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)

Glucocorticosteroids have a wide variety of effects which result in the long-term dampening of inflammatory responses. An important site of steroid action may be on the control of the activator protein-1 (AP-1) binding to deoxyribonucleic acid (DNA). AP-1 is a proinflammatory transcription factor composed of a heterodimer of Fos and Jun proto-oncogenes, which can be induced by phorbol esters and various cytokines. We have examined the hypothesis that dexamethasone may inhibit inflammation via an effect on AP-1 activation in human lung tissue. The effect of dexamethasone on the phorbol ester and cytokine activation of AP-1 and its monomers was examined in human lung tissue obtained from transplantation donors. AP-1 activation was measured by its ability to bind DNA, its localization in the nucleus by Western blotting, and the levels of fos and jun messenger ribonucleic acids (mRNAs) using Northern blotting. The phorbol ester, phorbol myristate acetate (PMA), caused a significant 2-3 fold increase in AP-1 DNA binding, which was sustained for 24 h and completely attenuated by co-incubation with dexamethasone. Dexamethasone alone caused a 40% decrease in AP-1 DNA binding. Dexamethasone modulated the expression of both c-jun and c-fos mRNA and produced long-term (24 h) 40% reduction in both mRNAs when compared to control tissues. PMA induced a rapid and prolonged increase in c-Fos and c-Jun nuclear localization, which was not attenuated by co-incubation with dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung. 771 92

The goal of this investigation was to determine if administration of the synthetic glucocorticoid dexamethasone modulates rat brain AP-1 DNA binding activity. Treatment with the selective excitatory amino acid agonist kainate was used to activate AP-1 formation. Kainate (12 mg/kg) administration induced a biphasic activation of AP-1 in rat cerebral cortex and hippocampus with maximal levels observed at 1.5 h and 4.5 h and lower levels at 3 h and 6 h. Kainate also induced biphasic increases in the concentrations of some of the AP-1 constituent proteins (immediate early gene protein products), with initial increases of c-Jun, Fos, and Jun B occurring at 1.5 h and secondary larger increases at 4.5 h, but the level of Jun D was not altered by kainate treatment. Pretreatment with dexamethasone (1 mg/kg) reduced AP-1 activity at both 1.5 h and 4.5 h after kainate administration in both brain regions. Dexamethasone pretreatment did not modify the concentrations of the AP-1 constituent proteins obtained after kainate administration except for a reduction of Jun B levels 1.5 h after kainate. These results demonstrate that elevated glucocorticoid levels reduce the stimulation by kainate of AP-1 activity in rat cortex and hippocampus without causing corresponding decreases in the levels of immediate early gene proteins. Binding of the activated glucocorticoid receptor to c-Jun or Fos is likely to contribute to the decreased AP-1 DNA binding activity following dexamethasone treatment.
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PMID:Dexamethasone attenuates kainate-induced AP-1 activation in rat brain. 796 67

Expression of the protooncogene c-jun is induced in the uteri of ovariectomized rats in response to treatment with 17 beta-estradiol (E2-17 beta). E2 also specifically induces the uterine expression of jun-B-encoding mRNA. Medroxyprogesterone acetate and testosterone propionate treatment had no effect on the expression of c-jun- and jun-B-encoding mRNAs. Dexamethasone treatment, however, induced expression of c-jun mRNA, although less than that observed in response to E2. Cycloheximide treatment failed to block the E2-induced expression of c-jun and jun-B mRNAs, indicating that these were immediate early responses. E2-16 alpha, a short-acting estrogen, also induced c-jun and jun-B mRNA expression. The expression of c-Jun protein was examined by immunohistological methods and detected in all uterine cell types in response to treatment with estrogen. The Jun-B protein, however, was localized in uterine epithelial cells. The results of these experiments suggest that the cell type-specific expression of members of the jun family of protooncogenes may be an important regulatory event in the response of the uterus to estrogen.
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PMID:Estrogen induces expression of c-jun and jun-B protooncogenes in specific rat uterine cells. 831 68

