of gamma-linolenic acid (GLA) induced morphological lesions typical of apoptosis, as well as DNA fragmentation, in HeLa cells. A lower concentration of GLA (20 micrograms/ml), caused an increased proliferating cell nuclear antigen (PCNA) labelling, with 92.7% cells positive, compared to 27.7% at a concentration of 50 micrograms/ml GLA. In correlation with these results, the number of cells with degraded DNA below the G0/G1 peak increased significantly in the 50 micrograms/ml GLA-treated cells, but increased only slightly in cells exposed to the lower level of GLA. The high levels of PCNA induced by 20 micrograms/ml GLA, in both G1 and S phases, may indicate a state of DNA repair synthesis, whilst at the higher concentration of GLA, most of the cells became apoptotic. Since apoptosis is associated with the deregulation of c-Myc expression, and as the Raf-1-MAP kinase cascade activates the expression of c-Myc and c-Jun, we investigated the effects of 20 and 50 micrograms/ml GLA on the Raf-1, c-Myc and c-Jun levels, and on the activity of MAP kinase. The results showed that 50 micrograms/ml GLA lowered the activity of MAP kinase. As expected with the decreased MAP kinase activity in the cells exposed to the higher level GLA, the c-Jun levels were also lowered. The levels of c-Myc, however, were increased. It is therefore possible that the deregulated expression of c-Myc in the HeLa cells exposed to the high level of GLA (50 micrograms/ml) may contribute to the induction of apoptosis in HeLa cells.
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PMID:The induction of apoptosis in human cervical carcinoma (HeLa) cells by gamma-linolenic acid. 901 18

Heparin-binding epidermal growth factor (HB-EGF) gene transcription is rapidly activated in NIH 3T3 cells transformed by oncogenic Ras and Raf and mediates the autocrine activation of the c-Jun N-terminal kinases (JNKs) observed in these cells. A 1.7-kb fragment of the promoter of the murine HB-EGF gene linked to a luciferase reporter was strongly induced following activation of deltaRaf-1:ER, a conditionally active form of oncogenic human Raf-1. Promoter activation by deltaRaf-1:ER required a composite AP-1/Ets transcription factor binding site located between bp -974 and -988 upstream of the translation initiation site. In vivo genomic footprinting indicated that the basal level of occupancy of this composite AP-1/Ets element increased following deltaRaf-1:ER activation. Cotransfection of Ets-2 and p44 mitogen-activated protein (MAP) kinase expression vectors strongly potentiated HB-EGF promoter activation in response to deltaRaf-1:ER. Potentiated activation required both p44 MAP kinase catalytic activity and threonine 72 in the Pointed domain of Ets-2. Biochemical assays demonstrated the ability of the p42 and p44 MAP kinases to phosphorylate Ets-2 on threonine 72. Importantly, in intact cells, the kinetics of phosphorylation of Ets-2 on this residue closely mirror the activation of the p42 and p44 MAP kinases and the observed onset of HB-EGF gene transcription following deltaRaf-1:ER activation. These data firmly establish Ets-2 as a direct target of the Raf-MEK-MAP kinase signaling pathway and strongly implicate Ets-2 in the regulation of HB-EGF gene expression.
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PMID:Rapid phosphorylation of Ets-2 accompanies mitogen-activated protein kinase activation and the induction of heparin-binding epidermal growth factor gene expression by oncogenic Raf-1. 911 9

The protooncogene G alpha(i-2) plays a pivotal role in signaling pathways that control renal cell growth and differentiation. Mitogen-activated protein kinases (MAPKs) are potential downstream effectors for G alpha(i-2) in these pathways. In predifferentiated LLC-PK1 renal cells, the temporal maximal expression of G alpha(i-2) coincided with maximal activation of MAPK(p42/p44). By contrast, pertussis toxin treatment of these cells inhibited cell growth and reduced MAPK(p42/p44) activity by 30%. These findings reflected upstream activation of MAPK kinase (MEK1), as transient transfection of cells with a plasmid encoding a constitutively active form of MEK1 increased MAPK(p42/p44) activity and cell growth, whereas treatment with PD-098059, an inhibitor of MEK1 activity, reduced MAPK(p42/p44) activity and cell growth. Expression of a guanosinetriphosphatase (GTPase)-deficient G alpha(i-2) in these cells increased MAPK(p42/p44) activity and correspondingly reduced cell doubling time from 24 to 10 h without altering the activity of Raf-1 or c-Jun/stress-activated protein kinases (SAPKs). By contrast, expression of a GTPase-deficient G alpha(i-3) in these cells reduced both their cell doubling time by 30% and MAPK(p42/p44) activity by 60%. As the known MEKK isoforms (MEKK1, -2, and -3) can also activate SAPKs, these findings suggest the GTP-charged G alpha(i-2) subunit transduces growth signals in renal cells via activation of MAPK(p42/p44) and that such activation may be linked to pathways containing novel MEKK isoforms that preferentially activate MEKs.
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PMID:G alpha(i-2) mediates renal LLC-PK1 growth by a Raf-independent activation of p42/p44 MAP kinase. 912 7

