Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New data regarding signal transduction triggered by opioid ligands in immune cells are reviewed, and the signal transduction in neuronal cells is documented. Similar signaling pathways are induced by opioids in immune as well as neuronal cells. Opioids altered second messenger cAMP, intracellular calcium, and second messenger-induced kinases in immune cells. Met-enkephalin, preferentially delta-opioid, was bimodally regulated, while kappa-opioids inhibited these second messengers. delta-, kappa- and micro-opioids altered nitric oxide secretion, inducing cGMP as the second messenger in immune cells. Coupling of opioid agonists to opioid receptors activated mitogen-activated protein/extracellular signal-regulated protein kinases and various transcription factors in immune cells. Activator protein 1 (AP-1), c-fos, and nuclear factor-kappaB (NF-kappaB) are transcription factors shared by neuronal and immune cells. Delta-opioids activated AP-1, c-fos, activating transcription factor 2, Ikaros-1 and Ikaros-2 transcription factors in immune cells. Induction of kappa-opioid receptor gene by retinoic acid resulted in increased binding of Sp1 transcription factor to the promoter of the kappa-opioid receptor. Micro-opioids inhibited synthesis of common transcription factors AP-1, c-fos, NF-kappaB, and nuclear factor of activated T cells in activated or stimulated immune cells, whereas micro-opioids activated NF-kappaB, GATA-3, and Kruppel-like factor 7 transcription factors in non-stimulated immune cells.
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PMID:Signal transduction induced by opioids in immune cells: a review. 1661 31

The critical role of polyamines in cell growth has led to the development of a number of agents that interfere with polyamine metabolism including a novel class of polyamine analogues, oligoamines. Here we demonstrate that oligoamines specifically suppress the mRNA and protein expression of estrogen receptor alpha (ERalpha) and ERalpha target genes in ER-positive human breast cancer cell lines, whereas neither ERbeta nor other steroid hormonal receptors are affected by oligoamines. The constitutive expression of a cytomegalovirus promoter-driven exogenous ERalpha in ER-negative MDA-MB-231 human breast cancer cells was not altered by oligoamines, suggesting that oligoamines specifically suppress ERalpha transcription rather than affect mRNA or protein stability. Further analysis demonstrated that oligoamines disrupted the DNA binding activity of Sp1 transcription factor family members to an ERalpha minimal promoter element containing GC/CA-rich boxes. Treatment of MDA-MB-231 cells with the JNK-specific inhibitor SP600125 or expression of the c-Jun dominant negative inhibitor TAM67 blocked the oligoamine-activated JNK/c-Jun pathway and enhanced oligoamine-inhibited ERalpha expression, suggesting that AP-1 is a positive regulator of ERalpha expression and that oligoamine-activated JNK/AP-1 activity may antagonize the down-regulation of ERalpha induced by oligoamines. Taken together, these results suggest a novel antiestrogenic mechanism for specific polyamine analogues in human breast cancer cells.
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PMID:Polyamine analogues down-regulate estrogen receptor alpha expression in human breast cancer cells. 1667 12

Human peptidoglycan recognition protein 2 (PGLYRP2) is an N-acetylmuramoyl-L-alanine amidase that hydrolyzes bacterial peptidoglycan and is differentially expressed in the two major organs in the human body, liver and skin. PGLYRP2 has a high constitutive expression in the liver but is not expressed in healthy human skin. PGLYRP2 mRNA is also not expressed in cultured human keratinocytes but is highly induced upon exposure to bacteria. In this study we identified the transcription start site for pglyrp2 and demonstrated that the differential expression of PGLYRP2 in hepatocytes and keratinocytes is regulated by different transcription factors whose binding sequences are located in different regions of the pglyrp2 promoter. Induction of pglyrp2 in keratinocytes is regulated by sequences in the distal region of the promoter and requires transcription factors NF-kappaB and Sp1, whereas constitutive expression of pglyrp2 in a hepatocyte cell line is regulated by sequences in the proximal region of the promoter and requires transcription factors c-Jun and ATF2. Regulation of constitutive and inducible expression of pglyrp2 is important for systemic and local innate immune responses to bacterial infections.
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PMID:Differential expression of peptidoglycan recognition protein 2 in the skin and liver requires different transcription factors. 1671 90

