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 are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.
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PMID:Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. 750 41

A human cDNA clone for ERM, a member of the ets gene family, has been obtained by polymerase chain reaction with degenerate primers corresponding to highly conserved regions within an Ets DNA binding domain. ERM mRNA is expressed ubiquitously. The gene was mapped to chromosome 3q27. In in vivo transient-expression assays, ERM induced transcription more efficiently from a synthetic element containing both an ets-binding site (EBS) and a cyclic AMP response element (CRE) than from one containing an EBS alone. The activation of a synthetic EBS-CRE site by ERM was likely to involve a leucine zipper protein capable of dimerizing with CRE-BP1 leucine zipper. Indeed, ERM and c-Jun synergistically activated the EBS-CRE without making an apparent ternary complex. The synergy between c-Jun and ERM may be attributed to the enhancing effect of c-Jun on the transcription activity of ERM, because c-Jun increased ERM transcription activity by more than 20-fold in an assay system using a variety of fusion proteins between a Gal4 DNA-binding domain and a portion of ERM. This enhancing effect of c-Jun required the amino-terminal portion of ERM.
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PMID:ERM, a PEA3 subfamily of Ets transcription factors, can cooperate with c-Jun. 755 55

Haloperidol has been shown to induce rapid and transient expression of c-fos messenger RNA and Fos protein in striatal neurons via dopamine D2 receptors. Regulation of the c-fos gene by cyclic AMP and Ca2+ has been shown to be dependent on a DNA regulatory element within its promoter that binds the constitutively expressed transcription factor cyclic AMP response element binding protein. Cyclic AMP response element binding protein binds to an oligonucleotide containing the calcium/cyclic AMP response element of the c-fos promoter sequence in striatal cell extracts; the amount of binding is not regulated by haloperidol treatment. We have previously shown that haloperidol induces cyclic AMP response element binding protein phosphorylation in the striatum. Here we show by intrastriatal injection of antisense oligonucleotides that haloperidol-induced Fos expression is dependent on cyclic AMP response element binding protein. Intrastriatal injections of phosphorothioate oligonucleotides, in antisense orientation to cyclic AMP response element binding protein messenger RNA, reduce levels of cyclic AMP response element binding protein and completely prevent haloperidol-mediated induction of Fos. Oligonucleotides in sense orientation have no such effect. We observed a markedly different time course of the Fos protein inhibition by cyclic AMP response element binding protein antisense oligonucleotides compared to c-fos antisense oligonucleotides. This most likely reflects the different half-lives of c-fos and cyclic AMP response element binding protein messenger RNA and proteins. Neither cyclic AMP response element binding protein nor c-fos antisense oligonucleotide injection reduced c-Jun immunostaining in the striatum. We conclude that haloperidol induces Fos via transcription factor cyclic AMP response element binding protein.
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PMID:Haloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein. 761 61

Dimerization plays a pivotal role in modulating the activity of the c-Jun proto-oncogene product. Heterodimerization with activating transcription factor-2 (ATF-2) alters the DNA-binding specificity of c-Jun, allowing its targeting to several cAMP responsive element (CRE)-related sequences, which control a subset of AP-1-responsive genes. Here we show that a c-Jun/ATF-2 heterodimer binds to the AP-1 site (uPA 5'-TRE) essential for the activity of the human urokinase enhancer, conferring on this element several distinctive regulatory properties. The c-Jun/ATF-2 heterodimer was identified by binding competition assays, u.v. cross linking, and monospecific antibodies. In vitro binding studies revealed that the uPA 5'-TRE sequence is recognized by the cyclic AMP-unresponsive ATF-2 factor, but not by the cyclic AMP-inducible CREB. In addition, in vivo studies suggest that ATF-2 can mediate, at the same time, the activation of the c-Jun/ATF-2 site and the repression of the canonical collagenase AP-1 site. We report that heterodimerization with c-Fos does not increase the binding of c-Jun to the uPA 5'-TRE, in contrast to the increased binding at a consensus AP-1 site. Our data further suggest that c-Fos can act as a repressor of the c-Jun/ATF-2 binding site, revealing an important functional difference, with respect to canonical AP-1 elements.
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PMID:Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer. 762 51