The biochemical mechanisms responsible for lung cell growth and proliferation are not well defined during tissue injury. We previously showed stimulation of DNA synthesis in intact lung tissue cultured in vitro after exposure to elevated fractions of O2. By use of this in vitro model, the current study examined the enzymatic activities of the extracellular-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways. ERK and JNK activities were transiently elevated in lung tissue cultured under serum-free conditions. Raf-1 kinase, the primary upstream activator of the ERK pathway, was also transiently activated, suggesting a receptor-mediated ERK activation. Phosphorylation of the guanine nucleotide exchange protein p170 son of sevenless further suggested a receptor-mediated activation of the ERK pathway. c-Fos and c-Jun expression, downstream targets of ERK and JNK, was dramatically increased in cultured tissue compared with uncultured tissue. After the initial transient activation, ERK and JNK could be reactivated with specific agonists, demonstrating that these signaling pathways were functional. These findings demonstrate activation of the ERK and JNK MAP kinase pathways in intact lung tissue and provide a model system to define signaling pathways involved in lung tissue remodeling injury.
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PMID:Activation of ERK and JNK1 MAP kinases in cultured lung tissue. 927 60

While it is known that the constitutive activity of a variety of signal transduction molecules leads to cell transformation, a key unresolved question is whether these wirings converge to a common intermediate(s) that dictates transformation. In this study, we investigated whether NIH3T3 and Rat-1 cells transformed by human ornithine decarboxylase (ODC), c-Ha-rasVal12 and temperature-sensitive v-src oncogene display common alteration(s) in the components that relay PDGF-mediated signals in normal fibroblasts. The ras- and ODC-transformed cells did not show constitutively elevated tyrosine phosphorylation of the phospholipase Cgamma-1 (PLCgamma-1), RasGTPase-activating protein (GAP), phosphotyrosine phosphatase Syp, Shc proteins, and phosphatidylinositol 3-kinase (PI3-K) or activation of the MAP kinase (Erk1 and Erk2), p70 S6 kinase or the Janus protein tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) protein-1 pathways. Instead, the Ras nucleotide exchange factor Sos-1 and Raf-1 kinase exhibited constitutive phosphorylations, as deduced from their electrophoretic mobility shifts in polyacrylamide gels. Hence a kinase distinct from Erk1 and Erk2, previously known to feedback phosphorylate Sos-1 and Raf-1, is responsible for the phosphorylation of these molecules in the transformants. We also demonstrate that the ras- and ODC-transformed cells exhibit loss of both the PDGF alpha- and beta-receptors, while the v-Src-transformants show a predominant reduction in the beta-receptors. Moreover, all the transformed cell lines were found to display a constitutive increase in phosphorylation of c-Jun on serines 63 and 73, which appears to be governed by an as yet unknown kinase.
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PMID:Cells transformed by ODC, c-Ha-ras and v-src exhibit MAP kinase/Erk-independent constitutive phosphorylation of Sos, Raf and c-Jun activation domain, and reduced PDGF receptor expression. 936 42