Acting via the estrogen receptor (ER), estradiol exerts pleomorphic effects on the uterus, producing cyclical waves of cellular proliferation and differentiation in preparation for embryo implantation. In the classical pathway, the ER binds directly to an estrogen response element to activate or repress gene expression. However, emerging evidence supports the existence of nonclassical pathways in which the activated ER alters gene expression through protein-protein tethering with transcription factors such as c-Fos/c-Jun B (AP-1) and Sp1. In this report, we examined the relative roles of classical and nonclassical ER signaling in vivo by comparing the estrogen-dependent uterine response in mice that express wild-type ERalpha, a mutant ERalpha (E207A/G208A) that selectively lacks ERE binding, or ERalpha null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17beta-estradiol (E2). The uterine epithelial proliferative response to E2 and 4-hydroxytamoxifen was retained in the AA/-females, and uterine luminal epithelial height increased commensurate with the extent of ERalpha signaling. This proliferative response was confirmed by 5-bromo-2'-deoxyuridine incorporation. Microarray experiments identified cyclin-dependent kinase inhibitor 1A as a nonclassical pathway-responsive gene, and transient expression experiments using the cyclin-dependent kinase inhibitor 1A promoter confirmed transcriptional responses to the ERalpha (E207A/G208A) mutant. These results indicate that nonclassical ERalpha signaling is sufficient to restore luminal epithelial proliferation but not other estrogen-responsive events, such as fluid accumulation and hyperemia. We conclude that nonclassical pathway signaling via ERalpha plays a critical physiologic role in the uterine response to estrogen.
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PMID:Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor alpha binding to classical estrogen response elements. 1684 62

Overexpression of Cu/Zn superoxide dismutase 1 (SOD1) in monocytes blocks reactive oxygen species-induced inhibition of cell growth and apoptosis and renders cells resistant to the toxic effect of tumor necrosis factor (TNF)-alpha, suggesting that TNF-alpha represses the SOD1 gene in these cells. We herein show that TNF-alpha decreases SOD1 mRNA, protein, and promoter activity in U937 cells. Electrophoretic mobility-shift assays (EMSA) show that TNF-alpha decreased binding of three different complexes. Ectopic Sp1 overexpression markedly increased SOD1-basal promoter activity and partially antagonized the TNF-alpha inhibitory effect. In contrast, ectopic c-Jun overexpression mimics TNF-alpha inhibitory effects and antagonizes Sp1 stimulatory effects. In agreement with these findings, EMSA shows a TNF-alpha-induced increase in AP-1 and a decrease in Sp1 DNA binding. Disruption of the C/EBP site decreases, whereas mutation in the Sp1/Egr-1 site completely abolishes DNA-binding and promoter activity. A JNK inhibitor antagonized the negative effects of TNF-alpha on SOD1 promoter activity, suggesting that JNK signaling through c-Jun protein activation is critical for the TNF-alpha-dependent SOD1 repression. A greater understanding of the mechanisms of TNF-alpha-induced SOD1 repression could facilitate the design and development of novel therapeutic drugs for inflammatory conditions.
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PMID:Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway. 1689 91

