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)

Oncogenic Ras appears to act via protein kinase C (PKC)-dependent and PKC-independent pathways. In several systems, oncogenic Ras cooperates with c-Jun to activate gene transcription from promoters containing an AP-1 site by augmenting phosphorylation of the transcriptional activation domain of c-Jun. We have previously shown that oncogenic valine 12 Ras and PKA each separately activate the rat PRL (rPRL) promoter but together are mutually antagonistic. The goal of this study was to determine whether oncogenic Ras acts through PKC and c-Jun to activate transcription of an rPRL-luciferase reporter construct transiently transfected into GH4 rat pituitary cells. Our results show that phorbol 12-myristate 13-acetate (TPA) activates rPRL promoter activity through PKC, and that TPA activation of PKC diminishes the Ras response in a dose-dependent manner. Additionally, inhibition of PKC with staurosporine does not block the oncogenic Ras effect. Similarly, rPRL promoter activity in GH4 cells expressing oncogenic Ras fails to respond to TPA activation of PKC. Finally, cotransfection of a c-Jun expression vector results in inhibition of basal, TPA, and oncogenic Ras-stimulated activity of the rPRL promoter. Thus, we show that the mechanism of Ras signaling does not involve PKC, and that PKC does not signal via Ras. Taken together, these results verify that the Ras and PKC signaling pathways are separate and mutually antagonistic, and that c-Jun is not the nuclear mediator of either the Ras or PKC signal. These findings emphasize the possibility that the roles and/or functions of specific components in signaling pathways may be different in distinct cell types.
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PMID:The Ras and protein kinase C signaling pathways are functionally antagonistic in GH4 neuroendocrine cells. 841 16

The hepatitis B virus (HBV) transactivator protein HBx is enigmatic in that it stimulates a striking variety of promoters which do not share a common cis-regulatory element. As it does not bind to DNA, it has been speculated that HBx acts indirectly through cellular pathways. Under certain conditions HBx can have an oncogenic potential, which may be relevant for HBV-associated liver carcinogenesis, but until now the mechanism for transactivation and cell transformation by HBx was unclear. We report here that HBx uses a complex signal transduction pathway for transactivation. An increase in the endogenous protein kinase C (PKC) activator sn-1,2-diacylglycerol and the subsequent activation of PKC give rise to activation of the transcription factor AP-1 (Jun-Fos). As a result, HBx transactivates through binding sites for AP-1 and other PKC-dependent transcription factors (AP-2, NF-kappa B), thereby explaining the as-yet incomprehensible variety of HBx-inducible genes. As the PKC signal cascade also mediates cell transformation by tumour-promoting agents, the mechanism presented here might account for the oncogenic potential of HBx.
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PMID:Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. 844 61

The promoter regions of several radiation-inducible genes contain AP-1 cis-acting regulatory elements that are dependent upon protein kinase C signaling. We analyzed nuclear protein from irradiated human tumor cell lines for binding to the AP-1 consensus sequence. The increase in nuclear protein binding following irradiation was specific for the AP-1 sequence and was reduced by antibodies to c-Jun and c-Fos. The AP-1 DNA binding sequence was found to regulate transcription in irradiated cells and mutation of the AP-1 site within the c-jun promoter abolished transcriptional induction by radiation. The gene encoding the chimeric transcription factor Gal4-Jun5-253, which includes the DNA binding region of Gal4 and the transcriptional regulatory region of c-Jun, was cotransfected with the reporter plasmid with Gal4 binding sequences (G5B-CAT). Transfection of RIT-3 and HeLa cells revealed that the regulatory region of Jun was sufficient to activate transcription following irradiation. Conversely, Hep G2 cells, which do not contain the cell type-specific Jun repressor, were not responsive to radiation-induced Jun activation. The c-Jun repressor was found to regulate Jun activation by experiments using the expression vector CMV-jun, which competes for Jun inhibitor and eliminates radiation-induction of Jun. We propose transcription factor dissociation from inhibitor proteins may participate in the initiation of cellular responses to ionizing radiation.
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PMID:Radiation signaling mediated by Jun activation following dissociation from a cell type-specific repressor. 844 68

Tumor promoter 12-O-tetradecanoylphorbol-13-acetate stimulates an increase in erythroid differentiation activity in human fibrosarcoma HT1080 cells. Here, we demonstrate that this process involves a rapid accumulation of five species of activin beta A/erythroid differentiation factor mRNA, followed by protein kinase C activation, and that variation in size of the activin transcripts is due to multiple 3' ends, presumably reflecting an alternative polyadenylation. In transiently transfected HT1080 cells, a 97-bp DNA fragment containing an AP-1 consensus sequence (TGAGTCA) located in the 3'-flanking region of the activin gene was capable of activating the heterologous herpes simplex virus thymidine kinase (tk) and SV40 early promoters, and a cotransfected c-Jun enhanced these fusion promoter activities. The deletion of TGAG sequences from the AP-1 element in the 97-bp DNA sequence context abolished its c-Jun-mediated activation from the tk promoter even in HT1080 cells overexpressing stably transfected c-Jun. Cotransfected adenovirus E1A products repressed the tk promoter activity enhanced by the activin AP-1 element itself or in concert with transiently transfected c-Jun, indicating that the putative AP-1 sequence acts as an activator element, depending upon c-Jun activity. These results suggest that the 3'-flanking DNA sequences of the human activin beta A subunit gene play an important role in its expression.
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PMID:Possible roles of the 3'-flanking sequences of the human activin beta A subunit gene in its expression. 848 45

