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)

A large body of evidence suggests that inhibiting cyclooxygenase-2 (COX-2), the inducible form of COX, will be an important strategy for preventing cancer. In this study, we investigated whether resveratrol, a chemopreventive agent found in grapes, could suppress phorbol ester (PMA)-mediated induction of COX-2 in human mammary and oral epithelial cells. Treatment of cells with PMA induced COX-2 mRNA, COX-2 protein, and prostaglandin synthesis. These effects were inhibited by resveratrol. Nuclear runoffs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by resveratrol. Resveratrol inhibited PMA-mediated activation of protein kinase C and the induction of COX-2 promoter activity by c-Jun. Phorbol ester-mediated induction of AP-1 activity was blocked by resveratrol. These data are likely to be important for understanding the anticancer and anti-inflammatory properties of resveratrol.
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PMID:Resveratrol inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. 1066 96

Mitogen activated protein kinases (MAPK) are activated by a wide variety of signals leading to cell proliferation and differentiation in different cell types. With aging, there is a marked decrease in proliferation of T-lymphocytes in response to a variety of mitogens. Several age-related changes in the activation of MAPK pathways in T-lymphocytes activated via the T-cell receptor (TCR) have been described in different species. This way, some TCR proximal defects in tyrosine kinase activity have been delineated. In this study, we have used rat splenic lymphocytes to measure the effect of aging on the activation of two MAP kinase families: ERK and JNK. In order to bypass the receptor-proximal age-dependent defects previously described, we used phorbol ester (PMA) and Ca2+ ionophore (A23187) as co-mitogens. Our results demonstrate that splenic lymphocytes from old rats have a disturbance in the activation of the ERK and JNK MAPK signal transduction pathways, that are located downstream of the receptor-proximal events. At least part of the age-related defect leading to decreased ERK activity appears to be located upstream of ERK itself, since activation of MEK is also impaired. On the other hand, the observed defects in MAPK activation do result in decreased activation of downstream events, such as c-Jun phosphorylation. Thus, we conclude that aging of splenic lymphocytes results in a functional decline in signal transduction, and at least some of these defects are located downstream of the receptor-proximal events previously described by others. The impaired activity of these two MAP kinase pathways is likely to play a role in the diminished lymphoproliferation observed in old individuals.
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PMID:Impaired signal transduction in mitogen activated rat splenic lymphocytes during aging. 1070 57

C/EBPbeta is present in monocytes and macrophages, binds to the proximal region of the TNF-alpha promoter, and contributes to its regulation. This study was performed to characterize the ability of C/EBPbeta to regulate the TNF-alpha gene in myelomonocytic cells and primary macrophages. In transient transfection assays, overexpression of wild type C/EBPbeta resulted in a 3-4-fold activation of a 120 base pair TNF-alpha promoter-reporter construct, while overexpression of a dominant negative (DN) C/EBPbeta inhibited LPS-induced activation. In vitro monocyte-differentiated macrophages, infected with an adenoviral vector expressing the DN C/EBPbeta (AdDNC/EBPbeta) or the control Adbetagal, expressed their transgenes weakly, however expression was greatly enhanced in the presence of PMA. Infection with AdDNC/EBPbeta resulted in 60% suppression of LPS induced TNFalpha secretion compared to Adbetagal infection (P<0.001) in PMA-treated macrophages. Northern blot analysis demonstrated approximately a 40% reduction of the TNF-alpha mRNA in the presence of the DN C/EBPbeta, suggesting that the effect of the DN C/EBPbeta was at the transcriptional level. In contrast, AdDNC/EBPbeta infection did not result in inhibition of LPS-induced TNF-alpha secretion in the absence of PMA. Further, DN versions of both C/EBPbeta and c-Jun, but not NF-kappaB p65, suppressed PMA-induced TNF-alpha secretion in macrophages. These observations demonstrate that, C/EBPbeta and c-Jun contribute to the regulation of the TNF-alpha gene in normal macrophages following treatment with PMA.
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PMID:Regulation of TNF-alpha expression in normal macrophages: the role of C/EBPbeta. 1093 Feb 93

