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)

Activation of either muscarinic cholinergic or thrombin receptors increases phosphoinositide turnover, Ca2+ mobilization, and redistribution of protein kinase C and induces rapid transient increases in c-fos mRNA and c-jun mRNA in 1321N1 cells. To determine whether the increases in c-fos and c-jun mRNA induced by carbachol and thrombin are sufficient to stimulate AP-1-mediated transactivation, 1321N1 cells were transfected with a reporter carrying two copies of the tetradecanoyl phorbol acetate response element and the firefly luciferase gene. Thrombin was significantly more effective than carbachol at stimulating AP-1-mediated transactivation. To identify the factors underlying the difference in AP-1 activity induced by carbachol and thrombin, members of the fos and jun families which encode components of AP-1 were examined. Carbachol and thrombin have similar effects on expression of c-fos, fosB, fra-2, junB, and junD, both acutely and over a 24-h time course. However, whereas carbachol leads only to transient induction of c-jun (maximal at 0.5 h), thrombin induces a biphasic increase in c-jun mRNA--an initial peak at 0.5 h and a second, more-prolonged increase at 12 h. Thrombin but not carbachol also induces a late increase in fra-1 mRNA, which peaks at 12 h. The secondary increase in c-jun mRNA is associated with marked increases in c-Jun protein levels and AP-1 DNA-binding activity. The late induction of c-jun and fra-1 mRNA can be prevented by adding the antagonist hirudin 30 min after thrombin, which results in loss of thrombin-stimulated increases in c-Jun protein, AP-1 DNA-binding activity, and AP-1-mediated transactivation. These findings suggest that rapid and transient conduction of c-fos and c-jun mRNA is insufficient to induce prominent changes in gene transcription, while the sustained increase in c-jun mRNA and perhaps the late induction of fra-1 mRNA are required for generation of AP-1 DNA-binding activity and transactivation through AP-1.
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PMID:Biphasic increase in c-jun mRNA is required for induction of AP-1-mediated gene transcription: differential effects of muscarinic and thrombin receptor activation. 132 61

Treatment of sensitive EL4 mouse thymoma cells with phorbol esters causes growth inhibition, adherence to substrate and production of several lymphokines including Interleukin 2. Resistant cells lack all of these responses. Since production of Interleukin 2 mRNA is dependent on protein synthesis, and the Interleukin 2 gene has a phorbol ester responsive element, we examined both cell lines for expression of the various Jun and Fos species which bind to this element. Phorbol ester induced c-fos, jun-B, and jun-D RNAs within 20 min in both cell lines. Fos-B was similarly induced in sensitive cells but induction was delayed and greatly enhanced in resistant cells. C-jun RNA induction was detected only in sensitive cells. Western analysis confirmed the induction of c-Jun and a Fos-related protein in sensitive cells only. Southern analysis indicated that both cell lines contain c-jun and fra-1 genes. These results suggest that defective induction of c-Jun and/or Fos-related proteins may contribute to the absence of phorbol ester-induced lymphokine production in resistant EL4 cells.
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PMID:Defective induction of Jun and Fos-related proteins in phorbol ester-resistant EL4 mouse thymoma cells. 171 62

We have investigated the role of the two AP-1 sites, located at approximately -150 and -180 bp relative to the transcription start site, in induction of the IL-2 promoter through the TCR/CD3 complex. We show that only the proximal (-150 bp) AP-1 site is functional in vitro, as judged by its ability to bind nuclear proteins from T cells stimulated with Ag or anti-CD3 epsilon. The inducible nuclear proteins binding to this site have the characteristics of AP-1, as judged by their kinetics of induction, the ability to compete and be competed efficiently by a metallothionein AP-1 site oligonucleotide, and their reaction with antibodies to Fos and Jun proteins. Mutations in the proximal AP-1 site greatly diminish or abrogate induction of the IL-2 promoter, indicating that the site is also functional in vivo. Although the distal (-180 bp) AP-1 site is incapable of direct binding to nuclear proteins from activated T cells, a mutation in this site diminishes IL-2 promoter induction, suggesting that this site may also be functional in vivo. Cotransfection of a 5' IL-2-chloramphenicol acetyltransferase plasmid with c-Fos and/or c-Jun enhances the induction of IL-2-chloramphenicol acetyltransferase activity, confirming that the IL-2 promoter contains a functional AP-1 site. Both AP-1 sites may be targets for c-Fos action, as inferred from the results of experiments in which c-Fos was cotransfected with internal deletion mutants of the IL-2 promoter lacking either AP-1 site. Northern analysis indicates that mRNAs for at least six members of the Fos/Jun family (c-fos, fosB, fra-1, c-jun, junB, and junD) are expressed in activated Ar-5 cells; thus the AP-1 sites of the IL-2 promoter may bind different dimeric Fos/Jun complexes at different times after T cell activation, perhaps mediating both positive and negative regulation of the IL-2 promoter.
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PMID:Analysis of the AP-1 sites in the IL-2 promoter. 173 37

