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 Ref-1 protein is a bifunctional nuclear enzyme involved in repair of DNA lesions and in redox regulation of DNA-binding activity of AP-1 family members, such as Fos and Jun transcription factors. In the present study, we demonstrate by in situ hybridization that transient global ischemia induced by cardiac arrest activates ref-1 mRNA expression in the granular cells of the rat dentate gyrus after 6 h and in CA1 pyramidal neurons of the hippocampus proper after 24 h, respectively. Immunohistochemical analysis revealed nuclear accumulation of Ref-1 protein in granular cells of the ischemia-resistant dentate gyrus, whereas Ref-1 protein expression progressively decreased in vulnerable CA1 neurons of the post-ischemic hippocampus from 24 h onwards. At the same time point, intense nuclear c-Jun immunoreactivity was observed in both neuronal cell populations. Our data suggest that oxidative stress induced by ischemia-reperfusion may increase neuronal ref-1 expression. However, inability of ref-1 mRNA translation and nuclear translocation of encoded protein in CA1 pyramidal neurons may inhibit repair of oxidative DNA damage or cellular adaptive responses leading to delayed neuronal cell death.
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PMID:Expression of nuclear redox factor ref-1 in the rat hippocampus following global ischemia induced by cardiac arrest. 949 40

In eukaryotes, protein de novo synthesis is mainly under the control of transcription factors at the level of gene transcription in cell nuclei. Gel retardation electrophoresis was employed for determination of DNA-binding activity of the transcription factor activator protein-1 (AP1), which is a dimer between c-Fos and c-Jun protein families. Binding of a radiolabeled double-stranded oligonucleotide probe for AP1 was rapidly potentiated in the CA1 and CA3 subfields and the dentate gyrus of the hippocampus of gerbils with forebrain ischemia for 5 min. Similarly marked potentiation was seen in the thalamus and the striatum, but not in the frontal cortex, following the recirculation of blood supply. The potentiation was transient in the vulnerable CA1 subfield, but was rather persistent in the thalamus and the striatum in addition to the resistant CA3 subfield and dentate gyrus. However, administration of the neuroprotective drug bifemelane (10 to 20 mg/kg, i.p.) resulted in prolongation of the potentiation of AP1 binding in the CA1 subfield up to 6 hr after ischemia, without significantly affecting that in other central structures. Limited proteolysis revealed that bifemelane induced expression of the AP1 consisting of constructive proteins different from those expressed in control animals in the CA1 subfield. These results suggest that bifemelane may protect neuronal cells against ischemic injuries through molecular mechanisms associated with prolongation of the potentiation of AP1 binding in the vulnerable CA1 subfield after ischemia.
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PMID:Prolongation by bifemelane of potentiation of AP1 DNA binding in hippocampal CA1 subfield of gerbils with transient forebrain ischemia. 951 1

The present study has investigated the congruence of mRNA induction and protein expression of inducible transcription factors (ITFs). The patterns of c-jun, junB, c-fos, fra-1 and fra-2 mRNAs were studied by radioactive and non-radioactive in situ hybridization in the adult rat brain following kainate-induced seizure activity and axotomy. In the same animals, the expression of c-Jun, JunB and c-Fos proteins was compared with the respective mRNA signals. Using radioactive labeled probes all investigated mRNAs showed an onset within 1 h after systemic kainate application and the maximal levels were generally reached after 3 h. Each mRNA displayed a specific temporo-spatial expression pattern. Whereas fra-1 and fra-2 were restricted to the hippocampus, c-jun, junB and c-fos were additionally induced in the cortex, amygdala and thalamus. The areas with maximal labeling were the dentate gyrus and the hippocampal CA1 and CA3 subfields. The expression patterns between c-jun, junB and c-fos mRNA were virtually congruent with the respective protein. Labeling of the junB and fra-2 probes with digoxigenin yielded similar results. Twenty-four hours, 3 and 10 days following transection of the medial forebrain bundle and the mamillo-thalamic tract, high levels of c-jun mRNA (either digoxigenin or radioactive labeled probes) and protein were seen in the axotomized neurons of the substantia nigra pars compacta and mamillary body whereas the other mRNAs studied and the JunB or c-Fos proteins could not be detected. These findings demonstrate that mRNAs encoding for ITFs are translated into the respective proteins following excitotoxic seizures and axotomy, and that the antisera used for immunocytochemistry yield specific expression patterns of homologous proteins.
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PMID:Expression of c-jun, junB, c-fos, fra-1 and fra-2 mRNA in the rat brain following seizure activity and axotomy. 962 45