Urinary trypsin inhibitor (UTI), a Kunitz-type protease inhibitor, interacts with cells as a negative modulator of the invasive cells. Human ovarian cancer cell line, HRA, was treated with phorbol ester (PMA) to evaluate the effect on expression of urokinase-type plasminogen activator (uPA), since the action of uPA has been implicated in matrix degradation and cell motility. Preincubation of the cells with UTI reduced the ability of PMA to trigger the uPA expression at the gene level and at the protein level. UTI-induced down-regulation of PMA-stimulated uPA expression is irreversible and is independent of a cytotoxic effect. Down-regulation of uPA by UTI is mediated by its binding to the cells. We next asked whether the mechanism of inhibition of uPA expression by UTI was due to interference with the protein kinase C second messenger system. An assay for PKC activity demonstrated that UTI does not directly inhibit the catalytic activity of PKC and that PMA translocation of PKC from cytosol to membrane was inhibited by UTI, indicating that UTI inhibits the activation cascade of PKC. PMA could also activate a signaling pathway involving MEK1/ERK2/c-Jun-dependent uPA expression. When cells were preincubated with UTI, we could detect suppression of phosphorylation of these proteins. Like several types of PKC inhibitor, UTI inhibited PMA-stimulated invasiveness. We conclude that UTI markedly suppresses the cell motility possibly through negative regulation of PKC- and MEK/ERK/c-Jun-dependent mechanisms, and that these changes in behavior are correlated with a coordinated down-regulation of uPA which is likely to contribute to the cell invasion processes.
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PMID:Suppression of urokinase expression and invasiveness by urinary trypsin inhibitor is mediated through inhibition of protein kinase C- and MEK/ERK/c-Jun-dependent signaling pathways. 1105 91

In rat astrocytes, forskolin (FSK; 5 microM) and phorbol-12-myristic-13-acetate (PMA; 2.5 microM) increase the proenkephalin (proENK) mRNA level via different pathways. FSK-induced proENK mRNA expression is independent of protein de novo synthesis, and well correlated with CREB phosphorylation. This is in contrast to PMA-induced proENK mRNA expression that is dependent on protein de novo synthesis and is well correlated with the increase of AP-1 DNA binding activity rather than CREB phosphorylation. Differential regulation of AP-1 proteins by PMA and FSK was also observed. While c-Fos, Fra-2 and JunB were increased in response to either stimuli, only Fra-1, c-Jun and JunD were increased by PMA. The combined treatment with FSK and PMA additively increased the proENK mRNA level, which was correlated with AP-1 or ENKCRE-2 DNA binding activity, and CREB phosphorylation. Dexamethasone (DEX; 1 microM) further enhanced FSK- or PMA-induced proENK mRNA expression, which was not correlated with the activation of AP-1 expression and CREB phosphorylation, suggesting that synergistic interaction of glucocorticoid with PKA or PKC pathway for the regulation of proENK mRNA expression appears to be mediated by other pathways rather than CREB and AP-1 families.
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PMID:The differential molecular mechanisms underlying proenkephalin mRNA expression induced by forskolin and phorbol-12-myristic-13-acetate in primary cultured astrocytes. 1111 30