We recently demonstrated that immortalized GT1-7 neurons co-express luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor and gonadotropin releasing hormone (GnRH) genes. Treatment of GT1-7 neurons with LH/hCG resulted in a transcriptional inhibition of GnRH gene. In the present study, we investigated the signaling and transacting factors involved in the action of hCG. Eight-bromo-cyclic AMP can mimic the down-regulating action of hCG on GnRH mRNA levels. H-89, a protein kinase (PK) A inhibitor, but not bisindolylmaleimide, a PKC inhibitor, blocked the down- regulating actions of hCG as well as of 8-bromocyclic AMP. Treatment with the PKA inhibitor alone modestly decreased GnRH mRNA levels suggesting that PKA signaling also controls the basal expression of the GnRH gene. The direct measurement of PK activities revealed that hCG treatment of GT1-7 neurons increased the PKA but not the PKC activity. New protein synthesis is required for the down-regulating action of hCG on GnRH mRNA levels. Since some of the new proteins could be nuclear transcription or transacting factors, we investigated the effects of hCG on cyclic AMP response element binding protein (CREB), c-Fos and c-Jun protein levels. Treatment of GT1-7 neurons with hCG resulted in an increase of 43 kDa phosphorylated CREB, 50 kDa c-Fos and 40 kDa c-Jun proteins compared to the corresponding controls. The kinetics of increases were different and in all cases the increases of the proteins preceded the decrease of GnRH mRNA levels. In summary, PKA signaling and transacting factors such as CREB, Fos and Jun are probably involved in transcriptional inhibition of GnRH gene by hCG in GT1-7 neurons.
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PMID:Signaling and transacting factors in the transcriptional inhibition of gonadotropin releasing hormone gene by human chorionic gonadotropin in immortalized hypothalamic GT1-7 neurons. 766 77

The large diurnal rhythm of circulating glucocorticoid levels was used to determine if physiological fluctuations of glucocorticoids were capable of modulating kainate-induced immediate early gene (IEG) activation, measured as AP-1 DNA binding activity, in rat brain since administered dexamethasone previously had been shown to be inhibitory. AP-1 activity in the cerebral cortex 1.5 h after kainate treatment measured at 08.00 h (4.9-fold control) was more than twice the stimulation obtained at 16.00 h (1.8-fold). These times of day are associated with reported low and high levels of circulating glucocorticoids at 08.00 and 16.00 h, respectively. To test if there was a causal relationship, kainate-induced AP-1 activity was measured at both times in adrenalectomized rats. Adrenalectomy abolished the attenuation of the response to kainate found in intact rats at 16.00 h, indicating that the diurnal fluctuations in circulating glucocorticoids contribute to modulation of IEG responses to kainate. Neither AP-1 activity in the hippocampus nor cyclic AMP response element activation in either brain region measured after kainate treatment was influenced by the time of day or by adrenalectomy. Immunoprecipitation of glucocorticoid receptors from cortical nuclear extracts co-precipitated c-Jun, indicating that the mechanism accounting for the suppression of AP-1 activity by glucocorticoids may involve direct interactions between activated glucocorticoid receptors and AP-1 constituent proteins. These results extend previous reports that administered glucocorticoids inhibit AP-1 activity by demonstrating that this occurs with endogenous glucocorticoids as a consequence of the circadian rhythm of circulating glucocorticoids and demonstrate that responses to kainate vary dependent upon the time of day.
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PMID:Diurnal variation in kainate-induced AP-1 activation in rat brain: influence of glucocorticoids. 772 18

Expression of the gene encoding neurotensin/neuromedin N (NT/N) is mostly limited to the brain and specialized enteroendocrine cells (N cells) of the distal small intestine. We have analyzed the NT/N DNA sequences upstream of the RNA start site that direct cell-specific expression using a novel human endocrine cell line, BON, that resembles intestinal N cells in several important aspects, including NT/N precursor protein processing, ratios of different NT/N mRNA forms, and high levels of constitutive expression of the NT/N gene. Transient transfection assays with plasmids with progressive 5' deletions of the rat NT/N promoter identified the proximal 216 bp of 5' flanking sequences as essential for high-level constitutive NT/N expression in BON cells. In addition, a detailed mutational analysis defined multiple regions within the proximal 216 bp that contribute to cell-specific NT/N expression. These elements include a proximal cyclic AMP response element (CRE)/AP-1-like motif (TGACATCA) that binds c-Jun, JunD, CRE-binding (CREB), and ATF proteins, a near-consensus glucocorticoid response element, and a distal consensus AP-1 site that binds c-Fos, Fra-1, and JunD. In addition, elements contained within two 21-bp imperfect direct repeats play an important role in NT/N expression in BON cells and may bind novel factors that act as positive regulators of NT/N expression. DNase I footprinting and gel shift analyses demonstrate that the sites identified by mutational analysis, and at least one additional site, specifically bind BON cell nuclear proteins in vitro. We speculate that a complex pattern of regulation requiring interaction between a proximal CRE/AP-1-like motif and other upstream control elements play an important role in the high-level constitutive expression of NT/N in the human endocrine cell line BON. In addition, the BON cell line provides a unique model to further characterize the factors regulating cell-specific NT/N expression and to better understand the mechanisms responsible for the terminal differentiation of the N-cell lineage in the gut.
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PMID:Characterization of promoter elements required for cell-specific expression of the neurotensin/neuromedin N gene in a human endocrine cell line. 779 94

