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)

Weaver and Purkinje cell degeneration (pcd) are autosomal recessive mutations in the mouse characterized by an almost complete loss of cerebellar Purkinje neurones and granule cells, respectively. Developmental neuronal death occurs by activation of an apoptotic pathway and chromatin condensation has been observed in degenerating granule cells of weaver mutants. In the present study we demonstrate nuclear DNA fragmentation in Purkinje cells of pcd mice and in granule cells of weaver mutants during the period of neuronal degeneration using in situ end labelling by terminal transferase and fluorescein-dUTP. Furthermore, activation of candidate cell death effector gene c-jun has been detected exclusively within the affected cell populations by immunohistochemistry. Both labelled DNA fragments and nuclear c-Jun immunoreactivity were virtually absent in wild-type animals. Thus, genetically determined cell death in pcd and weaver mutant mice has features of apoptosis and may require activation of cell death effector genes.
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PMID:DNA fragmentation and activation of c-Jun in the cerebellum of mutant mice (weaver, Purkinje cell degeneration). 854 77

The inducible transcription factor c-Jun increases in neurons in response to axotomy by unknown mechanisms, and it has been postulated that c-Jun may regulate genes involved in promoting either degeneration or regeneration of axotomized neurons. In this report, we investigated the effect of daily or twice daily intraventricular administration of the neurotrophins nerve growth factor or neurotrophin-4/5 on the decrease in choline acetyltransferase expression and the increase in c-Jun expression in rat medial septum/diagonal band neurons three, seven and 14 days following unilateral, complete, fornix fimbria lesion. We also examined whether medial septum/diagonal band neurons might die by apoptosis within two weeks of fornix fimbria lesion using terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling. Our results show that both nerve growth factor and neurotrophin-4/5 maintain the phenotype of basal forebrain cholinergic neurons following axotomy. Furthermore, using double-labelling immunofluorescence, we found that while c-Jun was expressed in cholinergic neurons in control-treated rats seven days following fornix fimbria lesion, cholinergic neurons rescued by either nerve growth factor or neurotrophin-4/5 in neurotrophin-treated rats failed to express c-Jun. At no time-point (three, seven or 14 days post-axotomy) did any neurons in the medial septum/diagonal band stain positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling, suggesting that medial septum/diagonal band neurons do not undergo apoptosis within the first two weeks following axotomy at the time-points observed by us. Therefore, these results show that both nerve growth factor and neurotrophin-4/5 rescue the phenotype of axotomized cholinergic neurons and that these rescued neurons fail to express c-Jun in response to axotomy. In addition, since neither nerve growth factor nor neurotrophin-4/5 induced c-Jun in medial septum/diagonal band cholinergic neurons, it seems unlikely that the neurotrophic effects of nerve growth factor and neurotrophin-4/5 on cholinergic neurons are mediated via c-Jun expression. Furthermore, since axotomy failed to increase terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling in septal neurons, it appears unlikely that c-Jun expression in these axotomized neurons is related to neuronal degeneration via apoptosis.
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PMID:Axotomized septal cholinergic neurons rescued by nerve growth factor or neurotrophin-4/5 fail to express the inducible transcription factor c-Jun. 917 72

