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)

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

c-Jun, a transcriptional activator, as well as cyclin D1, a key regulator of the cell cycle, have been described in vitro as mediators of programmed neuronal death. After trophic factor deprivation, the activation of c-jun and cyclin D1 genes is considered as a necessary step within the cellular machinery that leads to cell death. We show here that both c-Jun and cyclin D1 proteins are present in neurones within the infarcted area after experimental cerebral ischaemia in the mouse. Since their presence was associated with DNA fragmentation revealed by the TUNEL procedure, we propose that c-Jun and cyclin D1 are involved in the process of neuronal death.
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PMID:c-Jun and cyclin D1 proteins as mediators of neuronal death after a focal ischaemic insult. 914 Oct 81

Transcription factor c-Jun is proposed to control neuronal cell death and survival, but its activation by N-terminal phosphorylation and the underlying activity of the c-Jun N-terminal kinases (JNKs) remain to be elucidated in the adult mammalian brain. We generated a polyclonal antiserum that specifically recognizes c-Jun phosphorylated at its serine 73 (S73) residue after UV irradiation of 3T3 cells. Disruption of the c-jun locus in 3T3 cells abolished this reaction, and retransfection of the human c-jun at the c-jun-/- background restored it. The phospho-c-Jun antiserum was used to visualize N-terminally phosphorylated c-Jun in the adult rat brain with cellular resolution. Prolonged c-Jun S73 phosphorylation was detected in affected neurons up to 5 d after transient occlusion of medial cerebral artery or up to 50 d after transection of central nerve fiber tracts. After cerebral ischemia-reperfusion, phosphorylation of c-Jun was linked with induced expression of Fas-ligand (APO-1, CD95-ligand), whose gene is a putative c-Jun/AP-1 target, and with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity, a marker for apoptosis. After nerve fiber transection, however, lasting c-Jun phosphorylation occurred in axotomized neurons negative for Fas-ligand or TUNEL and regardless of degeneration or survival. In contrast to these lasting phosphorylation patterns, transient seizure activity by pentylenetetrazole provoked only a brief c-Jun phosphorylation and JNK activation. In extracts from ischemic or axotomized brain compartments, c-Jun phosphorylation correlated with enhanced long-term JNK activity, and in-gel kinase assays visualized proteins with sizes corresponding to JNK isoforms as the only c-Jun N-terminally phosphorylating enzymes. These results demonstrate that lasting c-Jun S73 phosphorylation and JNK activity are part of neuronal stress response after neurodegenerative disorders in the adult mammalian brain with Fas-ligand as a putative apoptotic effector.
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PMID:Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. 965 Nov 96

The neuroprotective role of the expression of heat shock protein (HSP) and immediate early gene remains unclear. Using immunoelectron microscopy, we examined the ultrastructural integrity of the neurons with expression of c-Fos, c-Jun and HSP70 in gerbils after transient cerebral ischemia and reperfusion. Induction of c-Fos and c-Jun was observed in the CA3 region resistant to ischemia, while HSP70 was expressed not only in the CA3 but also in the vulnerable CAI region. With immunoelectron microscopy, the expression of c-Fos/c-Jun and HSP70 was observed in the neurons which retained neuronal integrity except for mitochondrial swelling and polyribosomal disaggregation. In contrast, the CAI neurons without immunoreaction for HSP70 showed cytoplasmic vacuoles and parallel stacking of rough endoplasmic reticulum, the features associated with the process of delayed neuronal death. These findings suggested that c-Fos and c-Jun were induced selectively in reversibly damaged neurons, whereas HSP70 was up-regulated even in neurons with irreversible damage, but was more preferentially and intensely expressed in neurons with reversible damage.
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PMID:Immunoelectron microscopic study of c-Fos, c-Jun and heat shock protein after transient cerebral ischemia in gerbils. 993 Aug 91

