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

Blood reperfusion after temporary liver ischemia induces the expression of heat shock genes and the synthesis of heat shock proteins (hsps), in particular hsp 70. Induction requires a certain duration of ischemia, suggesting that cell damage before reperfusion is essential for activation of heat shock genes. The expression of the hsp 70 gene is preceded by activation of the cellular protooncogenes c-fos and c-jun. However, the product of these genes, which is transcription factor AP-1, seems unnecessary for activation of the hsp 70 gene, which does not require the integrity of protein synthesis. Hsp genes seem to behave as "early response genes," enabling the cell to respond to emergency situations.
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PMID:Stress proteins and reperfusion stress in the liver. 148 45

Early induction of the mRNAs encoding the c-Fos and c-Jun nuclear proteins was examined in rat brain by in situ hybridization at various timepoints following global forebrain ischemia by the method of four-vessel occlusion. All animals were subjected to 20 min of transient ischemia. This produced a pattern of proto-oncogene activation that was most intense in the granule cells of the dentate gyrus 30 min after ischemia, while the hilar cells in the dentate and the pyramidal cells of the CA3 region in the hippocampus showed a more delayed but robust expression of these immediate early genes at 1 h. The neurons of the CA1 region exhibited a more moderate hybridization signal at 1-2 h postischemia. Very little hybridization signal for either immediate early gene could be detected in animals perfused with fixative immediately following ischemia, suggesting that cellular energy levels may have to be restored to a certain level before efficient de novo mRNA synthesis can occur. In the cerebellum, a similar temporal pattern was observed: the granule cells exhibited a prompt but patchy expression of c-fos and c-jun that was followed by a delayed signal in the Purkinje cells. Without exception c-fos and c-jun appeared to be expressed in unison, although the time course of c-fos and c-jun mRNA accumulation and decay was different in various brain regions: invariably the cerebellum returned rapidly to its baseline with virtually no remaining signal at 3 h postischemia, while c-fos and c-jun activation in the hippocampus remained high at 3 h and returned to baseline by 6 h. Several other brain regions showed early production of c-fos and c-jun mRNAs, such as the medial habenula, piriform cortex, the amygdala, the centromedian, lateral posterior, paracentral, intermediodorsal and reuniens nuclei of the thalamus and the ventromedial and dorsal nuclei of the hypothalamus; in the brainstem, the trapezoid body and the noradrenergic neurons of the locus ceruleus as well as the adrenergic neurons in the ventrolateral medulla (C1 group) and nucleus tractus solitarius (C2 group) regions displayed slightly less intense hybridization signals. In addition, the ependyma of the lateral ventricles and the third ventricle showed a prompt albeit short-lived production of c-fos and c-jun mRNAs. Sham-operated animals as well as animals that had survived to one week postischemia showed either no or only trace levels of hybridization signal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In situ hybridization analysis of c-fos and c-jun expression in the rat brain following transient forebrain ischemia. 181 28

The expression of the protooncogenes, c-fos, jun B, c-jun, and jun D was investigated in a rat focal cerebral ischemia model by Northern analysis and in situ hybridization. Severe ischemia (reduction of regional blood flow by 88-92%) in this model is confined to cerebral cortex irrigated by the right middle cerebral artery. Ischemia for 30 minutes, which caused only slight cortical damage (infarct size, < 10 mm3), induced both jun B and c-fos mRNAs exclusively in the right cerebral cortex. Ischemia for 90 minutes, which led to large cortical infarction (infarct size, > 140 mm3), also induced the expression of these two genes in the right cerebral cortex as well as the ipsilateral hippocampus. The latter sustained very mild ischemia (reduction of regional blood flow by 10-20%). The coinduction of jun B and c-fos expression occurred immediately after reperfusion and peaked at 60 minutes after reperfusion. The expression of c-jun was enhanced in a similar pattern, but at a much lower magnitude. In contrast, no change in jun D expression was observed. Nuclear run-on assays indicated that the increase in c-fos, jun B, and c-jun mRNA levels was due to the increase of transcription rate in these genes. Mobility shift assays showed a basal DNA binding activity of transcription factor AP-1 in the right cerebral cortex. Ischemia for 30 or 90 minutes followed by reperfusion for 4 hours resulted in a four- to sixfold increase of AP-1 binding activity. The enhanced DNA binding activity persisted for as long as 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of c-fos and c-jun family genes after focal cerebral ischemia. 849 19

