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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha) are known to induce production of reactive oxygen species (ROS), which have been suggested to act as second messengers. Here we demonstrate that ROS production by bovine chondrocytes upon cytokine stimulation induces c-jun expression. Since c-jun expression is regulated by its own gene product via phosphorylation by c-Jun NH2-terminal kinases (JNKs), we investigated if cytokines and ROS could modulate JNK activity in chondrocyte monolayer cultures. Treatment of bovine chondrocytes with both IL-1 and TNFalpha leads to rapid induction of JNK activity, stimulating JNK activity 7- and 20-fold, respectively. Importantly, the observation that antioxidant treatment antagonizes IL-1 and TNFalpha activation of JNK provides strong evidence that ROS can act as mediators of JNK activity. Moreover, potent activation of JNK is also observed by direct addition of the ROS hydrogen peroxide (H2O2) to the chondrocyte cultures. Nitric oxide (NO), a multifunctional ROS, also appears to simulate JNK, albeit to a lesser extent. These findings identify JNK as another molecular target for the actions of NO and H2O2. In addition, the inhibitory effect of diphenyleneiodonium on JNK activation implicates the involvement of flavonoid-containing enzymes in the ROS-mediated signaling process. Overstimulation of JNK activity by excessive production of ROS may, therefore, underlie pathological conditions such as arthritis and cancer.
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PMID:Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal kinases. 866 89

Ceramide, produced through either the induction of SM hydrolysis or synthesized de novo transduces signals mediating differentiation, growth, growth arrest, apoptosis, cytokine biosynthesis and secretion, and a variety of other cellular functions. A generalized ceramide signal transduction scheme is shown in Fig. 2 in which ceramide is generated through the activation of distinct SMases residing in separate subcellular compartments in response to specific stimuli. Clearly, specificity of cellular responses to ceramide depends upon many factors which include the nature of the stimulus, co-stimulatory signals and the cell type involved. Ceramide derived from neutral SMase activation is thought to be involved in modulating CAPK and MAP kinases, PLA2 (arachidonic acid mobilization), and CAPP while ceramide generated through acid SMase activation appears to be primarily involved in NF-kappa B activation. While there is no apparent cross-talk between these two ceramide-mediated signalling pathways, there is likely to be significant cross-talk between ceramide signalling and other signal transduction pathways (e.g., the PKC and MAP kinase pathways). Other downstream targets for ceramide action include Cox, IL-6 and IL-2 gene expression, PKC zeta, Vav, Rb, c-Myc, c-Fos, c-Jun and other transcriptional regulators. Many, if not all, of these ceramide-mediated signalling events have been identified in the various cells comprising the immune system and are integral to the optimal functioning of the immune system. Although the role of the SM pathway and the generation of ceramide in T and B lymphocytes have only recently been recognized, it is clear from these studies that signal transduction through SM and ceramide can strongly affect the immune response, either directly through cell signalling events, or indirectly through cytokines produced by other cells as the result of signalling through the SM pathway. An overview of the signalling mechanisms coupling ceramide to the modulation of the immune response is depicted in Fig. 3 and shows how ceramide may play pivotal roles in regulating a number of complex processes. The SM pathway represents a potentially valuable focal point for therapeutic control of immune responses, perhaps for either enhancement of the activity of T cells in the elimination of tumors, or the down-regulation of lymphocyte function in instances of autoimmune disease. The recent explosion of knowledge regarding ceramide signalling notwithstanding, a number of critical questions need to be answered before a comprehensive, mechanistic understanding can be formulated relative to the incredibly varied effects of ceramide on cell function. For example, (i) how is a structurally simple molecule like ceramide able to mediate so many different, and sometimes paradoxical, physiological responses ranging from cell proliferation and differentiation to inhibition of cell growth and apoptosis, (ii) what are the molecular identities and modes of activation of the various SMase isoforms, (iii) what determines the distribution of the unique isoforms of SMase in cells of different lineages or at different stages of differentiation, (iv) what is the relative contribution of ceramide generated through SM hydrolysis versus de novo synthesis, and (v) by what means does ceramide interact with specific intracellular targets? Although a number of ceramide-activatable kinases, phosphatases, and their protein substrates have been identified, a more extensive search for additional cellular targets will be indispensable in determining the phosphorylation cascades linking the activation of the SM pathway to the regulation of nuclear events. Clearly, cross-talk between ceramide-induced signal transduction cascades and other signalling pathways adds to the inherent difficulty in distinguishing the specific effects of complex, intertwining signalling pathways.
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PMID:Ceramide signalling and the immune response. 866 39