Mouse MHC class I-specific mAbs recognizing the alpha 1/alpha 2, but not those directed against the alpha 3 domain of the molecule, inhibited RNA, protein, and DNA synthesis of splenic T cells in response to stimulation through the TCR/CD3 complex. Similar inhibition was seen with LFA-1-specific mAbs under the same stimulation conditions. The effect of class I- and LFA-1-specific mAbs reflected a decrease of both IL-2 and IFN-gamma synthesis and IL-2 receptor alpha chain induction. IL-2, IL-2 receptor alpha chain, IFN-gamma, c-fos, c-jun, and c-myc mRNAs were not detected. Activation of AP-1 (c-Fos and c-Jun proteins) and NF-kappa B transcription factors were also inhibited. Inhibition was observed both after treatment of cells in culture and after intravenous injection of Abs in mice. Although bulk phosphorylation was inhibited, early tyrosine phosphorylation and calcium ion influx were normally induced. Protein phosphatase inhibitors did not reverse this inhibition, ruling out an enhanced activation of these enzymes in the observed inhibition. Cell surface expression of one of early PKC activation marker, CD69 was also inhibited. Phorbol esters that directly activate PKC prevented inhibition. Thus, class I molecules are implicated in signal transduction involved at an early stage for T cell activation in a manner that suggests their implication in accessory signal transmission that contributes to the regulation of PKC activity.
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PMID:MHC class I molecules are implicated in costimulatory signals during TCR/CD3-induced activation. 859 31

We have recently shown that mechanical stress activates a phosphorylation cascade of protein kinases including Raf-1 and the extracellular signal-regulated kinases (ERKs) in cultured cardiac myocytes partially through the enhanced secretion of angiotensin II. Osmotic stress in budding yeast has been shown to activate similar signaling molecules including Hog-1, a distant relative of the ERK family. In the present study, we examined whether mechanical stretch of cardiac myocytes activates the stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinase, the mammalian homologs of yeast Hog-1 that regulate gene expression through activation of the transcription factor, AP-1. When cardiac myocytes of neonatal rats cultured on a deformable silicone dish were stretched, activity of SAPKs was increased from 10 min, peaked at 30 min, and gradually decreased thereafter. The increase in activity of SAPKs was proportional to the stretch. Unlike ERKs, the activation of SAPKs by stretching cardiac myocytes was not dependent on the secreted angiotensin II. The chelation of extracellular Ca2+ or down-regulation of protein kinase C did not attenuate activation of SAPKs by stretch. Transfection experiments using an AP-1 binding site-containing reporter gene revealed that stretch increases AP-1 activity in cardiac myocytes. In conclusion, like osmotic stress in yeast, mechanical stretch activates SAPKs in cardiac myocytes without the participation of angiotensin II. These results suggest that the activation of SAPKs may regulate gene expression during mechanical stress-induced cardiac hypertrophy.
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PMID:Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes. 862 Oct 62

Stimulation of pancreatic acini from male Sprague-Dawley rats by both cholecystokinin (CCK)-8 and anisomycin caused an increase in p46jnk and p55jnk activities. Both forms of c-Jun amino-terminal kinase (JNK) were slightly activated at 5 min, reached a maximum at 30 min, and remained significantly increased at 60 min of CCK stimulation. By contrast, p42mapkwas activated fully by 5 min. In pancreatic acini stimulated with different concentrations of CCK for 30 min, the minimal and maximal JNK responses were observed at 30 pm and 100 nM CCK, respectively; p42mapk activation was, as previously reported, much more sensitive, with maximal activation by 1 nm CCK. Carbachol and bombesin also stimulated JNK activity, while vasoactive intestinal peptide did not. Neither activating protein kinase C nor increasing intracellular Ca2+ significantly activated JNK. In in vivo experiments, rats were infused intravenously for 5 and 15 min with a secretory (0.1 microg/kg/h) or supramaximal (10 microg/kg/h) dose of the CCK analog caerulein (CER). Secretory doses of CER induced a 4-fold increase of both forms of JNK in pancreatic tissue at 5 and 15 min, while at the same time points, supramaximal stimulation with CER caused 4- and 27-fold increases, respectively, of these kinase activities. The secretory dose of CER slightly increased the activities of both forms of mitogen-activated protein kinase, while the supramaximal dose induced a 10-fold increase of p42mapk at 5 min. In conclusion, JNKs and mitogen-activated protein kinases are rapidly activated in rat pancreatic acini stimulated with CCK as well as in pancreatic tissue during in vivo stimulation with CER. The large response to supramaximal CER stimulation may be of importance in the early pathogenesis of acute pancreatitis.
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PMID:Jun kinases are rapidly activated by cholecystokinin in rat pancreas both in vitro and in vivo. 862 33