The signal transduction pathways that mediate activation of trans acting factors controlling an organ's response to ischemia are unknown. The stress-activated protein kinases (SAPKs), a subfamily of the extracellular signal-regulated kinases (ERKs), phosphorylate c-Jun within the amino-terminal transactivation domain and are activated in response to a variety of cellular stresses. We determined whether SAPKs are activated in response to ischemia, an extreme, albeit common, pathophysiologic stress. Rats underwent 40 min of renal ischemia followed by reperfusion for 0, 5, 20, or 90 min. SAPKs were immunoprecipitated from kidney lysates and kinase activity assayed with recombinant GST-c-Jun(1-135), containing the amino-terminal transactivation domain of c-Jun as substrate. SAPKs were not activated by ischemia alone, but reperfusion for as little as 5 min was associated with a 4.6-fold increase in kinase activity. Kinase activity was increased 7.6-fold at 20 min following reperfusion and remained elevated at 90 min of reperfusion (4.9-fold). In contrast, activity of the related ERK-1 and -2 was increased only 1.3-fold and only at the 5-min reperfusion time point. When SAPKs were immunodepleted from kidney extracts prior to incubation of the extracts with agarose-coupled GST-c-Jun(1-135), it was found that SAPKs accounted for the majority of the amino-terminal c-Jun kinase activity of kidney at 5 min following reperfusion. In Madin-Darby canine kidney epithelial cells, ATP repletion, following ATP depletion induced by chemical anoxia, was associated with a 9-15-fold activation of SAPKs with a similar time course of activation to that seen in the kidney after ischemia and reperfusion. In conclusion, the SAPKs are markedly activated very early after reperfusion of ischemic kidney and following ATP repletion of anoxic cells in culture. We propose that this activation of SAPKs may trigger part of the kidney's early genetic response to ischemia, possibly by enhancing trans acting activity of c-Jun.
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PMID:The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. 792 79

The transcription factors controlling the complex genetic response to ischemia and their modes of regulation are poorly understood. We found that ATF-2 and c-Jun DNA binding activity is markedly enhanced in post-ischemic kidney or in LLC-PK1 renal tubular epithelial cells exposed to reversible ATP depletion. After 40 min of renal ischemia followed by reperfusion for as little as 5 min, binding of ATF-2 and c-Jun, but not ATF-3 or CREB (cAMP response element binding protein), to oligonucleotides containing either an ATF/cAMP response element (ATF/CRE) or the jun2TRE from the c-jun promoter, was significantly increased. Binding to jun2TRE and ATF/CRE oligonucleotides occurred with an identical time course. In contrast, nuclear protein binding to an oligonucleotide containing a canonical AP-1 element was not detected until 40 min of reperfusion, and although c-Jun was present in the complex, ATF-2 was not. Incubating nuclear extracts from reperfused kidney with protein phosphatase 2A markedly reduced binding to both the ATF/CRE and jun2TRE oligonucleotides, compatible with regulation by an ATF-2 kinase. An ATF-2 kinase, which phosphorylated both the transactivation and DNA binding domains of ATF-2, was activated by reversible ATP depletion. This kinase coeluted on Mono Q column chromatography with a c-Jun amino-terminal kinase and with the peak of stress-activated protein kinase, but not p38, immunoreactivity. In conclusion, DNA binding activity of ATF-2 directed at both ATF/CRE and jun2TRE motifs is modulated in response to the extreme cellular stress of ischemia and reperfusion or reversible ATP depletion. Phosphorylation-dependent activation of the DNA binding activity of ATF-2, which appears to be regulated by the stress-activated protein kinases, may play an important role in the earliest stages of the genetic response to ischemia/reperfusion by targeting ATF-2 and c-Jun to specific promoters, including the c-jun promoter and those containing ATF/CREs.
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PMID:Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. 853 Apr 13

Hypoxia and reoxygenation are important pathophysiological conditions that occur during injury, ischemia, reperfusion and stroke. In tumors, hypoxia and oxidative stress are regarded as triggers for enhanced proliferation and metastasis. Hypoxia and reoxygenation exert part of their biological effects by inducing the expression of novel genes but very little is known about the transcription factors involved. Here, we have compared the behaviour of two redox-controlled factors, AP-1 and NF-kappa B, during hypoxia and reoxygenation. We report that the DNA-binding and transcriptional activity of transcription factor AP-1 is very strongly induced in a biphasic response when HeLa cells are exposed to reduced oxygen pressure. This induction required new AP-1 protein synthesis. Different members of the Jun/Fos family of transcription factors were found in the first and second maxima of activation. The pathogen-responsive, pre-existing transcription factor NF-kappa B was not activated under hypoxic conditions. However, a p50-p65 heterodimer of NF-kappa B was rapidly and strongly activated when HeLa cells were re-exposed to normal oxygen pressure. This explains the induction of NF-kappa B-controlled inflammatory cytokine genes during reperfusion of ischemic tissue. Our data suggest that the genomic response to hypoxia is primarily mediated by AP-1 while the inflammatory response to reoxygenation is mediated by NF-kappa B.
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PMID:The genomic response of tumor cells to hypoxia and reoxygenation. Differential activation of transcription factors AP-1 and NF-kappa B. 853 13