Photodynamic therapy (PDT) is currently under investigation in phase II and III clinical studies for the treatment of tumours in superficial localisations. Thus far, the underlying mechanisms of PDT regarding cellular responses and gene regulation are poorly understood. Photochemically generated singlet oxygen (1O2) is mainly responsible for cytotoxicity induced by PDT. If targeted cells are not disintegrated, photo-oxidative stress leads to transcription and translation of various stress response and cytokine genes. Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 and IL-6 are strongly induced by photodynamic treatment, supporting inflammatory action and immunological anti-tumour responses. To investigate the first steps of gene activation, this study focused on the proto-oncogenes c-jun and c-fos, both coding for the transcription factor activator protein 1 (AP-1), which was found to mediate IL-6 gene expression. We here determine the effects of photodynamic treatment on transcriptional regulation and DNA binding of transcription factor AP-1 in order to understand the modulation of subsequent regulatory steps. Photodynamic treatment of epithelial HeLa cells was performed by incubation with Photofrin and illumination with 630 nm laser light in vitro. Expression of the c-jun and c-fos genes was determined by way of Northern blot analysis, and DNA-binding activity of the transcription factor AP-1 was evaluated by electrophoretic mobility shift assay (EMSA). Photofrin-mediated photosensitisation of HeLa cells resulted in a rapid and dose-dependent induction of both genes but preferential expression of c-jun. Compared with the transient expression of c-jun and c-fos by phorbol ester stimulation, photodynamic treatment led to a prolonged activation pattern of both immediate early genes. Furthermore, mRNA stability studies revealed an increased half-life of c-jun and c-fos transcripts resulting from photosensitisation. Although mRNA accumulation after PDT was stronger and more prolonged compared with phorbol ester stimulation, with regard to AP-1 DNA-binding activity, phorbol ester was more efficient. Surprisingly, in addition to the activation of AP-1 DNA-binding via PDT, photodynamic treatment can decrease AP-1 DNA-binding of other strong inducers, such as the protein kinase C-mediated pathway of phorbol esters and the antioxidant pyrrolidine dithiocarbamate (PDTC). This study demonstrates a strong induction of c-jun and c-fos expression by PDT, with prolonged kinetics and mRNA stabilisation as compared with activation by phorbol esters. Interestingly, this observation is not coincident with an overinduction of AP-1 DNA-binding, hence suggesting that post-translational modifications are dominant regulatory mechanisms after PDT that tightly control AP-1 activity in the nucleus thus limiting the risk of deregulated oncogene expression.
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PMID:Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy. 867 54

Glomerular mesangial cells express matrix metalloproteinase-9 (MMP-9) in response to the proinflammatory cytokine interleukin-1 beta (IL-1 beta). To elucidate the signal transduction systems involved, we focused on the role of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), since the 5'-flanking region of MMP-9 gene contains binding sequences for these transacting molecules. In rat mesangial cells treated with an inhibitor of NF-kappa B, pyrrolidine dithiocarbamate, induction of MMP-9 by IL-1 beta was suppressed at both mRNA and protein levels. Mesangial cells stably transfected with a transdominant negative mutant of NF-kappa B also showed blunted induction of MMP-9. Transient transfection study with a kappa B reporter plasmid revealed that IL-1 beta indeed activated the kappa B site and that pyrrolidine dithiocarbamate abolished this activation. These results suggest that IL-1 beta induced MMP-9 via the stimulation of NF-kappa B pathway. to examine whether tyrosine kinase is involved in this pathway, mesangial cells were stimulated by IL-1 beta in the presence of a tyrosine kinase inhibitor genistein. This inhibitor dose dependently suppressed the expression of MMP-9, as well as the activation of the kappa B site by IL-1 beta, indicating the involvement of tyrosine kinase in the stimulation of NF-kappa B. Because mesangial cells stimulated by IL-1 beta transiently expressed c-fos and c-jun nRNAs prior to the expression of MMP-9, the role of these genes in mediating the IL-1 beta response was further examined. Transfection of mesangial cells with a c-jun antisense cDNA and treatment with a pharmacological inhibitor of c-Jun/ AP-1, curcumin, revealed that the induction of c-Jun/AP-1 is essential for the expression of MMP-9 by IL-1 beta. Although protein kinase C (PKC) is regarded as a potential inducer of AP-1, stimulation of mesangial cells with phorbol 12-myristate 13-acetate failed to induce MMP-9. Similarly, depletion of intracellular PKC did not obviously affect the induction of MMP-9 by IL-1 beta. These findings demonstrate that dual operation of tyrosine kinase-mediated NF-kappa B stimulation and c-Jun/AP-1 activation is essential to the induction of MMP-9 by IL-1 beta in cultured mesangial cells.
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PMID:Dual regulation of IL-1 beta-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kappa B and AP-1. 876 30