Exposure of neonatal rat cardiac myocytes to ouabain concentrations that caused partial inhibition of Na+/K+-ATPase but no loss of viability, increased c-fos and c-jun mRNAs and the transcription factor AP-1. The increased mRNAs were proportional to the extent of inhibition of Na+/K+-ATPase and the resulting rise in steady state intracellular Ca2+ concentration. The rapid and sustained increase of c-fos mRNA was shown to be due to increased transcriptional rate. Induction of c-fos by ouabain was prevented when either extracellular or intracellular Ca2+ was lowered and was attenuated by pretreatment of myocytes with a phorbol ester under conditions known to down-regulate protein kinase C. Exposure to ouabain for 24-48 h also increased total transcriptional activity and protein content of myocytes. The findings suggest that the same signal responsible for the positive inotropic action of ouabain, i.e. net influx of Ca2+ caused by partial inhibition of Na+/K+-ATPase, also initiates the rapid protein kinase C-dependent inductions of the early-response genes, the subsequent regulations of other cardiac genes by the resulting transcription factors, and stimulation of myocyte growth. Whether these hitherto unrecognized effects of cardiac glycosides are obtained in the intact heart and their relevance to the therapeutic uses of these drugs remain to be determined.
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PMID:Partial inhibition of Na+/K+-ATPase by ouabain induces the Ca2+-dependent expressions of early-response genes in cardiac myocytes. 862 9

Cytokines are involved in the etiology of different disorders of the CNS. For a better understanding of their pathogenic role, we analyzed signal transduction pathways mediating the interleukin (IL)-1 beta-induced synthesis of IL-6 and tumor necrosis factor alpha (TNF alpha) in the human astrocytoma cell line U373 MG. Both protein kinase C and reactive oxygen intermediates (ROIs) were involved in IL-6 and TNF alpha gene expression by IL-1 beta. In contrast, protein tyrosine kinases were only necessary for expression of the IL-6 gene. Whereas activation of protein kinase A was able to induce expression of the IL-6 gene, it did not induce TNF alpha gene expression and was not involved in IL-1 beta-induced IL-6 and TNF alpha gene expression. Activation of the transcription factor nuclear factor-kappa B by IL-1 beta involved ROIs, whereas the IL-1 beta-induced activation of the transcription factor AP-1 was mediated via protein kinase C. Our findings provide the basis for the development of specific drugs for the treatment of disorders of the CNS in which cytokines play a pathogenic role.
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PMID:Interleukin-1 beta uses common and distinct signaling pathways for induction of the interleukin-6 and tumor necrosis factor alpha genes in the human astrocytoma cell line U373. 862 4

The regulation of c-jun plays an important role in T cell activation, proliferation, and expression of interleukin-2. In the present study, we determined whether Ca2+ signals and the activity of protein tyrosine kinases (PTKs) were required for the induction of c-jun in Jurkat cells stimulated with cross-linked anti-T cell receptor/CD3 antibodies or exposed to oxidative stress in the form of micromolar concentrations of H2O2. Jurkat cells exhibited rapid elevations in intracellular calcium [Ca2+]i levels in response to H2O2 and cross-linked anti-CD3 antibodies that mainly reflected the influx of extracellular Ca2+. The Ca2+ flux in response to oxidative signals was distinguished by an exquisite sensitivity to inhibition with Ni2+, suggesting the involvement of cation channels. PTK activity was needed for [Ca2+]i elevations in response to both oxidative and anti-CD3 signals, although H2O2 induction of [Ca2+]i increases was more resistant to inhibition by genistein than anti-CD3 [Ca2+]i responses. Both oxidative signals and anti-CD3 stimulation induced increased levels of c-jun and c-fos mRNA. The increased expression of c-jun with H2O2 was preceded by [Ca2+]i increases and accompanied by activation of c-Jun aminoterminal kinases (JNKs), as well as increased AP-1 binding activity. Induction of c-jun with oxidative signals and anti-CD3 was also shown to be crucially dependent on [Ca2+]i elevations because the chelation of [Ca2+]i with BAPTA resulted in a dose-dependent inhibition of c-jun expression. Furthermore, inhibition studies demonstrated that the optimal induction of c-jun mRNA in response to oxidative signals required PTK as well as protein kinase C (PKC). Thus, these findings suggest that both [Ca2+]i signals and the activity of PTKs are essential for the optimal expression of c-jun in response to TCR/CD3 signals and changes in redox potentials.
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PMID:Calcium signals and protein tyrosine kinases are required for the induction of c-jun in Jurkat cells stimulated by the T cell-receptor complex and oxidative signals. 864 Apr 56


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