Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype, proliferate, and synthetize fibrosis components. We have shown that endothelin-1 (ET-1) inhibits the proliferation of activated human HSC via endothelin B (ETB) receptors. We now investigate the transduction pathway involved in the growth inhibitory effect of ET-1 in activated HSC. Endothelin-1 and the ETB receptor agonist, sarafotoxin-S6C, increased synthesis of PGI2 and PGE2, leading to elevation of cAMP. The cyclooxygenase inhibitor ibuprofen and the adenylyl cyclase inhibitor SQ22536 both blunted the growth inhibitory effect of ET-1. Analysis of early steps associated with growth inhibition indicated that: (a) similar to ET-1, forskolin decreased c-jun mRNA induction without affecting c-fos and krox 24 mRNA expression; (b) ET-1, sarafotoxin-S6C, as well as forskolin, reduced activation of both c-Jun kinase and extracellular signal-regulated kinase. Finally, forskolin, PGI2, and PGE2 raised by fivefold the number of ET binding sites after 6 h, and increased the proportion of ETB receptors from 50% in control cells to 80% in treated cells. In conclusion, ET-1 inhibits proliferation of activated HSC via ETB receptors, through a prostaglandin/cAMP pathway that leads to inhibition of both extracellular signal-regulated kinase and c-Jun kinase activities. Upregulation of ETB receptors by prostaglandin/cAMP raises the possibility of a positive feedback loop that would amplify the growth inhibitory response. These results suggest that ET-1 and agents that increase cAMP might be of interest to limit proliferation of activated HSC during chronic liver diseases.
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PMID:Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors. 898 23

The mitogen-activated protein kinase (MAPK) cascade is believed to function as an important regulator of prostaglandin biosynthesis. Previously we reported that interleukin-1beta induces activation of JNK/SAPK and p38 MAPK with concomitant up-regulation of cyclooxygenase (Cox)-2 expression and prostaglandin E2 (PGE2) synthesis. Our experiments demonstrate that overexpression of DeltaMEKK1 (a constitutively active truncation mutant of MEKK1 containing the C-terminal 324 amino acids) increases Cox-2 expression and PGE2 production which is completely blocked by SC68376, a pharmacologic inhibitor of p38 MAPK. DeltaMEKK1 overexpression results in activation of both c-Jun N-terminal kinases/extracellular signal-regulated kinases (JNK/SAPK) and p38 MAPK. Furthermore, activation of MEKK1 increases SEK1/MKK4 but not MKK3 or MKK6 activity. These findings suggest that MEKK1 --> SEK1/MKK4 may function as an upstream kinase capable of activating both p38 MAPK and JNK/SAPK with subsequent induction of Cox-2 expression and PGE2 production. We also found that overexpression of the constitutively active form of SEK1 (SEK1-ED) increases both p38 MAPK and JNK/SAPK phosphorylation, and increases PGE2 production and Cox-2 expression. By comparison, overexpression of the dominant negative form of SEK1 (SEK1-AL) decreases the phosphorylation of both p38 MAPK and JNK/SAPK and reduces Cox-2 expression. Together, this data suggests a potential role for the MEKK1 --> SEK1/MKK4 --> p38 MAPK -->--> Cox-2 cascade linking members of the MAPK pathway with prostaglandin biosynthesis.
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PMID:Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. 958 21