Glutathione (GSH) is an important physiological antioxidant in lung epithelial cells and lung lining fluid. We studied the regulation of GSH synthesis in response to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the anti-inflammatory agent dexamethasone in human alveolar epithelial cells (A549). TNF-alpha (10 ng/ml) exposure increased GSH levels, concomitant with a significant increase in gamma-glutamylcysteine synthetase (gamma-GCS) activity and the expression of gamma-GCS heavy subunit (gamma-GCS-HS) mRNA at 24 h. Treatment with TNF-alpha also increased chloramphenicol acetyltransferase (CAT) activity of a gamma-GCS-HS 5'-flanking region reporter construct, transfected into alveolar epithelial cells. Mutation of the putative proximal AP-1-binding site (-269 to -263 base pairs), abolished TNF-alpha-mediated activation of the promoter. Gel shift and supershift analysis showed that TNF-alpha increased AP-1 DNA binding which was predominantly formed by dimers of c-Jun. Dexamethasone (3 microM) produced a significant decrease in the levels of GSH, decreased gamma-GCS activity and gamma-GCS-HS mRNA expression at 24 h. The increase in GSH levels, gamma-GCS-HS mRNA, gamma-GCS-HS promoter activity, and AP-1 DNA binding produced by TNF-alpha were abrogated by co-treating the cells with dexamethasone. Thus these data demonstrate that TNF-alpha and dexamethasone modulate GSH levels and gamma-GCS-HS mRNA expression by their effects on AP-1 (c-Jun homodimer). These data have implications for the oxidant/antioxidant balance in inflammatory lung diseases.
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PMID:Molecular mechanism of the regulation of glutathione synthesis by tumor necrosis factor-alpha and dexamethasone in human alveolar epithelial cells. 998 57

Glucocorticoid drugs suppress tumor necrosis factor-alpha (TNF-alpha) synthesis by activated monocyte/macrophages, contributing to an anti-inflammatory action in vivo. In lipopolysaccharide (LPS)-activated human monocytic THP-1 cells, glucocorticoids acted primarily on the TNF-alpha promoter to suppress a burst of transcriptional activity that occurred between 90 min and 3 h after LPS exposure. LPS increased nuclear c-Jun/ATF-2, NF-kappaB(1)/Rel-A, and Rel-A/C-Rel transcription factor complexes, which bound specifically to oligonucleotide sequences from the -106 to -88 base pair (bp) region of the promoter. The glucocorticoid, dexamethasone, suppressed nuclear binding activity of these complexes prior to and during the critical phase of TNF-alpha transcription. Site-directed mutagenesis in TNF-alpha promoter-luciferase reporter constructs showed that the adjacent c-Jun/ATF-2 (-106 to -99 bp) and NF-kappaB (-97 to -88 bp) binding sites each contributed to the LPS-stimulated expression. Mutating both sites largely prevented dexamethasone from suppressing TNF-alpha promoter-luciferase reporters. LPS exposure also increased nuclear Egr-1 and PU.1 abundance. The Egr-1/Sp1 (-172 to -161 bp) binding sites and the PU.1-binding Ets site (-116 to -110 bp) each contributed to the LPS-stimulated expression but not to glucocorticoid response. Dexamethasone suppressed the abundance of the c-Fos/c-Jun complex in THP-1 cell nuclei, but there was no direct evidence for c-Fos/c-Jun transactivation through sites in the -172 to -52 bp region. Small contributions to glucocorticoid response were attributable to promoter sequences outside the -172 to -88 bp region and to sequences in the TNF-alpha 3'-untranslated region. We conclude that glucocorticoids suppress LPS-stimulated secretion of TNF-alpha from human monocytic cells largely through antagonizing transactivation by c-Jun/ATF-2 and NF-kappaB complexes at binding sites in the -106 to -88 bp region of the TNF-alpha promoter.
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PMID:Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter. 1074 79