The response of the kidney to ischemic injury includes increased DNA synthesis, which is preceded by rapid and brief expression of the c-fos proto-oncogene. While the timing of these two events would suggest that c-Fos participates in an immediate-early gene program leading to proliferation, no direct test of this hypothesis exists. The purpose of these studies was (1) to determine whether c-fos is expressed as part of a typical immediate-early (IE) gene response, which would require co-expression of c-jun and sensitivity to cycloheximide, and (2) to determine whether the cells expressing c-Fos are the same as those undergoing DNA synthesis. Northern analysis was performed on renal mRNA at different times following release of a 50 minute period of renal hilar clamping. c-jun and c-fos mRNA were rapidly and briefly expressed following renal ischemia and their expression was superinduced by cycloheximide in a manner typical of an immediate-early gene response. 3H-thymidine autoradiography performed on semi-thin sections from intravascularly perfusion fixed kidneys 24 hours following induction of ischemia showed labeled nuclei in cells lining the damaged proximal tubules of the outer stripe of the outer medulla, as well as proximal tubules in the cortex and interstitial cells throughout the kidney. However, immunohistochemical localization of c-Fos and c-Jun protein occurred predominantly in nuclei of the thick ascending limb, distal tubule and collecting duct cells. The studies demonstrate that c-fos and c-jun are expressed following renal ischemia as a typical immediate-early gene response, but they are expressed in cells that do not enter the cell cycle. The failure of the cells to enter the cell cycle may depend on the co-expression of jun-B and jun-D, which suppress the mitogenic activity of c-Jun in other cells. The data suggest that the IE response following renal ischemia is part of the stress response, which is antiproliferative rather than proliferative. The role of the stress response during renal ischemia and the fate of the cells undergoing it are unknown.
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PMID:DNA synthesis is dissociated from the immediate-early gene response in the post-ischemic kidney. 854 1

Ischemia and reperfusion lead to the rapid induction of proto-oncogenes in the heart and subsequent induction of genes with cardioprotective functions. The activity of the transcription factors c-Jun and ATF-2 can be stimulated by activation of c-Jun amino-terminal kinase (JNK) in response to a variety of stresses. Here we show that ischemia and reperfusion led to the activation of JNK and also of the distantly-related mitogen activated protein kinase (MAPK). Activation of JNK, but not (MAPK), was abolished by removal of calcium from the perfusate immediately prior to ischemia. In contrast, infusion of the hydrogen peroxide scavenger catalase abolished activation of MAPK in response to ischemia and reperfusion, but activation of JNK was inhibited significantly by catalase only when superoxide dismutase was also present. Hydrogen peroxide infusion activated MAPK but not JNK, supporting a role for hydrogen peroxide produced during reperfusion in MAPK activation. We conclude that while ischemia and reperfusion activate both JNK and MAPK, the mechanisms of activation are different for the 2 kinases. Activation of these kinases is likely to contribute to altered gene expression in response to ischemia and reperfusion.
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PMID:Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat heart. 857 81

It has recently been recognized that cellular stresses activate certain members of the mitogen-activated protein kinase (MAPK) superfamily. One role of these "stress-activated" MAPKs is to increase the transactivating activity of the transcription factors c-Jun, Elk1, and ATF2. These findings may be particularly relevant to hearts that have been exposed to pathological stresses. Using the isolated perfused rat heart, we show that global ischemia does not activate the 42- and 44-kD extracellular signal-regulated (protein) kinase (ERK) subfamily of MAPKs but rather stimulates a 38-kD activator of MAPK-activated protein kinase-2 (MAPKAPK2). This activation is maintained during reperfusion. The molecular characteristics of this protein kinase suggest that it is a member of the p38/reactivating kinase (RK) group of stress-activated MAPKs. In contrast, stress-activated MAPKs of the c-Jun N-terminal kinase (JNK/SAPKs) subfamily are not activated by ischemia alone but are activated by reperfusion following ischemia. Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/ SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response. We speculate that activation of multiple parallel MAPK pathways may be important in the responses of hearts to cellular stresses.
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PMID:Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. 875 92

The redox status of the cell plays an essential role in regulating signal transduction, transcription factor activity, and expression of cell surface molecules. In this study, we show that pyrrolidine dithiocarbamate (PDTC), a potent antioxidant agent, upregulated the cell surface expression of intercellular adhesion molecule-1 (ICAM-1) in human endothelial cells (EC). Further analysis of PDTC-mediated ICAM-1 up-regulation revealed that PDTC increased ICAM-1 mRNA levels and augmented its gene promoter activity. Transfection experiments in EC with reporter constructs harboring nested deletion fragments of the ICAM-1 promoter indicated the presence of a functional PDTC-responsive region located between positions -136 to -353 of the promoter. Gel retardation assays together with supershift analysis revealed that PDTC induced the binding of c-fos and c-jun to a consensus activating protein-1 (AP-1) binding site located at position -284. PDTC alone or in combination with TNF-alpha enhanced AP-1-dependent transactivation in HUVEC, as determined by DNA binding assays. The functional implication of AP-1 in the transcription of the ICAM-1 gene was further demonstrated by cotransfection experiments in which a c-jun expression vector induced the promoter activity of the PDTC-responsive element of the ICAM-1 promoter. Taken together, these results indicate that the antioxidant PDTC induces transcriptional activation of ICAM-1 and that this induction is mediated at least in part by the transcription factor AP-1. This mechanism might be operative in pathologic conditions in which a redox imbalance plays a key role, such as ischemia/reperfusion injury or arteriosclerosis.
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PMID:Transcriptional up-regulation of intracellular adhesion molecule-1 in human endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves the activation of activating protein-1. 887 59


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