Dissociated cerebellar granule cells maintained in medium containing 25 mM potassium undergo an apoptotic death when switched to medium with 5 mM potassium. Granule cells from mice in which Bax, a proapoptotic Bcl-2 family member, had been deleted, did not undergo apoptosis in 5 mM potassium, yet did undergo an excitotoxic cell death in response to stimulation with 30 or 100 microM NMDA. Within 2 h after switching to 5 mM K+, both wild-type and Bax-deficient granule cells decreased glucose uptake to <20% of control. Protein synthesis also decreased rapidly in both wild-type and Bax-deficient granule cells to 50% of control within 12 h after switching to 5 mM potassium. Both wild-type and Bax -/- neurons increased mRNA levels of c-jun, and caspase 3 (CPP32) and increased phosphorylation of the transactivation domain of c-Jun after K+ deprivation. Wild-type granule cells in 5 mM K+ increased cleavage of DEVD-aminomethylcoumarin (DEVD-AMC), a fluorogenic substrate for caspases 2, 3, and 7; in contrast, Bax-deficient granule cells did not cleave DEVD-AMC. These results place BAX downstream of metabolic changes, changes in mRNA levels, and increased phosphorylation of c-Jun, yet upstream of the activation of caspases and indicate that BAX is required for apoptotic, but not excitotoxic, cell death. In wild-type cells, Boc-Asp-FMK and ZVAD-FMK, general inhibitors of caspases, blocked cleavage of DEVD-AMC and blocked the increase in TdT-mediated dUTP nick end labeling (TUNEL) positivity. However, these inhibitors had only a marginal effect on preventing cell death, suggesting a caspase-independent death pathway downstream of BAX in cerebellar granule cells.
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PMID:Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. 931 40

The expression of c-Jun, JunB, JunD, c-Fos and ATF-2 transcription factors was studied in L4/L5 dorsal root ganglion neurons of adult rats, in order to determine the extent to know to which extend the expression of transcription factors in vitro parallels the pathophysiological expression in vivo. First, dorsal root ganglia were dissociated and cultured for up to 15 days in vitro (culture). Second, the dorsal root and the peripheral nerve fibres were transected close at the dorsal root ganglia, and the completely axotomized dorsal root ganglia were kept in artificial cerebrospinal fluid for up to 24 h. This procedure (explantation) preserves the intraganglionic morphology intact. Culture evoked a persistent expression of c-Jun and JunD in the majority of small neurons independent on neurite extension, In contrast, the number of large neurons with c-Jun decreased and with JunD increased with incubation time. JunB and c-Fos, which were also visible in the majority of neurons, strongly decreased with culture time in both small and large neurons. ATF-2 was visible in the vast majority of neurons and did not change during the observation period. Incubation with brain-derived neurotrophic factor for 15 days reduced JunB expression and raised c-Fos expression, but did not affect c-Jun or JunD labelings. Explantation of dorsal root ganglia evoked a dramatic and rapid induction of c-Jun in neurons located in the periphery of the ganglia, an area that showed prominent apoptosis as visualized by transferase dUTP nick end-labelling, followed by a delayed increase in neurons of the central parts of dorsal root ganglia. Expression of JunB showed a dramatic increase within 2 h in the whole ganglion, but disappeared within the following hours. JunD dropped from its basal levels within 4 h and was almost absent after 8 h. c-Fos did not appear until 6 h, when transferase dUTP nick end-labelling also became detectable, and remained visible in a rather small number of neurons. As with culture, incubation of explanted dorsal root ganglia with brain-derived neurotrophic factor prevented the initial rise in JunB, accelerated and enhanced c-Fos expression, but did not alter c-Jun and JunD expression. Immunoreactivity of ATF-2 declined or disappeared in those dorsal root ganglia compartments that showed a rise in c-Jun and transferase dUTP nick end-labelling. These findings demonstrate that inducible transcription factors such as Jun and Fos proteins are differentially expressed in adult neurons in vitro when compared to pathophysiological conditions in vivo such as nerve fibre transection (axotomy or rhizotomy). Moreover, the comparison between the explantation and culture experiments suggests that it is the complete axotomy of neurons that provokes those expression patterns found in neuronal cultures of adult neurons. The rapid and persisting expression of c-Jun during neurite extension and apoptosis points at the activation of a pivotal program that might be determined by the presence or absence of ATF-2 and that is involved in regeneration or degeneration.
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PMID:Expression of Jun, Fos, and ATF-2 proteins in axotomized explanted and cultured adult rat dorsal root ganglia. 952 71