Curcumin (diferuloylmethane), the naturally occurring yellow pigment in turmeric and curry, is isolated from the rhizomes of the plant Curcuma longa Linn. Curcumin inhibits tumorigenesis during both initiation and promotion (post-initiation) periods in several experimental animal models. Topical application of curcumin inhibits benzo[a]pyrene (B[a]P)-mediated formation of DNA-B[a]P adducts in the epidermis. It also reduces 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in skin inflammation, epidermal DNA synthesis, ornithine decarboxylase (ODC) mRNA level, ODC activity, hyperplasia, formation of c-Fos, and c-Jun proteins, hydrogen peroxide, and the oxidized DNA base 5-hydroxymethyl-2'-deoxyuridine (HmdU). Topical application of curcumin inhibits TPA-induced increases in the percent of epidermal cells in synthetic (S) phase of the cell cycle. Curcumin is a strong inhibitor of arachidonic acid-induced edema of mouse ears in vivo and epidermal cyclooxygenase and lipoxygenase activities in vitro. Commercial curcumin isolated from the rhizome of the plant Curcuma longa Linn contains 3 major curcuminoids (approximately 77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin). Commercial curcumin, pure curcumin, and demethoxycurcumin are about equipotent as inhibitors of TPA-induced tumor promotion in mouse skin, whereas bisdemethoxycurcumin is somewhat less active. Topical application of curcumin inhibits tumor initiation by B[a]P and tumor promotion by TPA in mouse skin. Dietary curcumin (commercial grade) inhibits B[a]P-induced forestomach carcinogenesis, N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced duodenal carcinogenesis, and azoxymethane (AOM)-induced colon carcinogenesis. Dietary curcumin had little or no effect on 4-(methylnitosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis and 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in mice. Poor circulating bioavailability of curcumin may account for the lack of lung and breast carcinogenesis inhibition.
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PMID:Inhibitory effects of curcumin on tumorigenesis in mice. 959 Nov 90

Arachidonic acid (AA) and its metabolites play important roles in a variety of biological processes, such as signal transduction, contraction, chemotaxis, and cell proliferation and differentiation. It was demonstrated recently that AA can activate mitogen-activated protein kinases (MAPKs), which are crucial for transducing signals initiating cell growth and apoptosis. Here we studied the effect of AA on the induction of MAPK phosphatase-1 (MKP-1) in vascular smooth muscle cells (VSMCs) and found that AA stimulated induction of MKP-1 mRNA and proteins in VSMCs in a time- and dose-dependent manner. Specific inhibitors of cyclooxygenase-, lipoxygenase-, and cytochrome P450-dependent metabolism did not affect AA-induced MKP-1 expression, indicating that eicosanoid biosynthesis was not involved in this process. The glutathione precursor N-acetylcysteine, an antioxidant, abolished AA-stimulated MKP-1 gene expression, whereas inhibition of protein kinase C by calphostin C had no influence on MKP-1 induction. VSMC pretreatment with genistein, a tyrosine kinase inhibitor, completely blocked AA-stimulated MKP-1 induction. MAPK kinase inhibitor PD 98059 did abolish AA-stimulated activation of extracellular signal-regulated kinases but not MKP-1 induction. Furthermore, agonists that increase AA release stimulated MKP-1 induction and activation of MAPKs, including extracellular signal-regulated kinases and c-Jun NH2-terminal protein kinases or stress-activated protein kinases. Taken together, our findings demonstrate that AA induced MKP-1 expression in VSMCs via activation of tyrosine kinases involving AA-induced free radical generation, suggesting an important role for MKP-1 in the regulation of AA-initiated signal transduction in VSMCs.
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PMID:Induction of mitogen-activated protein kinase phosphatase-1 by arachidonic acid in vascular smooth muscle cells. 983 5

In the present study, we studied the signal transduction mechanism that is involved in the expression of c-Jun protein evident after exposure of rat liver epithelial RL34 cells to the major end product of oxidized fatty acid metabolism, 4-hydroxy-2-nonenal (HNE). HNE treatment of the cells resulted in depletion of intracellular glutathione (GSH) and in the formation of protein-bound HNE in plasma membrane. In addition, HNE strongly induced intracellular peroxide production, suggesting that HNE exerted oxidative stress on the cells. Potent expression of c-Jun occurred within 30 min of HNE treatment, which was accompanied by a time-dependent increase in activator protein-1 (AP-1) DNA binding activity. We found that HNE caused an immediate increase in tyrosine phosphorylation in RL34 cells. In addition, HNE strongly induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases and also moderately induced phosphorylation of extracellular signal-regulated kinases. The phosphorylation of JNK was accompanied by a rapid and transient increase in JNK and p38 activities, whereas changes in the activity of extracellular signal-regulated kinase were scarcely observed. GSH depletion by L-buthionine-S, R-sulfoximine, a specific inhibitor of GSH biosynthesis, only slightly enhanced peroxide production and JNK activation, suggesting that HNE exerted these effects independent of GSH depletion. This and the findings that (i) HNE strongly induced intracellular peroxide production, (ii) HNE-induced JNK activation was inhibited by pretreatment of the cells with a thiol antioxidant, N-acetylcysteine, and (iii) H2O2 significantly activated JNK support the hypothesis that pro-oxidants play a crucial role in the HNE-induced activation of stress signaling pathways. In addition, we found that, among the inhibitors of tyrosine kinases, cyclooxygenase, and Ca2+ influx, only quercetin exerted a significant inhibitory effect on HNE-induced JNK activation. In light of the JNK-dependent induction of c-jun transcription and the AP-1-induced transcription of xenobiotic-metabolizing enzymes, these data may show a potential critical role for JNK in the induction of a cellular defense program against toxic products generated from lipid peroxidation.
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PMID:Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. 989 Sep 86

