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)

Many growth factors and agonists for G protein-coupled receptors activate mitogen-activated protein (MAP) kinase pathways, including the extracellular signal-regulated kinase (ERK) pathway and the c-Jun kinase (JNK) pathway. Transient transfection of dominant negative and constitutively active pathway components in COS-7 cells shows that two G protein subunits, Galpha12 and Galpha13, inhibit the ERK pathway and stimulate the JNK pathway. Constitutively active (GTPase-deficient) Galpha12 and Galpha13 both inhibit ERK pathway activation by epidermal growth factor. A Galpha13/alphaz chimera, which responds to stimulation by Gi-coupled receptors, mediates inhibition of ERK via such a receptor, the dopamine-2 receptor. In addition, expression of a dominant negative mutant of the GTPase, Cdc42, blocks activation of the JNK pathway by Galpha12 and Galpha13 but does not alter inhibition of ERK activation by the same Galpha proteins; conversely, mutationally activated Cdc42 stimulates the JNK pathway but has no effect on the ERK pathway. Our results show that different mechanisms mediate two effects of Galpha12 and Galpha13: the ERK pathway inhibition is mediated at the level of MAP kinase kinase in a Ras- and Raf-independent fashion, whereas the JNK pathway stimulation is mediated by Cdc42.
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PMID:Galpha12 and Galpha13 regulate extracellular signal-regulated kinase and c-Jun kinase pathways by different mechanisms in COS-7 cells. 870 75

The HBx protein of hepatitis B virus is a dual-specificity activator of transcription, stimulating signal transduction pathways in the cytoplasm and transcription factors in the nucleus, when expressed in cell lines in culture. In the cytoplasm, HBx was shown to stimulate the Ras-Raf-mitogen-activated protein kinase (MAP kinase) cascade, which is essential for activation of transcription factor AP-1. Here we show that HBx protein stimulates two independently regulated members of the MAP kinase family when expressed transiently in cells. HBx protein stimulates the extracellular signal-regulated kinases (ERKs) and the c-Jun N-terminal kinases (JNKs). HBx activation of ERKs and JNKs leads to induction and activation of AP-1 DNA binding activity involving transient de novo synthesis of c-Fos protein and prolonged synthesis of c-Jun, mediated by N-terminal phosphorylation of c-Jun carried out by HBx-activated JNK. New c-Jun synthesis was blocked by coexpression with a dominant-negative MAP kinase kinase (MEK kinase, MEKK-1), confirming that HBx stimulates the prolonged synthesis of c-Jun by activating JNK signalling pathways. Activation of the c-fos gene was blocked by coexpression with a Raf-C4 catalytic mutant, confirming that HBx induces c-Fos by acting on Ras-Raf linked pathways. HBx activation of ERK and JNK pathways resulted in prolonged accumulation of AP-1-c-Jun dimer complexes. HBx activation of JNK and sustained activation of c-jun, should they occur in the context of hepatitis B virus infection, might play a role in viral transformation and pathogenesis.
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PMID:Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. 876 4

The ERK, JNK/SAPK and p38/RK MAP kinase subtypes (reviewed in [1]) are differentially activated in mammalian cells by various stimuli, which elicit induction of immediate-early (IE) genes, such as c-fos and c-jun (reviewed in [1-3]), as well as phosphorylation of histone H3 [4] and HMG-14 [5]. Anisomycin and UV radiation have been suggested to induce c-fos and c-jun transcription via JNK/SAPK-mediated phosphorylation of TCF (ternary complex factor), for c-fos induction [6-8], and c-Jun and/or ATF-2 for c-jun induction [9-11] [12,13]. We report here that anisomycin and ultraviolet radiation (UV) activate MAP kinase kinase-6 (MKK6) [14,15], p38/RK [16] [17,18] and MAPKAP kinase-2 (MAPKAP K-2) [17-19]. By using the p38/RK inhibitor SB 203580 [20,21], we show that activation of p38/RK and/or its downstream effectors are essential for anisomycin- and UV-stimulated c-fos/c-jun induction and histone H3/HMG-14 phosphorylation, whereas JNK/SAPK activation and phosphorylation of c-Jun and ATF-2 are insufficient for these responses.
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PMID:p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient. 880 35