The c-Jun/Sp1 interaction is essential for growth factor- and phorbol 12-myristate 13-acetate (PMA)-induced genes expression, including human 12(S)-lipoxygenase, keratin 16, cytosolic phospholipase A2, p21(WAF1/CIP1), and neuronal nicotinic acetylcholine receptor beta4. Here, we examined the mechanism underlying the PMA-induced regulation on the interaction between c-Jun and Sp1. We found that treatment of cells with PMA induced a dephosphorylation at the C terminus of c-Jun at Ser-243 and a concomitant inhibition of PP2B by using PP2B small interfering RNA, resulting in reduction of PMA-induced gene expression as well as the c-Jun/Sp1 interaction. The c-Jun mutant TAM-67-3A, which contains three substitute alanines at Thr-231, Ser-243, and Ser-249 compared with TAM-67, binds more efficaciously with Sp1 and is about twice as efficacious as TAM-67 in inhibiting the PMA-induced activation of the 12(S)-lipoxygenase promoter. Importantly, PP2B not only dephosphorylates the c-Jun at Ser-243 but also interacts with c-Jun in PMA-treated cells. PMA stimulates the association of the PP2B/c-Jun/Sp1 complex with the promoter. These findings indicate the dephosphorylation of c-Jun C terminus is required for the c-Jun/Sp1 interaction and reveal that PP2B plays an important role in regulating c-Jun/Sp1 interaction in PMA-induced gene expression.
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PMID:PP2B-mediated dephosphorylation of c-Jun C terminus regulates phorbol ester-induced c-Jun/Sp1 interaction in A431 cells. 1721 18

Vimentin exhibits a complex pattern of developmental and tissue-specific expression regulated by such growth factors as TGFbeta1, PDGF, FGF, EGF and cytokines. Vimentin is expressed in the more migratory, mesenchymal cell and its expression is often down-regulated to make way for tissue-specific intermediate filaments proteins such as desmin in muscle. Here, we suggest a mechanism to explain how TGFbeta1 contributes to the up-regulation of vimentin expression while blocking myogenesis. TGFbeta1 binds to serine/threonine kinase receptors resulting in the phosphorylation of Smad2 and Smad3, followed by formation of a heteromeric complex with Smad4. The translocation of this complex to the nucleus modulates transcription of selected genes such as vimentin. However, the vimentin gene lacks a consensus TGFbeta1 response element. By transient transfection analysis of vimentin's various promoter elements fused to the CAT reporter gene, we have determined that tandem AP-1 sites surrounded by GC-boxes are required for TGFbeta1 induction. Mutations within this region eliminated the ability of Smad3 to induce reporter gene expression. DNA precipitation and ChIP assays suggest that c-Jun, c-Fos, Smad3 and Sp1/Sp3 interact over this region, but this interaction changes during myogenesis with TGFbeta1 induction.
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PMID:TGFbeta1 regulation of vimentin gene expression during differentiation of the C2C12 skeletal myogenic cell line requires Smads, AP-1 and Sp1 family members. 1727 Feb 92

Peptidoglycan-activated gene expression is mediated through various transcription factors including CCAAT/enhancer-binding protein delta (C/EBPdelta). The purpose of the present study is to elucidate the mechanism of PGN-activated C/EBPdelta gene. PGN stimulated C/EBPdelta protein and mRNA expression in mouse macrophages RAW 264.7 cells. Analysis of C/EBPdelta promoter activity by luciferase reporter assay indicated that PGN-induced C/EBPdelta gene activation is partially mediated by the -345 to +24 bp of C/EBPdelta gene promoter. The in vitro protein-DNA binding assay showed that Sp1, c-Rel and c-Jun are the major protein binding to this PGN-response element of C/EBPdelta promoter, and the binding of c-Rel and c-Jun is increased after PGN treatment. All of these binding activities were abolished when Sp1-, NF-kappaB/APRE-, CRE-sites were mutated. Furthermore, analysis of this promoter region by site-directed mutants constructed in luciferase reporter vector indicated that two Sp1-sites, one NF-kappaB/APRE-site and one CRE-site are prominent for PGN-induced gene expression. In addition, when Sp1, c-Rel or c-Jun transcription factors were overexpressed in cells, all of them enhanced C/EBPdelta promoter activity. In summary, we suggest that Sp1, c-Rel and c-Jun transcription factors play important roles in activation of C/EBPdelta gene promoter under the stimulation of PGN. Given the importance of C/EBPdelta in inflammatory disease, these results reveal a clue as a potential therapeutic target for suppression of C/EBPdelta expression under PGN stimulation.
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PMID:Peptidoglycan enhances transcriptional expression of CCAAT/enhancer-binding protein delta gene in mouse macrophages. 1727

