UNIPROT:P05412 - FACTA Search

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

We have recently observed that protein kinase C (PKC) was involved in the regulation of the accumulation of mRNAs of the AP-1 components in cultured Abelson-transformed murine fetal-liver-derived mast cells stimulated by exocytotic stimuli. Here we analyzed the probable regulatory effect of PKC on the synthesis and DNA-binding activity of AP-1 complexes in immunologic stimulated mast cells. In this study we used the interleukin-3--dependent murine fetal-liver--derived mast cells that were not transformed by the Abelson oncogene. Study of PKC-depleted cells showed PKC dependency of c-fos mRNA accumulation and protein expression in IgE-Ag stimulated cells. In contrast, the c-jun mRNA accumulation was unaffected by PKC depletion, whereas its protein expression was dependent on this enzymatic activity. This suggests the involvement of PKC in the regulation of translation of c-Jun, a level of c-Jun regulation that was not previously described. The amount of AP-1 DNA-bound complex was also lowered in PKC-depleted cells. Therefore, PKC plays an important regulatory role in different stages of the signal transduction pathway because of IgE-Ag stimulation. Surprisingly, we have observed that although the amount of total synthesized c-Fos began to increase 15 minutes after immunologic stimulation, the amount of c-Fos associated with Juns did not increase, even after 45 minutes. This association was not affected by PKC. Using a Fos-interacting protein (FIP)-cDNA probe, an expression of 2.9 kb mRNA was detected in these cells. Furthermore, immunologic stimulation caused an increase in the amount of a Fos-containing protein complex that bound to an FIP-binding DNA oligonucleotide. Therefore, we propose that this protein complex that contains most of the immunologically induced c-Fos has an important role in IgE-Ag-stimulated signal transduction.
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PMID:Regulation of AP-1 expression and activity in antigen-stimulated mast cells: the role played by protein kinase C and the possible involvement of Fos interacting protein. 826 Jul 11

Colonization or emergence of microbial pathogens may result in tissue destruction by activation of one or more of five distinct host degradative pathways (matrix metalloproteinase pathway, plasminogen-dependent pathway, phagocytic pathway, PMN-serine proteinase pathway and osteoclastic bone resorption) or by direct cleavage of extracellular matrix constituents by microbial proteinases. Activation of endogenous destructive pathways may be mediated by immune responses resulting in expression of degradative cellular phenotypes among both immigrant and resident cell populations. In addition, expression of degradative phenotypes may be triggered by direct influences on host cells of microbial products (LPS, enzymes, toxins). A body of evidence suggests that each of these mechanisms involves local production of proinflammatory cytokines and growth factors. The matrix metalloproteinase pathway is centrally involved in dissolution of all unmineralized connective tissues and perhaps in resorption of bone as well. The matrix metalloproteinase family consists of nine or more genetically distinct Zn++ endopeptidases which collectively cleave all of the constituents of the extracellular matrix. Recent studies have uncovered many essential elements of a complex, but still incomplete, regulatory network that governs tissue destruction. Proinflammatory cytokines and growth factors induce signalling pathways several of which are dependent on protein kinase C and result in transient expression of the transcription factors c-jun and c-fos. Initiation of transcription of most matrix metalloproteinase genes requires binding of the transcription factor AP-1 (c-jun/c-fos) to a specific promoter sequence but attainment of maximal transcription rates is dependent on interaction with other promoter elements as well. Several matrix metalloproteinases have been detected in crevicular fluids and tissues of inflamed human gingiva as have the proinflammatory cytokines (IL-1 and TNF-alpha) which regulate their transcription. Although the mere presence of enzymes and cytokines does not necessarily impart function per se, these observations suggest that some level of spatial or temporal linkage exists between metalloproteinase/cytokine expression and gingival inflammation.
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PMID:Role of cytokines and inflammatory mediators in tissue destruction. 826 20