Expression of the ovine P-450 side-chain cleavage enzyme gene (CYP11A1) is stimulated by epidermal growth factor (EGF) through a pathway that involves c-Jun in JEG-3 placental cells. Growth factor signaling involves ras-dependent and ras-independent signaling pathways, which in turn regulate gene transcription through related but distinct mitogen-activated protein kinase pathways (MAPKs) including the extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs). We investigated the intracellular signaling pathways governing EGF induction of the CYP11A1 promoter. EGF stimulation of the CYP11A1 promoter (4-fold) was reduced 60% by a dominant negative mutant of ras (N17), and 30-40% by antisense ras. EGF induced both ERK and SAPK activity in JEG-3 cells. EGF-induced CYP11A1 promoter activity was reduced 60% by the MEK1 inhibitor PD098059 and 50% by a dominant negative mutant of the ERK-specific regulator MEK1. In contrast, dominant negative mutants of the SAPK-specific activator, SEK1, induced a further increase in EGF-induced CYP11A1 promoter activity. Constitutively active mutants of ras (V12 or L61) increased CYP11A1 promoter activity 6- to 8-fold. Deletion of the EGF response element (EGF-RE) between -92 and -77 bp reduced ras induction by 60%; however, a residual 3-fold induction remained through the proximal -77 bp. Mutation of the EGF-RE AP-1-like sequence in the context of the native promoter reduced CYP11A1 promoter activation by ras 60%. The EGF-RE sequence was sufficient for 6-fold activation by ras in the context of an heterologous thymidine kinase promoter. Candidate transcription factor targets (c-Jun, c-Ets-2) for the ras-signaling cascade were examined for their effects on CYP11A1 promoter activity. Overexpression of c-Jun induced the CYP11A1 promoter through the EGF-RE; however, c-Ets-2 activation of the CYP11A1 promoter (12-fold) required the proximal ras-responsive promoter sequences that are distinct from the EGF/MEK/c-Jun-responsive element. Induction of the CYP11A1 promoter by EGF involves a ras/MEK1/AP-1-dependent pathway that is distinct from induction by ras/c-Ets-2.
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PMID:Stimulation of the P-450 side chain cleavage enzyme (CYP11A1) promoter through ras- and Ets-2-signaling pathways. 888 43

The Drosophila MAP kinase DJNK is a homolog of the mammalian c-Jun amino-terminal kinase (JNK). Mutations in the DJNK gene correspond to the complementation group basket. DJNK is phosphorylated and activated by the Drosophila MAP kinase kinase HEP. Substrates of DJNK include the transcription factor DJun. DJNK participates in multiple physiological processes. Exposure to endotoxic lipopolysaccharide initiates an insect immune response and leads to DJNK activation. In addition, embryos lacking DJNK are defective in dorsal closure, a process in which the lateral epithelial cells migrate over the embryo and join at the dorsal midline. These data demonstrate that the DJNK signal transduction pathway mediates an immune response and morphogenesis in vivo.
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PMID:A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila. 894 15