The erythroleukemia-inducing Friend spleen focus-forming virus (SFFV) encodes a unique envelope glycoprotein which allows erythroid cells to proliferate and differentiate in the absence of erythropoietin (Epo). In an attempt to understand how the virus causes Epo independence, we have been studying signal transduction pathways activated by Epo to determine if SFFV exerts its biological effects by constitutively activating any of these pathways in the absence of Epo. We previously demonstrated that Stat proteins, the downstream components of the Epo-induced Jak-Stat pathway, are constitutively activated in SFFV-infected cells. In this study, we demonstrate that SFFV also activates Raf-1, MEK and mitogen-activated protein (MAP) kinase, the downstream components of the Raf-1/MAP kinase pathway. This pathway was activated in cells infected with the polycythemia-inducing strain of SFFV, which induces both proliferation and differentiation of erythroid cells in the absence of Epo, as well as in cells infected with the anemia-inducing strain of the virus, which still require Epo for differentiation. Inhibition of Raf-1 by using antisense oligonucleotides led to a partial inhibition of the Epo-independent proliferation of SFFV-infected cells. Expression of the transcription factors c-Jun and JunB, but not c-Fos, was induced in SFFV-infected cells in the absence of Epo, suggesting that constitutive activation of the Raf-1/MAP kinase pathway by the virus may result in deregulation of AP-1 activity. We conclude from our studies that infection of erythroid cells with SFFV leads to the constitutive activation of signal transduction molecules in both the Jak-Stat and Raf-1/MAP kinase pathways and that both of these pathways must be activated to achieve maximum proliferation and differentiation of erythroid cells in the absence of Epo.
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PMID:Both the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus induce constitutive activation of the Raf-1/mitogen-activated protein kinase signal transduction pathway. 944 83

In a previous study, we demonstrated that bufalin caused apoptosis in human leukemia U937 cells by the anomalous activation of mitogen-activated protein kinase (MAPK) via a signaling pathway that included Ras, Raf-1 and MAPK kinase-1. We report here the effect of bufalin on c-Jun N-terminal protein kinase (JNK), a member of the MAPK family, and on the signaling pathway downstream of MAPKs in U937 cells. When U937 cells were treated with 10(-8) M bufalin, the activity of JNK1 was markedly elevated 3 h after the start of treatment and remained so for 9 h. This activation of JNK and the induction of apoptosis by bufalin were suppressed by expression of antisense mRNA for MAPK kinase-1. c-Jun was translocated from the cytoplasm to the nucleus after treatment of U937 cells with bufalin. The transcriptional activity of AP-1 was transiently enhanced by the treatment with bufalin and this activation was suppressed by the expression of antisense mRNA for MAPK kinase-1. Both curcumin (1,7-bis[4-hydroxy-3-methoxy-phenyl]-1,6-heptadiene-3,5-dione), an inhibitor of the biosynthesis of AP-1, and the expression of dominant negative c-Jun inhibited the activation of AP-1 and the induction of apoptosis by bufalin. Expression of a constitutively active mutant form of MAPK kinase-1 induced the activation of AP-1 and subsequent apoptosis in U937 cells. These results suggest that the activation of AP-1 via a MAPK cascade that includes JNK is required for the induction of apoptosis by bufalin in U937 cells.
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PMID:Activation of AP-1 is required for bufalin-induced apoptosis in human leukemia U937 cells. 948 42

T cells from elderly humans often display impaired IL-2 production, but the mechanisms are unknown. Because the activities of extracellular signal-regulated kinases (ERK) and c-Jun NH2-terminal kinases (JNK) are important for IL-2 production, the current study evaluated if aberrancies in the expression and activation of ERK2 or JNK might underlie decreased IL-2 production by human T cells during aging. The present results show that diminished ERK2 and JNK catalytic activities were commonly detected in T cells from elderly humans stimulated with anti-CD3 mAb OKT3 plus PMA. These reductions did not represent temporal shifts in activation or altered expression of ERK2 or JNK. In addition, the reductions of ERK2 activation in stimulated T cells from elderly individuals were accompanied by decreased Raf-1 kinase activation and could be observed without coexisting impairments in JNK activation. Stimulation of ERK2 activation in elderly T cells correlated with IL-2 production and decreased ERK2 activation was consistently associated with reduced IL-2 production. Although the age-related decreases in JNK activation were accompanied by reduced IL-2 production, substantial impairments of JNK activation were observed with diminished ERK2 activation. Moreover, anti-CD3/PMA-stimulated T cells from elderly individuals that displayed normal JNK activation and impaired ERK2 activation continued to demonstrate reduced IL-2 production. These findings show that impairments in the activation of ERK2 and JNK can accompany decreased IL-2 production by T cells from elderly humans and further suggest that aberrancies in TCR/CD3-dependent activation of the Raf-1/MEK/ERK2 cascade may be rate-limiting for the full induction of IL-2.
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PMID:Reductions in the activation of ERK and JNK are associated with decreased IL-2 production in T cells from elderly humans stimulated by the TCR/CD3 complex and costimulatory signals. 951 99

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