The glycosylphosphatidylinositol-anchored molecule C4.4A, which shares structural features with uPAR, is frequently expressed on carcinomas with upregulated expression during tumor progression. Moreover, rare expression on nontransformed epithelial cells is strongly increased during tissue remodeling, e.g., during wound healing. This strictly regulated expression prompted us to define transcriptional activation of the C4.4A gene. C4.4A transcription was analyzed in 2 syngenic rat tumor cell lines with low or high metastatic potential, respectively. Though genomic C4.4A DNA was present in both lines, C4.4A mRNA and transcription of a reporter construct containing the C4.4A promoter was only observed in the metastasizing subline. Deletions and point mutations in the C4.4A promoter-driven reporter construct revealed that activation of the TATA-less, GC-rich core promoter (-1 to -50 bp) does not suffice to initiate transcription that requires coactivation of a proximal response element (-71 to -88 bp) and can be further increased by more distal response elements (-89 to -133 bp). Mobility-shift and cotransfection studies showed that Sp3 binding enhances C4.4A transcription, whereas potential Sp1 binding sites were ineffective. C4.4A transcription essentially requires C/EBPbeta binding to a TRE/CCAAT composite element (-71 to -88 bp) as measured by ChIP assay. C4.4A transcription is strikingly enhanced by cotransfection with JunD or c-Jun, such that C4.4A is most strongly transcribed even in the C4.4A-negative tumor cell line after cotransfection with C/EBPbeta plus JunD or c-Jun. Thus, upregulation of C/EBPbeta during tumor progression and wound repair may well provide a sufficient trigger for transcription of the C4.4A gene.
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PMID:CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene. 1727 3

The urokinase receptor [urokinase plasminogen activator receptor (u-PAR)] promotes invasion and metastasis and is associated with poor patient survival. Recently, it was shown that Src induces u-PAR gene expression via Sp1 bound to the u-PAR promoter region -152/-135. However, u-PAR is regulated by diverse promoter motifs, among them being an essential activator protein-1 (AP-1) motif at -190/-171. Moreover, an in vivo relevance of Src-induced transcriptional regulators of u-PAR-mediated invasion, in particular intravasation, and a relevance in resected patient tumors have not sufficiently been shown. The present study was conducted (a) to investigate if, in particular, AP-1-related transcriptional mediators are required for Src-induced u-PAR-gene expression, (b) to show in vivo relevance of AP-1-mediated Src-induced u-PAR gene expression for invasion/intravasation and for resected tissues from colorectal cancer patients. Src stimulation of the u-PAR promoter deleted for AP-1 region -190/-171 was reduced as compared with the wild-type promoter in cultured colon cancer cells. In gelshifts/chromatin immunoprecipitation, Src-transfected SW480 cells showed an increase of phospho-c-Jun, in addition to JunD and Fra-1, bound to region -190/-171. Src-transfected cells showed a significant increase in c-Jun phosphorylated at Ser(73) and also Ser(63), which was paralleled by increased phospho-c-jun-NH(2)-kinase. Significant decreases of invasion/in vivo intravasation (chorionallantoic membrane model) were observed in Src-overexpressing cells treated with Src inhibitors, u-PAR-small interfering RNA, and dominant negative c-Jun (TAM67). In resected tissues of 20 colorectal cancer patients, a significant correlation between Src activity, AP-1 complexes bound to u-PAR region -190/-171, and advanced pN stage were observed. These data suggest that Src-induced u-PAR gene expression and invasion/intravasation in vivo is also mediated via AP-1 region -190/-171, especially bound with c-Jun phosphorylated at Ser(73/63), and that this pathway is biologically relevant for colorectal cancer patients, suggesting therapeutic potential.
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PMID:Src induces urokinase receptor gene expression and invasion/intravasation via activator protein-1/p-c-Jun in colorectal cancer. 1751 Mar 14


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