fra-1 encodes a serum-inducible protein (Fra-1) that is antigenically related to Fos. We have characterized Fra-1 expression in serum-stimulated cells using antibodies raised against several regions of this protein. Fra-1, expressed transiently in COS cells or in serum-stimulated rat fibroblasts, undergoes extensive post-translational modification, primarily by phosphorylation of serine residues. It is present in both the nucleus and the cytoplasm and participates in a protein complex with Jun. Using proteins synthesized in reticulocyte lysates, we have shown that Fra-1, like Fos, binds to the AP-1 recognition element cooperatively with Jun. A truncated Fra-1 protein that contains the leucine zipper region but not an adjacent basic amino acid domain, complexes with Jun in vitro but fails to bind AP-1 oligonucleotides. These results demonstrate that Fra-1 contributes to the DNA-binding activity ascribed to transcription factor AP-1.
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PMID:The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes. 249 53

Primary mouse brain astrocytes were stimulated with phorbol 12-myristate 13-acetate (PMA), serum, forskolin and ionophore A23187, in order to investigate the effect of distinct signalling pathways on the expression of the nerve growth factor (NGF) gene and of proto-oncogenes encoding transcription factors of the Fos and Jun families. PMA, and to a lesser extent serum, induced a marked accumulation of NGF transcripts, in agreement with published observations [Brain Res., 570 (1992) 316-322]. The effect of A23187 was less pronounced and that of forskolin barely detectable. No relationship was observed between the expression of NGF gene and that of c-fos, fos-B, fra-1, jun-B proto-oncogenes. In contrast, changes in the levels of NGF transcripts were associated with corresponding modifications of the levels of c-jun transcripts, a fact which suggests that the c-Jun protein exerts a regulatory role on the expression of the NGF gene. In these cells, however, the regulation of NGF synthesis appears complex, since a pretreatment with forskolin or ionophore A23187 interfered with the promoting effect elicited by PMA or serum in inducing an early decline of the levels of NGF transcripts. This phenomenon was accompanied by a corresponding decrease in the amounts of cell-secreted NGF in cells treated with forskolin and PMA. A23187 had a much more striking effect on the production of mature NGF since this compound maintained the level of cell-secreted NGF to basal values, irrespective of the presence of PMA. A similar inhibitory effect was observed with thapsigargin, another compound able to increase the cytosolic concentration of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions between second messenger pathways influence NGF synthesis in mouse primary astrocytes. 774 33

Induction of phase 2 detoxification enzymes by phenolic antioxidants can account for prevention of tumor initiation but cannot explain why these compounds inhibit tumor promotion. Phase 2 genes are induced through an antioxidant response element (ARE). Although the ARE resembles an AP-1 binding site, we show that the major ARE binding and activating protein is not AP-1. Interestingly, AP-1 DNA binding activity was induced by the phenolic antioxidant tert-butylhydroquinone (BHQ), but the induction of AP-1 transcriptional activity by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by this compound. BHQ induced expression of c-jun, junB, fra-1, and fra-2, which encode AP-1 components, but was a poor inducer of c-fos and had no effect on fosB. Like c-Fos and FosB, the Fra proteins heterodimerize with Jun proteins to form stable AP-1 complexes. However, Fra-containing AP-1 complexes have low transactivation potential. Furthermore, Fra-1 repressed AP-1 activity induced by either TPA or expression of c-Jun and c-Fos. We therefore conclude that inhibitory AP-1 complexes composed of Jun-Fra heterodimers, induced by BHQ, antagonize the transcriptional effects of the tumor promoter TPA, which are mediated by Jun-Fos heterodimers. Since AP-1 is an important mediator of tumor promoter action, these findings may explain the anti-tumor-promoting activity of phenolic antioxidants.
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PMID:Antitumor promotion by phenolic antioxidants: inhibition of AP-1 activity through induction of Fra expression. 776 34

Constitutive expression of c-Fos, FosB, Fra-1, or c-Jun in rat fibroblasts leads to up-regulation of the immediate-early gene fra-1. Using the posttranslational FosER induction system, we demonstrate that this AP-1-dependent stimulation of fra-1 expression is rapid, depends on a functional DNA-binding domain of FosER, and is a general phenomenon observed in different cell types. In vitro mutagenesis and functional analysis of the rat fra-1 gene in stably transfected Rat-1A-FosER fibroblasts indicated that basal and AP-1-regulated expression of the fra-1 gene depends on regulatory sequences in the first intron which comprise a consensus AP-1 site and two AP-1-like elements. We have also investigated the transactivating and transforming properties of the Fra-1 protein to address the significance of fra-1 up-regulation. The entire Fra-1 protein fused to the DNA-binding domain of Ga14 is shown to lack any transactivation function, and yet it possesses oncogenic potential, as overexpression of Fra-1 in established rat fibroblasts results in anchorage-independent growth in vitro and tumor development in athymic mice, fra-1 is therefore not only induced by members of the Fos family, but its gene product may also contribute to cellular transformation by these proteins. Together, these data identify fra-1 as a unique member of the fos gene family which is under positive control by AP-1 activity.
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PMID:Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron. 779 82