We have previously described a tumor necrosis factor alpha (TNF-alpha) response element, located between residues -188 and -140 of the human decorin promoter, that mediates the inhibitory effect of TNF-alpha on decorin gene expression (Mauviel, A., Santra, M., Chen, Y.-Q., Uitto, J., and Iozzo, R. V. (1995) J. Biol. Chem. 270, 11692-11700). In this report, we demonstrate that interleukin 1 (IL-1), a pleiotropic cytokine that shares a wide variety of biological properties with TNF-alpha, uses the same cis element to up-regulate decorin gene expression. Specifically, IL-1 enhances the expression of the human decorin gene, and this effect is mediated by activation of the corresponding promoter, as shown in transient cell transfection experiments using decorin promoter-chloramphenicol acetyl transferase reporter gene constructs. Additional transfection experiments with various 5'-deletion promoter-chloramphenicol acetyltransferase constructs demonstrate that both the inhibitory effect of TNF-alpha and the stimulatory effect of IL-1 are mediated by a 48-base pair segment of the promoter, between residues -188 and -140. This region, which contains a canonical AP-1 binding site, TGAGTCA, allows an antagonistic effect of these two cytokines on the decorin promoter activity. When cloned upstream of the thymidine kinase promoter, this promoter fragment requires the AP-1 sequence to be responsive to IL-1. Supershift assays with various AP-1 antibodies identified c-Jun, Jun-B, and Fra-1 as components of the complex binding to the decorin promoter. Overexpression of c-jun, an oncogene encoding the c-Jun/AP-1 transcription factor, reduces the basal activity of both decorin and -188/-140 thymidine kinase promoter constructs. In contrast, blockage of c-jun expression with an antisense c-jun construct potentiates the stimulatory effect of IL-1 and reverses the response to TNF-alpha. These data indicate that the region between residues -188 and -140 of the human decorin promoter functions as a bimodal regulatory element and allows transcriptional repression by c-Jun/AP-1 complexes.
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PMID:Identification of a bimodal regulatory element encompassing a canonical AP-1 binding site in the proximal promoter region of the human decorin gene. 879 56

Soluble staphylococcal peptidoglycan (sPGN) is an inducer of cytokine secretion and may activate macrophages through the CD14 lipopolysaccharide (LPS) receptor. To elucidate sPGN-activated signal transduction pathways, stimulation of mitogen-activated protein (MAP) kinases by sPGN was studied in mouse RAW264.7 macrophages. sPGN strongly activated extracellular signal-regulated kinase (ERK) 1 and ERK2, moderately activated c-Jun NH2 terminal kinase (JNK), and weakly activated p38 MAP kinase, in contrast to LPS, which strongly activated all of these kinases, and phorbol 12,13-dibutyrate (PDB), which strongly activated ERK1 and ERK2 but did not activate p38 or JNK. sPGN- and LPS-induced activation of ERK1 and ERK2, unlike PDB-induced activation, was sensitive to inhibition by herbimycin A and insensitive to inhibition by increased intracellular cAMP. These results demonstrate differential activation of MAP kinases by sPGN, similar but not identical activation of signal transduction pathways by sPGN and LPS, and different mechanisms of MAP kinase activation by bacterial stimulants and phorbol esters.
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PMID:Differential activation of extracellular signal-regulated kinase (ERK) 1, ERK2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases by bacterial peptidoglycan. 884 16

Coordination of the immune response to injury or disease in the brain is postulated to involve bi-directional discourse between the immune system and the central nervous system. This cross communication involves soluble mediators, including various growth factors, cytokines, and neuropeptides. In this report, we demonstrate that the supernatant from activated T-lymphocytes is able to induce the transcription of a potent cytokine, TGF-beta 2 in glial cells. The activating stimulus invokes signaling mechanisms distinct from known kinase or protease pathways. Activation of TGF-beta 2 transcription correlates with the loss of binding activity for an 80 kDA glial labile repressor protein, GLRP, to a responsive region within the TFG-beta 2 promoter. Although GLRP shares some characteristics with the inducible transcription factor AP-1, it appears to be distinct from known AP-1 family members. These data along with previous observations demonstrating the potent immunosuppressive activity of TGF-beta 2, support a model for a feedback mechanism between the activated T-lymphocytes and astrocytes via TGF-beta 2 to regulate the immune response.
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PMID:Soluble factors secreted by activated T-lymphocytes modulate the transcription of the immunosuppressive cytokine TGF-beta 2 in glial cells. 887 6