Treatment of human myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C (PKC), is associated with induction of monocytic differentiation. Since PKC can act immediately upstream to the cytoplasmic Raf-1 serine/threonine protein kinase, we studied activation of Raf-1 during induction of the differentiated monocytic phenotype. The results demonstrate that Raf-1 is activated during TPA-induced monocytic differentiation of HL-60 cells. In contrast, there was little effect of TPA on this kinase in an HL-60 variant, designated HL-525, which is resistant to TPA-induced differentiation. Treatment of both HL-60 and HL-525 cells with okadaic acid, an inhibitor of serine/threonine protein phosphatases 1 and 2A, was associated with Raf-1 activation and induction of the monocytic phenotype. Since Raf-1 can activate the mitogen-activated protein (MAP) kinases, we also studied the relationship between MAP kinase activation and monocytic differentiation. Treatment of HL-60, but not HL-525, cells with TPA was associated with increased MAP kinase activity as determined by phosphorylation of myelin basic protein and the c-Jun Y peptide. Okadaic acid-induced differentiation of both HL-60 and HL-525 cells was similarly accompanied by increases in MAP kinase activity. These findings indicated that activation of Raf-1/MAP kinase signaling is associated with induction of a differentiated monocytic phenotype and that okadaic acid bypasses a defect in this cascade in TPA-treated HL-525 cells. While recent studies have shown that HL-525 cells are deficient in PKC beta, the present results demonstrate that PKC beta expression is up-regulated in the HL-525 variant by treatment with retinoic acid. The results also demonstrate that retinoic acid-treated HL-525 cells respond to TPA with activation of Raf-1 and MAP kinase, as well as induction of monocytic differentiation. Taken together, the results indicate that activation of Raf-1/MAP kinase signaling is associated with monocytic differentiation and that stimulation of serine/threonine protein phosphorylation by TPA or okadaic acid is sufficient for reversal of the leukemic HL-60 phenotype.
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PMID:Activation of Raf-1 and mitogen-activated protein kinases during monocytic differentiation of human myeloid leukemia cells. 828 41

Bryostatin 1 and phorbol 12-myristate 13-acetate (PMA) are both potent activators of protein kinase C (PKC), although in many systems bryostatin 1 induces only a subset of the responses to PMA and blocks those which it does not induce. We report here that in NIH 3T3 fibroblasts PMA showed similar potencies for translocating PKC isozymes alpha, delta, and epsilon to the Triton X-100-soluble and -insoluble fractions and for the down-regulation of the three isozymes. Bryostatin 1 was slightly was more potent than PMA for down-regulating it. Bryostatin 1 was markedly more potent than PMA for translocating PKC delta but showed a biphasic dose-response curve for down-regulating this isozyme. 1-10 nM bryostatin 1 down-regulated PKC delta to a similar extent as PMA; lower (10-100 pM) or, unexpectedly, higher (100 nM to 1 microM) doses of bryostatin 1 caused either no or reduced down-regulation. Moreover, these high (100 nM to 1 microM) doses of bryostatin 1 inhibited the down-regulation of PKC delta by 1 microM PMA when coapplied. Bryostatin 1 caused translocation of PKC epsilon with slightly higher potency than PKC delta, but there was no protection of this isozyme at any of the doses examined. Bryostatin 1 induced a long-term increase in c-Jun level. The dose-response curve for bryostatin 1 was biphasic, with maximal induction at 1-10 nM bryostatin 1, coincident with the maximal down-regulation of PKC delta. We conclude that bryostatin 1 showed substantially different regulation for PKC alpha, PKC delta, and PKC epsilon, whereas PMA distinguished only weakly between these isozymes.
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PMID:Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. 829 65

We have previously shown that the tumor promoter okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, transcriptionally induces the urokinase-type plasminogen activator (uPA) gene in LLC-PK1 cells. This induction occurs independently of the protein kinase C- and cAMP-dependent signaling pathways. Here we show that a sequence located 2.0 kilobases upstream of the uPA gene, which resembles an AP-1-recognition sequence, mediates the action of OA. DNA-protein interaction studies, together with mRNA and protein analyses, indicate that c-Jun, but not c-Fos, is involved in OA-dependent uPA gene induction. The appearance of high levels of uPA mRNA and DNA binding activity of c-Jun to the AP-1-like site correspond to the appearance of c-Jun accumulation, suggesting that c-Jun accumulation is a critical event in OA-dependent uPA gene induction. c-Jun protein levels increase significantly between 100 and 160 min following OA treatment, whereas c-Jun translation increases only slightly in this time frame, suggesting that post-translation mechanisms are also involved in c-Jun accumulation. Pulse-chase analyses shows that OA specifically stabilizes c-Jun. We discuss our results with respect to the possibility that protein phosphatase 2A maintains c-Jun in its down-regulated state in LLC-PK1 cells.
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PMID:Okadaic acid-dependent induction of the urokinase-type plasminogen activator gene associated with stabilization and autoregulation of c-Jun. 830 Jun 23

Urokinase-type plasminogen activator (uPA) is an extracellular protease and expressed in various cells that exhibit dynamic changes in cell morphology, suggesting a link between cytoskeletal reorganization (CSR) and uPA expression. CSR can be induced by pharmacological agents, such as by colchicine for microtubule cytoskeleton and by cytochalasin for microfilament cytoskeleton. Using these agents, we previously showed that CSR induced the uPA gene in LLC-PK1 cells independently of the protein kinase C and cAMP-dependent protein kinase. Here we show that the induction of the uPA gene by CSR is mediated by the activation of c-Jun which interacts with an AP-1-like site located 2 kb upstream of the uPA gene. 12-O-tetradecanoylphorbol 13-acetate (TPA) induces the uPA gene through the same elements, but additionally utilizes an adjacent PEA3 element and induces c-fos. Furthermore, CSR induces a greater accumulation and a more pronounced phosphorylation of c-Jun than TPA induction. AP-1 is a positive regulator of growth and oncogenesis, and CSR is an integral part of these processes. Our results provide a view how CSR and AP-1 could be coupled in these processes. We also show that TPA and CSR act synergistically, suggesting a model where an initial activation signal could be amplified by CSR.
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PMID:Cytoskeletal reorganization and TPA differently modify AP-1 to induce the urokinase-type plasminogen activator gene in LLC-PK1 cells. 834 15