Activation of platelets results in shedding of membrane microparticles (MP) with potentially bioactive properties. Platelet MP modulate platelet, monocyte, and vascular endothelial cell function, both by direct effects of MP arachidonic acid (AA) and by its metabolism to bioactive prostanoids. We have previously reported that platelet MP induce expression of cyclooxygenase (COX)-2 and prostacyclin production in monocytes and endothelial cells. To elucidate further the molecular mechanisms that underlie MP-induced up-regulation of COX-2 expression, we investigated the response of a human monocytoid (U-937) cell line to platelet MP stimulation. In U-937 cells, MP-induced COX-2 expression and eicosanoid formation is prevented by pharmacological inhibitors of protein kinase C (PKC), PI 3-kinase, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, and p38 kinase. Treatment with the PI 3-kinase inhibitors wortmannin and LY294002 also blocked MP-induced p42/p44 MAPK, p38, and JNK1 phosphorylation. Conversely, platelet MP stimulation of U-937 cells results in direct activation of PKC, p42/p44 MAPK, p38 kinase, and c-Jun N-terminal kinase (JNK) as well as activation of the transcription factors c-Jun and Elk-1. However, MP failed to activate the cAMP response element. Activation of U-937 cells by MP induces translocation of classical (PKCbeta), novel (PKCdelta) and atypical (PKCzeta and PKClambda) isozymes of PKC from the cytosol to the membrane, with concomitant activation of downstream MAPK. While MP-induced activation of p42/p44 MAPK and p38 kinase is transient, a sustained activation of JNK1 was observed. Although PKC activation is required for MP-induced p42/p44 MAPK, activation of the stress kinases p38 and JNK1 was PKC-independent. The fatty acid fraction of the MP accounted for these effects, which were mimicked by MP AA. Rather than acting directly via nuclear receptors, MP AA activates COX-2-dependent prostaglandin production by a PKC/p42/p44 MAPK/p38 kinase-sensitive pathway in which PI 3-kinase plays a significant role. MP AA also stimulates transcriptional activation of COX-2 as well as c-Jun and Elk-1.
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PMID:Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway. 1006 22

Inducible cyclooxygenase (COX-2) was transiently induced in the neurons throughout the entire hippocampus between 6 and 24 h after injection of kainic acid (KA). The induction of COX-2 correlated more closely with the induction of c-Jun than with that of c-Fos. Phosphorylated c-Jun was induced 6-12 h after in the CA3 pyramidal neurons, which undergo apoptosis. Almost all of neurons with phosphorylated c-Jun were colocalized with COX-2. These results suggest that COX-2 and c-Jun phosphorylation may participate in KA-induced neurodegeneration.
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PMID:Kainic acid-induced inducible cyclooxygenase and c-Jun phosphorylation in the rat hippocampal formation. 1041 22