To analyze the role of specific genes and proteins in neuronal signaling cascades following global cerebral ischemia, it would be useful to have a reproducible model of global cerebral ischemia in mice that potentially allows the investigation of mice with specific genomic mutations. We first report on the development of a model of reversible cardiocirculatory arrest in mice and the consequences of such an insult to neuronal degeneration and expression of immediate early genes (IEG) in the hippocampus. Cardiocirculatory arrest of 5 min duration was induced via ventricular fibrillation in mechanically ventilated NMRI mice. After successful cardiopulmonary resuscitation (CPR), animals were allowed to reperfuse spontaneously for 3 h (n=7) and 7 days (n=7). TUNEL staining revealed a selective degeneration of a subset of neurons in the hippocampal CA1 sector at 7 days. About 30% of all TUNEL-positive nuclei showed condensed chromatin and apoptotic bodies. Immunohistochemical studies of IEG expression performed at 3 h exhibited a marked induction of c-Fos, c-Jun, and Krox-24 protein in all sectors of the hippocampus, peaking in vulnerable CA1 pyramidal neurons and in dentate gyrus. In contrast, sham-operated animals (n=3) did not reveal neuronal degeneration or increased IEG expression in the hippocampus when compared with untreated control animals (n=3). In conclusion, we present a new model of global cerebral ischemia and reperfusion in mice with the use of complete cardiocirculatory arrest and subsequent CPR. Following 5 min of ischemia, a subset of CA1 pyramidal neurons was TUNEL-positive at 7 days. The expression of IEG was observed in all sectors of the hippocampus, including selectively vulnerable CA1 pyramidal neurons. This appears to be a good model which should be useful in evaluating the role of various genes in transgenic and knockout mice following global ischemia.
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PMID:Global cerebral ischemia due to cardiocirculatory arrest in mice causes neuronal degeneration and early induction of transcription factor genes in the hippocampus. 1006 84

Programmed cell death plays an important role in the neuronal degeneration after cerebral ischemia, but the underlying mechanisms are not fully understood. Here we examined, in vivo and in vitro, whether ischemia-induced neuronal death involves death-inducing ligand/receptor systems such as CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). After reversible middle cerebral artery occlusion in adult rats, both CD95 ligand and TRAIL were expressed in the apoptotic areas of the postischemic brain. Further recombinant CD95 ligand and TRAIL proteins induced apoptosis in primary neurons and neuron-like cells in vitro. The immunosuppressant FK506, which most effectively protects against ischemic neurodegeneration, prevented postischemic expression of these death-inducing ligands both in vivo and in vitro. FK506 also abolished phosphorylation, but not expression, of the c-Jun transcription factor involved in the transcriptional control of CD95 ligand. Most importantly, in lpr mice expressing dysfunctional CD95, reversible middle cerebral artery occlusion resulted in infarct volumes significantly smaller than those found in wild-type animals. These results suggest an involvement of CD95 ligand and TRAIL in the pathophysiology of postischemic neurodegeneration and offer alternative strategies for the treatment of cardiovascular brain disease.
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PMID:CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. 1023 13

Persistent activation of c-Jun N-terminal kinases (JNKs) and phosphorylation of c-Jun has been shown in various cell death paradigms. Inhibition of the JNK signal transduction pathway prevented neuronal cell death both in vitro and in vivo. In the present study, nuclear phospho-c-Jun immunoreactivity became apparent selectively in vulnerable hippocampal CA1 neurons at 24 h after transient global cerebral ischemia. A high constitutive expression of phospho-JNK1 was detected by immunoblot analysis of hippocampal extracts. Expression of JNK interacting protein-1 (JIP-1), which facilitates JNK signaling, remained unchanged in post-ischemic hippocampal neurons. By contrast, p53-activated gene 608 (PAG608), which promotes cell death in vitro, was strongly induced in post-ischemic CA1 neurons. Our data suggest that transcription factors p53 and phospho-c-Jun may contribute to programmed CA1 cell death following ischemia.
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PMID:Expression of cell death-associated phospho-c-Jun and p53-activated gene 608 in hippocampal CA1 neurons following global ischemia. 1058 7