The transcription factor AP-1 is thought to play an important role in the control of cell proliferation, but the function of individual Fos and Jun family members is a largely unresolved issue. To directly analyse the function of c-Fos in the control of cell proliferation we have used embryonic stem (ES) cells and fibroblasts lacking c-Fos due to a disruption of the c-fos gene by homologous recombination. Our results demonstrate that proliferation of normally cycling cells and reentry of quiescent cells into the cell cycle following serum stimulation are not c-Fos-dependent and occur with similar efficiency in c-fos-/- and control cells. We also show that there is no compensatory overexpression or activation of other known Fos or Jun family members. On the contrary, the c-fos-/- cells showed a reduced induction of fra-1 after serum stimulation which is in agreement with the previous identification of fra-1 as a c-Fos target gene. Comparison of the AP-1 binding and transactivation activities in c-fos-/- and +/+ fibroblasts by electrophoretic mobility antibody supershift and CAT assays suggests that c-Fos is not a major component of AP-1 complexes in these cells. It is therefore conceivable that the lack of any detectable effect on cell proliferation in c-fos-/- cells might be due to a functional redundancy among the different AP-1 family members.
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PMID:Cell proliferation and cell cycle progression are not impaired in fibroblasts and ES cells lacking c-Fos. 782 81

Previous studies have demonstrated that human HL-60 myeloid leukemia cells differentiate in response to phorbol esters. This event is associated with induction of the c-jun early response gene and appearance of a monocytic phenotype. The present studies have examined the effects of vincristine-selected, multidrug resistance on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced HL-60 cell differentiation. The results demonstrate that multidrug-resistant HL-60 cells, designated HL-60/vinc, fail to respond to TPA with an increase in c-jun transcripts or other phenotypic characteristics of monocytic differentiation. By contrast, treatment of HL-60/vinc cells with okadaic acid, an inhibitor of serine/threonine protein phosphatases, induces c-jun transcription, growth arrest, and expression of the c-fms gene. Studies were also performed with an HL-60/vinc revertant (HL-60/vinc/R) line that has regained partial sensitivity to vincristine. The finding that HL-60/vinc/R cells respond to TPA with induction of a monocytic phenotype, but not c-jun expression, suggests that c-jun induction is not obligatory for monocytic differentiation. Other studies further demonstrate that the jun-B and fra-1 genes are induced by TPA in both HL-60/vinc and HL-60/vinc/R cells, whereas c-fos expression is attenuated in the HL-60/vinc line. Since TPA activates protein kinase C (PKC), we examined translocation of PKC from the cytosol to the membrane fraction. Although HL-60 and HL-60/vinc/R cells demonstrated translocation of PKC activity, this subcellular redistribution was undetectable in HL-60/vinc cells. Activity of the mitogen-activated protein kinase family with associated phosphorylation of c-Jun Y-peptide was markedly diminished in TPA-treated HL-60/vinc cells, but not in response to okadaic acid. Taken together, these findings suggest that vincristine resistance confers insensitivity to TPA-induced differentiation and can include defects in PKC-mediated signaling events and induction of jun/fos early response gene expression.
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PMID:Defective translocation of protein kinase C in multidrug-resistant HL-60 cells confers a reversible loss of phorbol ester-induced monocytic differentiation. 838 57

The products of two proto-oncogenes, c-fos and c-jun, have been implicated in signal transduction pathways as regulators of gene expression. Both proto-oncogenes are members of gene families encoding closely related proteins that together make up transcription factor AP-1. The expression of members of this transcription factor has been associated with cellular pathways that result in both mitosis and differentiation. We have been studying the process of spermatogenesis, which is a complex, continual cycle of cell renewal, proliferation and differentiation. Using a seasonal breeder, the European red fox (Vulpes vulpes), as our model, we have examined the expression of five AP-1 family members (c-fos, fra-1, fra-2, c-jun and junB) with a view to elucidating their role in the regulation of spermatogenesis. Unique patterns of expression, falling into three broad categories, were observed for the five genes: (i) continuous expression throughout the spermatogenic cycle (c-fos); (ii) expression only at times corresponding to the onset and shutdown of spermatogenesis (fra-1, fra-2 and c-jun); and (iii) expression only at the onset of the cycle (junB). Furthermore, the proteins were expressed in both premeiotic and post-meiotic cell types, suggesting a role in haploid, as well as diploid, gene expression in this tissue. The data suggest distinct, although not necessarily unrelated, roles for the different components of transcription factor AP-1 in the regulation of spermatogenesis.
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PMID:Transcriptional regulation in the testis: a role for transcription factor AP-1 complexes at various stages of spermatogenesis. 842 49


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