Accumulating evidence on the molecular and cellular basis of ischemia/reperfusion-induced neurodegeneration suggests that oxidative stress is involved. Heme oxygenase (HO) and cyclooxygenase (COX) play physiologically important roles in the CNS. Conversely, HO and COX also can increase oxidative stress. Recent studies suggest that c-Jun phosphorylation is an important step in some forms of stress-induced neuronal apoptosis. In this study, the authors tried to clarify the association of HO and COX with c-Jun phosphorylation. Inducible forms of HO and COX (HO-1 and COX-2, respectively) were transiently induced in CA1 pyramidal neurons after ischemia. c-Jun also was induced in pyramidal neurons throughout the hippocampal formation, but its phosphorylation was limited to CA1. In contrast, these molecules were constitutively expressed at low levels. Most (84%) of the CA1 pyramidal neurons examined expressed HO-1, COX-2, or both, and such expression showed good co-localization with c-Jun phosphorylation. These results suggest the following: (1) c-Jun phosphorylation was associated with ischemia/reperfusion-induced neuronal apoptosis; (2) HO-1 and COX-2 were induced in CA1 pyramidal neurons, which undergo cell death; and (3) most CA1 pyramidal neurons expressed HO-1, COX-2, or both, which strongly suggests that these are candidates for neuron killers.
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PMID:Phosphorylation of c-Jun and its localization with heme oxygenase-1 and cyclooxygenase-2 in CA1 pyramidal neurons after transient forebrain ischemia. 1056 71

In astrocyte-enriched cultures, arachidonic acid (AA, 100 microM) significantly increased the proenkephalin (proENK) mRNA level (4. 9-fold at 8 h). In addition, AA also increased several AP-1 proteins, such as c-Fos, Fra-1, Fra-2, JunB, JunD, and c-Jun, or AP-1 and ENKCRE-2 DNA-binding activity. As well as AP-1 proteins and their DNA-binding activities, proENK mRNA level induced by AA was reduced by the pretreatment with 15 microM of cycloheximide (CHX; 1.6-fold). AA-dependent increase of proENK mRNA is not mediated by cyclooxygenase- or lipoxygenase-dependent metabolites, or free radicals, because the AA-induced increase of proENK mRNA levels was not affected by indomethacin (10 microM), nordihydroguaiaretic acid (10 microM), or N-acetylcysteine. However, as well as proto-oncoprotein levels, such as Fra-1, Fra-2, c-Jun, JunB, but not JunD, AA-induced increase of proENK mRNA was significantly reduced by the pretreatment with 10 microM of PD98059 (1.3-fold) or 10 microM of SB203580 (1.8-fold). These results strongly suggest that AA rather than one of its metabolites is involved in the increase of proENK mRNA. In addition, the activation of both the p38 and ERK pathways appears to be involved in the AA-induced increase of proENK mRNA via activating the expression of proto-oncoprotein, such as Fra-1, Fra-2, c-Jun, and JunB.
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PMID:Stimulation of astrocyte-enriched culture with arachidonic acid increases proenkephalin mRNA: involvement of proto-oncoprotein and mitogen activated protein kinases. 1076 17

We have previously reported that transcriptional induction of cyclooxygenase-2 (COX-2) isoenzyme occurs early after T cell receptor triggering, suggesting functional implications of cyclooxygenase activity in this process. Here, we identify the cis-acting elements responsible for the transcriptional activation of this gene in human T lymphocytes. COX-2 promoter activity was induced upon T cell activation both in primary resting T lymphocytes and in Jurkat cells. This induction was abrogated by inhibition of calcineurin phosphatase with the immunosuppressive drug cyclosporin A, whereas expression of an active calcineurin catalytic subunit enhanced COX-2 transcriptional activation. Moreover, cotransfection of nuclear factor of activated T cells (NFAT) wild type protein transactivated COX-2 promoter activity. Conversely, dominant negative mutants of NFATc or c-Jun proteins inhibited COX-2 induction. Electrophoretic mobility shift assays and site-directed mutagenesis allowed the identification of two regions of DNA located in the positions -117 and -58 relative to the transcriptional start site that serves as NFAT recognition sequences. These results emphasize the central role that the Ca(2+)/calcineurin pathway plays in COX-2 transcriptional regulation in T lymphocytes pointing to NFAT/activator protein-1 transcription factors as essential for COX-2 promoter regulation in these cells.
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PMID:An essential role of the nuclear factor of activated T cells in the regulation of the expression of the cyclooxygenase-2 gene in human T lymphocytes. 1081 57


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