The immunosuppressive and antiinflammatory actions of glucocorticoid hormones are mediated by their transrepression of activating protein-1 (AP-1) and nuclear factor-kappa B (NFkappaB) transcription factors. Inhibition of the c-Jun NH(2)-terminal kinase (JNK) signaling pathway, the main mediator of AP-1 activation, has been described in extracts of hormone-treated cells. Here, we show by confocal laser microscopy, enzymatic assays, and immunoblotting that the synthetic glucocorticoid dexamethasone inhibited tumor necrosis factor alpha (TNF-alpha)-induced phosphorylation and activation of JNK in the cytoplasm and nucleus of intact HeLa cells. As a result, c-Jun NH(2)-terminal domain phosphorylation and induction were impaired. Dexamethasone did not block the TNF-alpha-induced JNK nuclear translocation, but rather induced, per se, nuclear accumulation of the enzyme. Consistently with previous findings, a glucocorticoid receptor mutant (GRdim), which is deficient in dimerization, DNA binding, and transactivation, but retains AP-1 transrepressing activity, was as efficient as wild-type GR in mediating the same effects of dexamethasone on JNK in transfected Cos-7 cells. Our results show that glucocorticoids antagonize the TNF-alpha-induced activation of AP-1 by causing the accumulation of inactive JNK without affecting its subcellular distribution.
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PMID:Glucocorticoids antagonize AP-1 by inhibiting the Activation/phosphorylation of JNK without affecting its subcellular distribution. 1097 6

The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox-sensitive transcription factors such as nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), which regulate the genes for proinflammatory mediators and protective antioxidant genes. GSH, a ubiquitous tripeptide thiol, is a vital intra- and extracellular protective antioxidant against oxidative stress, which plays a key role in the control of proinflammatory processes in the lungs. The rate-limiting enzyme in GSH synthesis is gamma-glutamylcysteine synthetase (gamma-GCS), which consists of a catalytic heavy and a regulatory light subunit. The promoter regions of the human gamma-GCS subunits contain AP-1, NF-kappa B, and antioxidant response elements and are regulated by oxidants, growth factors, inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), and anti-inflammatory agent (dexamethasone) in lung cells. TNF-alpha depletes intracellular GSH, concomitant with an increase in oxidised glutathione levels in alveolar epithelial cells. TNF-alpha also induces the activation of NF-kappa B and AP-1 and the subsequent increase in gamma-GCS heavy subunit transcription in these cells. Dexamethasone depleted both basal and TNF-alpha-stimulated GSH levels by down-regulating the gamma-GCS-heavy subunit transcription via a mechanism involving AP-1 (c-Jun). The existence of this fine tuning between the redox GSH levels and the activation of transcription factors may determine the balance of transcription for proinflammatory and antioxidant gamma-GCS genes in inflammation. More studies are required to understand the signalling mechanism of the redox regulation of NF-kappa B and AP-1 and gene transcription in inflammation. This could lead to the development of therapeutic strategies based on the pharmacological manipulation of the production of this important antioxidant in inflammation.
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PMID:Regulation of nuclear factor-kappa B, activator protein-1, and glutathione levels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells. 1100 40

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 antigen stimulation of RBL-2H3 cells induced interleukin 13 (IL-13) production, which was inhibited by the steroidal anti-inflammatory drug dexamethasone and by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Dexamethasone did not inhibit the antigen-induced phosphorylation of JNK but inhibited that of c-Jun. In a cell-free system, the phosphorylation of glutathione S-transferase-fused c-Jun by recombinant JNK was not inhibited by dexamethasone but was inhibited by the addition of recombinant glucocorticoid receptor (GR). These findings suggest that the inhibition of antigen-induced IL-13 production by dexamethasone is due to the GR-mediated inhibition of c-Jun phosphorylation induced by JNK.
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PMID:Inhibition by dexamethasone of interleukin 13 production via glucocorticoid receptor-mediated inhibition of c-Jun phosphorylation. 1462 17

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
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PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6


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