Glomerular mesangial cells express matrix metalloproteinase sromelysin in response to the proinflammatory cytokine IL-1 beta. The present study was conducted to identify intracellular machinery involved in this IL-1 action, especially focusing on the role of the TPA response element (TRE) located in the 5'-flanking region of the stromelysin gene. Using transient transfection with a pTRE-LacZ reporter plasmid, we detected no obvious up-regulation of TRE activity in rat mesangial cells following the IL-1 stimulation. However, the basal activity of TRE was found to be essential to the stromelysin induction, since (i) mesangial cells stably expressing a transdominant negative mutant of c-Jun, which effectively suppressed both basal and inducible TRE activity, exhibited the blunted expression of stromelysin in response to IL-1 beta, whereas (ii) transfection with a c-fos antisense gene, which suppressed only the inducible TRE activity, did not affect the stromelysin induction. To seek cooperative pathways required for the IL-1 action, we next focused on protein kinases, the potential regulators of the stromelysin gene. Stimulation of mesangial cells with a protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), induced the stromelysin transcript without affecting TRE activity. Depletion of intracellular PKC by high-dose PMA or inhibition of PKC activity with calphostin C suppressed the stromelysin induction by IL-1 beta, suggesting the crucial contribution of a PKC-mediated, but TRE-independent pathway. In contrast, either cAMP inducer forskolin or dibutyryl cAMP suppressed the IL-1-mediated stromelysin expression. An inhibitor of cAMP-dependent protein kinase A (PKA), HA1004, enhanced the IL-1 effect in a dose-dependent manner. Unexpectedly, the inhibitory action of PKA was not through cAMP response element (CRE) but through TRE, because (i) activation of CRE was not induced by IL-1 beta, and (ii) cAMP-mediated activation of PKA suppressed the basal TRE activity. These findings elucidated the unique, binary regulation of stromelysin by IL-1 beta; that is, IL-1 up-regulated the transcript via the PKC-dependent pathway under the cooperation with constitutively active TRE, and this stimulatory effect was in part counterbalanced by the IL-1-inducible PKA which down-regulated the basal TRE activity.
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PMID:Opposite, binary regulatory pathways involved in IL-1-mediated stromelysin gene expression in rat mesangial cells. 887 64

Stimulation of HEL 299 cells with tumor necrosis factor alpha (TNF-alpha) or interleukin 1beta (IL-1beta) had no effect on M2 muscarinic receptor expression. However, the combination of these two cytokines markedly down-regulated muscarinic M2 receptor protein and mRNA expression and uncoupled M2 receptors from adenylyl cyclase. There was no effect of TNF-alpha and IL-1beta on the m2 muscarinic receptor mRNA stability, and nuclear run-on assays showed reduced m2 receptor gene transcription. Sequential cytokine addition suggests that the synergy involves postreceptor events. Although the cAMP-dependent protein kinase inhibitor H8 provided a significant protection against receptor down-regulation, the protein kinase C inhibitor GF109203X had no effect. The ceramide analog C2-ceramide (N-acetylsphingosine) was without effect on m2 receptor expression. However, a strong synergistic effect was demonstrated when cells were treated with the combination of C2-ceramide and TNF-alpha or IL-1beta. TNF-alpha and/or IL-1beta combination also activated the 46- and 55-kDa c-Jun NH2-terminal protein kinases and to a lesser extent p42 and p44 mitogen-activated protein kinase isoforms. Cycloheximide abolished the TNF-alpha and IL-1beta effect, suggesting that de novo protein synthesis is required for receptor down-regulation. These results suggest that the TNF-alpha and IL-1beta synergize to induce transcriptional down-regulation of the M2 muscarinic receptor, which seems to be mediated through activation of both ceramide and cAMP-dependent protein kinase pathways. Furthermore, these results suggest that M2 receptor expression is under the control of a cytokine network.
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PMID:Synergy between tumor necrosis factor alpha and interleukin 1beta in inducing transcriptional down-regulation of muscarinic M2 receptor gene expression. Involvement of protein kinase A and ceramide pathways. 895 85

Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNF-alpha). Moreover, TNF-alpha-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.
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PMID:Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. 897 1


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