Cardiac myocyte survival is of central importance in the maintenance of the function of heart, as well as in the development of a variety of cardiac diseases. To understand the molecular mechanisms that govern this function, we characterized apoptosis in cardiac muscle cells following serum deprivation. Cardiotrophin 1 (CT-1), a potent cardiac survival factor (Sheng, Z., Pennica, D., Wood, W. I., and Chien, K. R. (1996) Development (Camb.) 122, 419-428), is capable of inhibiting apoptosis in cardiac myocytes. To explore the potential downstream pathways that might be responsible for this effect, we documented that CT-1 activated both signal transducer and activator of transcription 3 (STAT3)- and mitogen-activated protein (MAP) kinase-dependent pathways. The transfection of a MAP kinase kinase 1 (MEK1) dominant negative mutant cDNA into myocardial cells blocked the antiapoptotic effects of CT-1, indicating a requirement of the MAP kinase pathway for the survival effect of CT-1. A MEK-specific inhibitor (PD098059) (Dudley, D. T., Pang, L., Decker, S.-J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. USA 92, 7686-7689) is capable of blocking the activation of MAP kinase, as well as the survival effect of CT-1. In contrast, this inhibitor did not block the activation of STAT3, nor did it have any effect on the hypertrophic response elicited following stimulation of CT-1. Therefore, CT-1 promotes cardiac myocyte survival via the activation of an antiapoptotic signaling pathway that requires MAP kinases, whereas the hypertrophy induced by CT-1 may be mediated by alternative pathways, e.g. Janus kinase/STAT or MEK kinase/c-Jun NH2-terminal protein kinase.
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PMID:Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. 903 92

Mitogen-activated protein kinases (MAPKs) are components of sequential kinase cascades that are activated in response to a variety of extracellular signals. Members of the MAPK family include the extracellular response kinases (ERKs or p42/44(MAPK)), the c-Jun amino-terminal kinases (JNKs), and the p38/Hog 1 protein kinases. MAPKs are phosphorylated and activated by MAPK kinases (MKKs or MEKs), which in turn are phosphorylated and activated by MKK/MEK kinases (Raf and MKKK/MEKKs). We have isolated two cDNAs encoding splice variants of a novel MEK kinase, MEKK4. The MEKK4 mRNA is widely expressed in mouse tissues and encodes for a protein of approximately 180 kDa. The MEKK4 carboxyl-terminal catalytic domain is approximately 55% homologous to the catalytic domains of MEKKs 1, 2, and 3. The amino-terminal region of MEKK4 has little sequence homology to the previously cloned MEKK proteins. MEKK4 specifically activates the JNK pathway but not ERKs or p38, distinguishing it from MEKKs 1, 2 and 3, which are capable of activating the ERK pathway. MEKK4 is localized in a perinuclear, vesicular compartment similar to the Golgi. MEKK4 binds to Cdc42 and Rac; kinase-inactive mutants of MEKK4 block Cdc42/Rac stimulation of the JNK pathway. MEKK4 has a putative pleckstrin homology domain and a proline-rich motif, suggesting specific regulatory functions different from those of the previously characterized MEKKs.
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PMID:Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. 907 50

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

Mitogen-activated protein (MAP) kinases are important mediators of the cellular stress response. Here, we investigated the relationship between activation of the MAP kinase p38 and transcription factor NF-kappaB. Different forms of cellular stress were found to preferentially trigger either p38 or NF-kappaB. Arsenite or osmotic stress potently activated p38 but were ineffective in inducing NF-kappaB activation. Tumor necrosis factor-alpha and hydrogen peroxide, in contrast, led to NF-kappaB activation but only modestly stimulated p38. The activation of NF-kappaB was strongly abolished by antioxidants, while the activity of p38 and transcription factor AP-1 were increased. Inhibition of small GTPases including Rac and Cdc42 prevented p38 and AP-1 activation without interfering with NF-kappaB. In addition, inhibition of p38 by a pharmacological inhibitor or a dominant-negative mutant of MAP kinase kinase-6, an activator of the p38 pathway, interfered with NF-kappaB-dependent gene expression but not its DNA binding activity. Our results indicate that activation of p38 and NF-kappaB are mediated by separate pathways, which may converge further downstream in the cell nucleus. Different forms of cellular stress, however, initially trigger distinct signaling cascades involving either oxidative stress or GTPase-coupled pathways.
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PMID:Activation of transcription factor NF-kappaB and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways. 913 89

The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by phosphorylation on Thr and Tyr. Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK. In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway. MKK7 is therefore established to be a novel component of the JNK signal transduction pathway.
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PMID:Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. 920 92


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