The human tissue-type plasminogen activator (t-PA) gene is regulated in a cell-type dependent manner. The t-PA gene is transcriptionally induced by the phorbol ester PMA in HeLa cells, but suppressed by PMA in HT-1080 cells. A cAMP responsive element (tPACRE) and a Sp-1 site located within the proximal t-PA gene promoter are functionally important in both cell systems. HeLa and HT-1080 cells contain a different repertoire of factors that associate with the tPACRE. In HT-1080 cells, CREB and c-Jun are the two major t-PACRE binding proteins identified, while activating transcription factor 2 (ATF-2) is a predominant t-PACRE binding protein in HeLa cells. To determine whether alteration in the distribution of tPACRE binding proteins would influence the differential regulation of the t-PA gene in these cells, the tPACRE binding profiles in these two cell systems were manipulated by over expressing ATF-2 in HT-1080 cells and CREB in HeLa cells. Supershift experiments confirmed that the overexpression of these factors resulted in binding to the tPACRE site. However, the presence of ATF-2 in HT-1080 cells did not affect either constitutive or PMA-mediated suppression of the endogenous t-PA gene. In contrast, enforced tPACRE-binding activity of CREB in HeLa cells significantly reduced the magnitude of PMA-mediated induction of t-PA mRNA in HeLa cells. These results indicate that the introduction of CREB into HeLa cells disrupts the regulation of the t-PA gene.
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PMID:Ectopic expression of the cAMP-responsive element binding protein inhibits phorbol ester-mediated induction of tissue-type plasminogen activator gene expression. 1117 65

We investigated whether peroxisome proliferator-activated receptor gamma (PPARgamma) ligands (ciglitazone, troglitazone, and 15-deoxy-Delta(12,14) prostaglandin J(2)) inhibited cyclooxygenase-2 (COX-2) induction in human epithelial cells. Ligands of PPARgamma inhibited phorbol ester (phorbol 12-myristate 13-acetate, PMA)-mediated induction of COX-2 and prostaglandin E(2) synthesis. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by PPARgamma ligands. PMA-mediated induction of COX-2 promoter activity was inhibited by PPARgamma ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPARgamma or a PPAR response element decoy oligonucleotide. The stimulatory effects of PMA were mediated by a cyclic AMP response element in the COX-2 promoter. Treatment with PMA increased activator protein-1 (AP-1) activity and the binding of c-Jun, c-Fos, and ATF-2 to the cyclic AMP response element, effects that were blocked by PPARgamma ligands. These findings raised questions about the mechanism underlying the anti-AP-1 effect of PPARgamma ligands. The induction of c-Jun by PMA was blocked by PPARgamma ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPARgamma ligands. When CREB-binding protein and c-Jun were overexpressed together, the ability of PPARgamma ligands to suppress PMA-mediated induction of COX-2 promoter activity was essentially abrogated. Bisphenol A diglycidyl ether, a compound that binds to PPARgamma but lacks the ability to activate transcription, also inhibited PMA-mediated induction of AP-1 activity and COX-2. Taken together, these findings are likely to be important for understanding the anti-inflammatory and anti-cancer properties of PPARgamma ligands.
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PMID:Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. 3190 Mar 73

Wogonin (Wog), an active component of Scutellaria baicalensis, has antioxidant and anti-inflammatory properties. Monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, plays a crucial role in case of early inflammatory responses, including atherosclerosis. In this study, we investigated the effect of Wog on phorbol ester (PMA)-induced MCP-1 expression in human umbilical vein endothelial cells (ECs). The MCP-1 mRNA levels and MCP-1 release in Wog-treated ECs were measured. Wog inhibited PMA-induced MCP-1 mRNA levels and MCP-1 secretion in a dose-dependent manner. The inhibition of MCP-1 induction by Wog is a transcriptional event, as shown by Wog's significant reduction of both MCP-1 promoter and 4x 12-O-tetradecanoylphorbol-13-acetate response element-luciferase reporter activities. By electrophoretic mobility assay, Wog significantly reduced the AP-1 binding activity induced by PMA. Furthermore, the PMA-induced extracellular signal-regulated kinase 1/2 and c-Jun amino-terminal kinase activities that contributed to AP-1 activity and MCP-1 gene induction were obviously attenuated after pretreating ECs with Wog. The decrease of MCP-1 secretion by Wog pretreatment led to a reduction of monocyte adhesion to ECs. Taken together, our results demonstrate that Wog inhibits MCP-1 induction in ECs; this inhibition is mediated by reducing AP-1 transcriptional activity via the attenuation of ERK1/2 and JNK signal transduction pathways. We conclude that Wog has the potential therapeutic development for use in anti-inflammatory and vascular disorders.
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PMID:Chinese herbal remedy wogonin inhibits monocyte chemotactic protein-1 gene expression in human endothelial cells. 1150 81