Transcription factors are nuclear proteins with an ability to recognize particular nucleotide sequences on double stranded genomic DNAs and thereby modulate the activity of RNA polymerase II which is responsible for the formation of messenger RNAs in cell nuclei. Gel retardation electrophoresis revealed that transient forebrain ischemia for 5 min led to drastic potentiation of binding of a radiolabelled double-stranded oligonucleotide probe for the transcription factor activator protein-1, in the thalamus as well as the CA1 and CA3 subfields and the dentate gyrus of the hippocampus of the gerbils previously given ischemia for 2 min two days before, which is known to induce tolerance to subsequent severe ischemia in the CA1 subfield. By contrast, ischemia for 5 min resulted in prolonged potentiation of activator protein-1 binding in the vulnerable CA1 subfield of the gerbils with prior ischemia for 5 min 14 days before, which is shown to induce delayed death of the pyramidal neurons exclusively in this subfield. Similar prolongation was seen with activator protein-1 binding in the vulnerable thalamus but not in the resistant CA3 subfield and dentate gyrus of the gerbils with such repeated ischemia for 5 min. Limited proteolysis by Staphylococcus aureus V8 protease as well as supershift assays using antibodies against c-Fos and c-Jun proteins demonstrated the possible difference in constructive partner proteins of activator protein-1 among nuclear extracts of the CA1 subfield obtained from gerbils with single, tolerated and repeated ischemia. These results suggest that de novo protein synthesis may underlie molecular mechanisms associated with acquisition of the ischemic tolerance through modulation at the level of gene transcription by activator protein-1 composed of different constructive partner proteins in the CA1 subfield. Possible participation of glial cells in the modulation is also suggested in particular situations.
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PMID:Possible involvement of activator protein-1 DNA binding in mechanisms underlying ischemic tolerance in the CA1 subfield of gerbil hippocampus. 969 45

A unilateral hypoxic-ischemic (HI) episode in immature rat brain was used to investigate the role of the immediate early genes c-fos and c-jun in delayed neuronal death and survival. This HI paradigm results in an apoptotic cell death in selectively vulnerable areas, in particular the hippocampal CA1 pyramidal cell layer. In susceptible regions undergoing delayed neuronal death there was a prolonged induction of both c-Jun and c-Fos (mRNA and protein). This expression occurred in parallel with a pronounced increase in AP-1 DNA binding activity but was not associated with either increased levels of Jun NH2-terminal kinase or phosphorylation of c-Jun (ser-63). In addition to changes in immediate early gene expression, the CA1 neurons showed a delayed increase in the expression of amyloid precursor protein (APP751) mRNA, suggesting that APP, which contains an AP-1 site, might be a down-stream gene regulated by the Jun transcription factor in neurons dying by apoptosis. The surviving dentate granule cells also showed an increase in Fos, Jun, and APP751 although this expression occurred earlier than in the CA1 neurons and declined rapidly. These results are discussed with respect to the role of these proteins in neuronal death and survival.
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PMID:Do c-Jun, c-Fos, and amyloid precursor protein play a role in neuronal death or survival? 969 61