Treatment of porcine aortic endothelial cells with thrombin induced a time- and dose-dependent expression of preproendothelin-1 (PPET-1) mRNA. The thrombin-induced expression of PPET-1 mRNA was markedly inhibited by calphostin C, a specific inhibitor of protein kinase C, and phorbol 12-myristate 13-acetate (TPA) induced the expression of PPET-1 mRNA dose-dependently, but 4 alpha-phorbol 12, 13-didecanoate, an inactive enantiomer of phorbol ester, had no effect on the expression of PPET-1 mRNA. On the other hand, challenge of the endothelial cells with thrombin induced a marked and time-dependent increase in the binding activity of nuclear extract to the TPA-responsive element. Furthermore, thrombin elicits synthesis of c-Jun protein as well as triggering its dephosphorylation. From these results, it is concluded that thrombin-stimulated expression of PPET-1 mRNA in porcine aortic endothelial cells can be induced not only by c-Jun protein synthesis but also by initial dephosphorylation in response to activation of protein kinase C.
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PMID:The role of c-Jun protein in thrombin-stimulated expression of preproendothelin-1 mRNA in porcine aortic endothelial cells. 834 69

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 effect of lipopolysaccharide (LPS) on the activation of junB in a mouse macrophage cell line (J774) was investigated. J774 cells responded to either phorbol 12-myristate 13-acetate (PMA) or LPS by the transient increase in the expression levels of c-jun and junB mRNA, but not of junD mRNA. The prior depletion of protein kinase C from J774 cells blocked the action of PMA, but not of LPS, to activate junB. Pretreatment of cells with H-89 or H-7, but not with HA1004, W-7, ML-7, or tyrphostin 47, inhibited LPS-triggered junB activation. Treatment with forskolin also activated junB of J774 cells through an H-89- or H-7-sensitive pathway. Since cAMP-dependent protein kinase activity of J774 cells was inhibited by H-89, but not by H-7, LPS appears to activate junB through a cascade involving two steps, the one sensitive to H-89 and the other to H-7. Western blot analysis showed that LPS-triggered junB activation is accompanied by the increased expression of JunB proteins in the cell lysate as well as in the nuclear extract. JunB in nuclear fraction appears to specifically bind to 12-O-tetradecanoylphorbol-13-acetate-response element (TRE), since preincubation of nuclear extracts with anti-JunB serum reduced the amount of TRE-binding proteins and since the amount of JunB, but not of c-Jun or JunD, immunoprecipitated from TRE-cross-linked nuclear proteins increased in response to LPS. Thus, JunB may play an important role in LPS-triggered gene activation.
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PMID:Mechanism of lipopolysaccharide-triggered junB activation in a mouse macrophage-like cell line (J774). 839 62

Fluid shear stress induces a number of morphological and functional changes in vascular endothelium, including a rapid and significant down-regulation of endothelin 1 (ET-1) mRNA and peptide release in bovine aortic endothelial cells. We show here that both the cell alignment and ET-1 down-regulation depend on on-going protein synthesis, and that the latter is the result of a decrease in transcription, as shown by nuclear run-off assay, and not the result of changes in ET-1 mRNA half-life. The treatment of endothelial cells with either phorbol 12-myristate 13-acetate (100 nM) to activate protein kinase C (PKC) or forskolin (10 microM) to stimulate adenylate cyclase sharply decreased ET-1 mRNA. However, the phorbol-induced ET-1 decrease was, unlike the shear-induced down-regulation, independent of active protein synthesis. Physiological shear stress (20 dynes/cm2) did not significantly activate PKC, as assessed by PKC translocation and enzymatic activity assay and failed to increase intracellular cAMP content. Furthermore treatment with calphostin C (1 microM) did not prevent the shear-induced down-regulation of ET-1. DNA transfection experiments suggest that the shear stress-responsive element of the ET-1 gene is contained in the sequence between -2.5 kb and -2.9 kb of the 5'-upstream region. Neither the transcription factor AP-1 binding site nor the GATA-2-factor binding site, necessary for the basal level of transcription of ET-1 gene, is sufficient to confer shear-responsiveness to the reporter gene. These results suggest that shear stress regulates the transcription of the ET-1 gene via an upstream cis element by a distinct mechanism not dependent on the PKC or cAMP pathways.
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PMID:Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP. 839 84

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