G(q)-coupled receptor agonists, such as endothelin-1 (ET-1) and phenylephrine (PE), initiate a hypertrophic response in cardiac myocytes that is characterized by increased expression of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC), skeletal muscle alpha-actin (SkalphaA) and ventricular myosin light chain-2 (vMLC2). ET-1 and PE activate both the extracellular signal-regulated kinases and c-Jun N-terminal kinases (JNKs) in cardiac myocytes, but the extent to which each contributes to the hypertrophic response is uncertain. Here we have used the JNK-binding domain of JNK-interacting protein 1 (JIP-1), a cytosolic scaffold protein that binds to JNK and inhibits its signalling when overexpressed, to assess the contribution of JNK activation to the hypertrophic response. Expression of JIP-1 inhibited the increase in ANF, beta-MHC, SkalphaA and vMLC2 reporter gene expression in response to ET-1 (by 45-86%) and PE (by 56-60%). However, activation of these reporter genes by PMA, which does not activate JNK significantly in myocytes, was much less affected by overexpression of JIP-1. JIP-1 also failed to inhibit reporter gene activation in response to constitutively active Ras or Raf, but attenuated reporter gene activation induced by a constitutively active mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1), an upstream kinase that preferentially activates JNKs, by 50%. Overexpression of JIP-1 also significantly reduced the increase in cell area in response to PE from 63% to 56%, but had no effect on the increase in cell size in response to ET-1 (38%). These results suggest that activation of the JNK pathway contributes to the transcriptional and morphological responses to G(q) receptor-coupled hypertrophic agonists.
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PMID:c-Jun N-terminal kinase-interacting protein 1 inhibits gene expression in response to hypertrophic agonists in neonatal rat ventricular myocytes. 1151 49

A novel polyunsaturated fatty acid (PUFA), beta-oxa 21:3n-3, containing an oxygen atom in the beta position, was chemically synthesized, and found to have more selective biological activity than the n-3 PUFA, docosahexaenoic acid (22:6n-3) on cells of the immune system. Although beta-oxa 21:3n-3 was very poor compared with 22:6n-3 at stimulating oxygen radical production in neutrophils, it was more effective at inhibiting human T lymphocyte proliferation (IC(50) of 1.9 vs 5.2 microM, respectively). beta-Oxa 21:3n-3 also inhibited the production of TNF-beta, IFN-gamma, and IL-2 by purified human T lymphocytes stimulated with PHA plus PMA, anti-CD3 plus anti-CD28 mAbs, or PMA plus A23187. Metabolism of beta-oxa 21:3n-3 via the cyclooxygenase and lipoxygenase pathways was not required for its inhibitory effects. Consistent with its ability to suppress T lymphocyte function, beta-oxa 21:3n-3 significantly inhibited the delayed-type hypersensitivity response and carrageenan-induced paw edema in mice. In T lymphocytes, beta-oxa 21:3n-3 inhibited the agonist-stimulated translocation of protein kinase C-betaI and -epsilon, but not -alpha, -betaII, or -theta to a particulate fraction, and also inhibited the activation of the extracellular signal-regulated protein kinase, but not c-Jun NH(2)-terminal kinase and p38. In contrast, 22:6n-3 had no effects on these protein kinase C isozymes. The increase in antiinflammatory activity and loss of unwanted bioaction through the generation of a novel synthetic 22:6n-3 analogue provides evidence for a novel strategy in the development of anti-inflammatory agents by chemically engineering PUFA.
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PMID:A novel long chain polyunsaturated fatty acid, beta-Oxa 21:3n-3, inhibits T lymphocyte proliferation, cytokine production, delayed-type hypersensitivity, and carrageenan-induced paw reaction and selectively targets intracellular signals. 1156 17


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