Apoptosis, or programmed cell death, has been proposed as a mechanism of neuropathology in Alzheimer's disease (AD). Activation of immediate early genes (IEG) c-jun and c-fos appears to be required for the initiation of apoptosis. Furthermore, the expression of c-jun is induced in cultured neurons that undergo beta-amyloid-mediated apoptosis suggesting a direct role for c-jun in the apoptosis of AD neurons. Using immunohistochemical methods, we calculated the average number of neuronal profiles per unit area expressing c-Jun and c-Fos within hippocampal regions CA1, CA2/3, and CA4 in postmortem brain samples from AD patients and age-matched non-AD patients. There was an increase in c-Jun-positive and c-Fos-positive neuronal profile density in nearly all AD hippocampal regions examined. In cerebellum there was no evidence of apoptosis as determined by using TUNEL technique, and negligible c-Jun labeling.
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PMID:Quantitative neuronal c-fos and c-jun expression in Alzheimer's disease. 988 41

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

Transient global ischemia caused by 5 min of cardiac arrest induced delayed neuronal cell death (apoptosis) in the CA1 region of the rat hippocampus. To characterize the molecular mechanisms that regulate apoptosis in vivo, the contributions to cell death of mitogen-activated protein kinase family members were examined in the hippocampal region after brain ischemia-reperfusion. Ischemia-reperfusion led to a strong activation of the JNK/SAPK (c-Jun NH2-terminal protein kinase/stress activated protein kinase), ERK (extracellular signal-regulated kinase), and p38 enzymes. These results with other previous studies suggest that the activation of JNK/SAPK in accordance with p38 contributes to the induction of apoptosis in CA1 neurons.
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PMID:Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. 1007 72

Animals exposed to kainic acid (KA) induced status epilepticus display a striking pattern of selective neuronal vulnerability in the hippocampus. Neurons in the hilus/CA3 and CA1 subfields appear particularly sensitive whereas dentate gyrus (DG) granule cells are resistant. The molecular basis for this differential susceptibility remains largely unknown. Recently, an involvement of nitric oxide, c-Jun amino-terminal kinases (JNK) and interleukin-1 beta converting enzyme (ICE)-related proteases has been proposed in KA induced neuronal cell death. In the present study, we have determined the regional expression of transcripts for two modulating genes operating in these pathways, i.e., the endogenous protein inhibitor of neuronal nitric oxide synthase (PIN), and a cytoplasmic inhibitor of the JNK signal transduction pathway, designated JNK interacting protein-1 (JIP-1) and of the gene for the apoptosis-executing protease Caspase-3 in KA-treated animals. The expression of PIN and JIP-1 was found significantly upregulated in granule cells of the resistant DG. In contrast, an induction of the ICE-related protease Caspase-3 was observed in vulnerable hippocampal regions, i.e. CA1, CA3 and hilus. These results point towards PIN and JIP-1 as antiapoptotic factors contributing to selective resistance of granule cells, whereas Caspase-3 may be involved in cell death of hippocampal CA1, CA3 and hilar neurons in the kainate epilepsy model.
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PMID:Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus. 1010 Dec 44

Previous studies in our laboratory have shown that the mood stabilizers, lithium and valproate (VPA), regulate the transcription factors, cyclic AMP responsive element binding protein (CREB), c-Fos and c-Jun, differentially in cultured human neuroblastoma SH-SY5Y cells. Here, we confirm these findings in rat brain and further study the brain-regional effects of these drugs using immunohistochemistry. We found that although chronic treatment with LiCl or VPA did not change the expression of c-Fos and c-Jun, acute treatment with either drugs increased c-Fos expression but not c-Jun expression in CA1 and CA3 regions of hippocampus. Chronic treatment with LiCl, but not VPA, decreased CREB phosphorylation in rat cerebral cortex and hippocampus. These results suggest that lithium and VPA may act on different pathways to bring about their long-term prophylactic effects on bipolar disorder (BD). The regulation of CREB phosphorylation may be relevant to lithium effect. VPA, which is also effective in BD, may be linked to other pathways.
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PMID:Lithium and valproate differentially regulate brain regional expression of phosphorylated CREB and c-Fos. 1038 42


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