Growth factors and cyclic AMP (cAMP) are known to activate distinct intracellular signaling pathways. Fibroblast growth factor (FGF) activates ras-dependent kinase cascades, resulting in the activation of MAP kinases, whereas cAMP activates protein kinase A. In this study, we report that growth factors and cAMP act synergistically to stimulate proenkephalin gene expression. Positive synergy between growth factor- and cAMP-activated signaling pathways on gene expression has not been previously reported, and we suggest that these synergistic interactions represent a useful model for analyzing interactions between these pathways. Transfection and mutational studies indicate that both FGF-dependent gene activation and cAMP-dependent gene activation require cAMP response element 2 (CRE-2), a previously characterized cAMP-dependent regulatory element. Furthermore, multiple copies of this element are sufficient to confer FGF regulation upon a minimal promoter, indicating that FGF and cAMP signaling converge upon transcription factors acting at CRE-2. Among many different ATF/AP-1 factors tested, two factors, ATF-3 and c-Jun, stimulate proenkephalin transcription in an FGF- or Ras-dependent fashion. Finally, we show that ATF-3 and c-Jun form heterodimeric complexes in SK-N-MC cells and that the levels of both proteins are increased in response to FGF but not cAMP. Together, these results indicate that growth factor- and cAMP-dependent signaling pathways converge at CRE-2 to synergistically stimulate gene expression and that ATF-3 and c-Jun regulate proenkephalin transcription in response to both growth factor- and cAMP-dependent intracellular signaling pathways.
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PMID:Fibroblast growth factor and cyclic AMP (cAMP) synergistically activate gene expression at a cAMP response element. 793 70

F9 teratocarcinoma is a useful model for studying early embryogenesis since these cells can differentiate into primitive or parietal endoderm under the influence of retinoic acid or retinoic acid and cyclic AMP, respectively. We have found that three isoforms of protein kinase C (PKC alpha, -beta, and -gamma) were expressed in undifferentiated stem cells. When the cells were treated with retinoic acid either alone or in the presence of cAMP for 120 h, PKC alpha mRNA and protein levels increased, whereas those of PKC beta and PKC gamma became undetectable. These changes began within 24 h of drug treatment and were complete by 48-72 h. In order to determine the functional significance of the induction of PKC alpha during F9 differentiation, we established two stable transfectants that overexpressed PKC alpha protein between 4- and 5-fold compared to wild type cells. Characterization of these cell lines revealed an altered pattern of expression of some of the markers of F9 differentiation. The clone that had the highest amount of PKC alpha protein constitutively expressed mRNA for type IV collagen and c-Jun, which are not normally expressed until 24-48 h of treatment with differentiation agents. In the other overexpressing clone, these markers were induced much faster than in wild type cells. The growth rate of both overexpressing clones was less than wild type cells, while the expression of the PKC beta protein in these clones was similar to the levels found in differentiated F9 cells. However, other markers of differentiation, including the cellular morphology and levels of pST6-135 and c-myc RNA, responded to agents identically in both wild type and PKC-alpha-overexpressing clones. Therefore, overexpression of PKC alpha is not sufficient to induce full differentiation of F9 cells. However, our data suggest that certain pathways that lead to the expression of differentiation-dependent genes are regulated by PKC alpha protein levels.
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PMID:Characterization of conventional protein kinase C (PKC) isotype expression during F9 teratocarcinoma differentiation. Overexpression of PKC alpha alters the expression of some differentiation-dependent genes. 796 96

Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (HTLV-I) Tax in human Jurkat T lymphocytes. This transactivation was further enhanced in Jurkat cells treated with concanavalin A, cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetate. Deletion and cis-element transfer analyses of the human proenkephalin promoter identified a cyclic AMP-responsive AP-1 element (-92 to -86) as both necessary and sufficient to confer Tax-dependent transactivation. Different AP-1 or cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) proteins which bind this element were expressed in murine teratocarcinoma F9 cells to identify those capable of mediating Tax-dependent transactivation of human proenkephalin gene transcription. Although CREB, c-Fos, c-Jun, and JunD did not have significant effects, JunB inhibited the Tax-dependent transactivation. In contrast, ATF3 dramatically induced Tax-dependent transactivation, which was further enhanced by protein kinase A. Electrophoretic mobility shift assays with recombinant fusion proteins expressed and purified from bacteria indicate that the DNA-binding activity of ATF3 is also dramatically enhanced by Tax. Chimeric fusion proteins consisting of the DNA-binding domain of the yeast transcription factor Gal4 and the amino-terminal domain (residues 1 to 66) of ATF3 were able to mediate Tax-dependent transactivation of a Gal4-responsive promoter, which suggests a direct involvement of this region of ATF3. Recombinant fusion proteins of glutathione S-transferase with either the amino- or carboxy-terminal (residues 139 to 181) domain of ATF3 were able to specifically interact with Tax. Furthermore, specific antisera directed against Tax coimmunoprecipitated ATF3 only in the presence of Tax.
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PMID:Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. 800 91


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