Immediate early genes (IEC) are expressed in a variety of experimental paradigms including cerebral ischemia and trauma. There is a paucity of information on whether the results of laboratory experiments can be extrapolated from animals into man. To examine this further we hypothesized that expression of c-Fos and c-Jun occurs after contusional head injury in man. We also sought to identify whether there was an association between the level of immediate early gene expression and 1. the outcome one year after head injury, 2. the timing of surgery after head injury. IEG expression was examined using in situ hybridization and immunocytochemistry in brain tissue therapeutically removed in 14 patients with head injury 6 h to 6 days after contusional injury. IEG expression was also examined in tissue removed during elective non-traumatic neurosurgery for comparative purposes. Expression of c-fos and c-jun mRNA was observed in 50% and 64% of head-injured patients respectively. Protein immunoreactivity for these IEGs was evident in 67% of head injured patients. The expression of c-Fos and c-Jun was associated with final outcome. Patients with poorer outcomes had higher levels of gene expression (p = 0.08 for c-Fos and p = 0.006 for c-Jun). No correlation between the timing of surgery and the intensity of gene expression was evident in the trauma patients (r2 = 0.09 and 0.10 for c-Fos and c-Jun respectively). In the non-trauma patients 36% expressed c-fos and 73% expressed c-jun mRNA, with all patients studied expressing c-Fos and c-Jun proteins. We conclude that differential expression of c-Fos and c-Jun occurs in the patients with cerebral contusions. The difference in expression rates between mRNA and protein emphasises the need for analysis of gene products when investigating gene expression. These results support the hypothesis that IEGs may be involved in the pathogenetic mechanisms of contusional head injury. Observations of IEG expression in human brain injury are important in steering animal experimental programmes towards studies that may yield information directly applicable to human brain injury.
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PMID:Expression of the immediate early genes c-Fos and c-Jun after head injury in man. 1076 99

The purpose of this study was to examine the activation, topographic distribution, and cellular location of three mitogen-activated protein kinases (MAPKs) after permanent middle cerebral artery occlusion (MCAO) in mice. Phosphorylated MAPKs expression in the ischemic region was quantified using Western blot analysis and localized immunohistochemically using the diaminobenzide staining and double-labeled immunostaining. Extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38 mitogen-activated protein (p38), and c-Jun NH2-terminal kinase or stress-activated protein kinase (SAPK/JNK) were initially activated at 30 minutes, 10 minutes, and 5 minutes, respectively, after focal cerebral ischemia. Peak expression represented a 2.7-fold, 3.7-fold, and 4.8-fold increase in each of these MAPKs, respectively. The immunohistochemical expressions of ERK1, ERK2, p38, and SAPK/JNK protein paralleled the Western blot analysis results. Double-labeled immunofluorescent staining demonstrated that the neurons and astrocytes expressed ERK1, ERK2, p38, and SAPK/JNK during the early time points after MCAO. The current results demonstrate that brain damage after ischemia rapidly triggers time-dependent ERK1, ERK2, p38, and SAPK/ JNK phosphorylation, and reveals that neurons and astrocytes are involved in the activation of the MAPK pathway. This very early expression of MAPKs suggests that MAPKs may be closely involved in signal transduction during cerebral ischemia.
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PMID:Activation of mitogen-activated protein kinases after permanent cerebral artery occlusion in mouse brain. 1099 54

Mitogen-activated protein kinases (MAPKs) have crucial roles in signal transduction from the cell surface to the nucleus and regulate cell death and survival. Recent papers support the hypothesis that neuronal apoptosis and cerebral ischemia induce the robust activation of MAPK cascades. Although extracellular signal-regulated kinases pathways promote cell survival and proliferation, and c-Jun N-terminal protein kinases/p38 pathways induce apoptosis in general, the roles of MAPK cascades in neuronal death and survival seem to be complicated and altered by the type of cells and the magnitude and timing of insults. Some specific inhibitors of MAPK cascades provide important information in clarifying the roles of each molecule in neuronal death and survival, but the results are still controversial. Further studies are necessary to elucidate the activated signal transduction upstream and downstream of the cascades in cerebral ischemia, and to define the crosstalk between the cascades and other signaling pathways, before MAPK cascades can be candidate molecules in the treatment of cerebral ischemia.
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PMID:Mitogen-activated protein kinases and cerebral ischemia. 1164 41


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