Hyperthermia has been shown to inhibit glioma growth both in vitro and in vivo, and has been reported to induce apoptosis of a variety of cells. We investigated the role of apoptosis in tumor cell death following hyperthermia in a rat glioma model representing human glioblastoma. Apoptotic cell death was evaluated by terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) and hematoxylin and eosin (H & E) staining. We also examined c-Jun expression immunohistochemically. Apoptotic cell death in rat brain tumors that grew after implantation of C6 glioma cells showed regional differences. In all rats, apoptotic cells, characterized by extreme chromatin condensation and fragmented nuclei with apoptotic bodies in H & E-stained sections, were observed in the gliomas' necrotic cores. TUNEL-positive cells were observed in the border zones between necrotic and vital tumor cells. Before hyperthermia, TUNEL-positive cells were sporadically distributed in the vital tumor tissue. After hyperthermia, the number of TUNEL-positive cells in the peripheral region of the tumor mass increased significantly, reached a peak after 6 h and returned to the basal level within 24 h (P < 0.01). C-Jun protein immunoreactivity was not observed in the cells at the tumor periphery. These data indicate that significantly apoptotic cell death unrelated to c-Jun expression occurs after hyperthermia, and that this form of cell death may be the mechanism of tumor regression following hyperthermia treatment of intracranial gliomas.
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PMID:Apoptotic cell death induced by local brain hyperthermia in a rat glioma model. 979 99

The cellular processes with a potential to lead to delayed death of neurons following transient (5 min) ischemia in gerbil hippocampus were evaluated. Neuronal apoptosis, visualized by the terminal transferase dUTP nick-end labelling (TUNEL) reaction, selectively appeared in the CA1 region of the pyramidal cell layer between the third and fourth days after the insult. Concomitantly, an enhanced immunoreactivity to anti-cJun/AP1 (N) antibody as a major component of activator protein 1 (AP1) transcriptional factor was observed in CA1 neurons. In contrast, in the early postischemic phase, the cJun/AP1 reaction was noticed in numerous neurons and glia-like cells of the CA2/CA3 region, hilus of the dentate gyrus, and region of mossy fiber terminals. In parallel, hippocampal protein binding to AP1, measured by the electrophoretic mobility shift assay (EMSA), showed biphasic enhancement at 3 and then 72-120 hours after ischemia. Supershifts, with antibodies against c-Fos and phospho-c-Jun constituencies of the AP1 dimer, revealed an increased amount of phosphorylated c-Jun in the late postischemic phase. Collectively, these results suggest diversity of AP1 complex function, regulated by its dimer composition as well as time and place of expression during postischemic reperfusion. The early, survival-supporting AP1 response, located mainly in ischemia-resistant areas of CA2/3, is followed by the delayed phase, characteristic of massive neuronal apoptosis in CA1 with concomitant increase of phospho-c-Jun in AP1 dimer.
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PMID:AP1 transcriptional factor activation and its relation to apoptosis of hippocampal CA1 pyramidal neurons after transient ischemia in gerbils. 1046 55

In endothelial cells (ECs), the transcription factor c-Jun is induced by a variety of stimuli that perturb EC function. To extend our understanding of the role of c-Jun in EC physiology, we have directed overexpression of c-Jun in human umbilical vein ECs by using a tetracycline-regulated adenoviral expression system. In this study, we report a novel observation using this system. Specific expression of c-Jun is a sufficient trigger for ECs to undergo apoptosis, as demonstrated by a set of combined assays including an ELISA specific for histone-associated DNA fragmentation, DNA laddering, and TdT-mediated dUTP nick end labeling (TUNEL). Tetracycline can effectively shut off c-Jun overexpression and prevent EC apoptosis. Cleavage of poly(ADP-ribose) polymerase was also detected in ECs overexpressing c-Jun. Moreover, inhibitors of cysteine proteases blocked the apoptosis, suggesting a caspase-associated mechanism involved in proapoptotic effects of c-Jun. To gain further insight into the role of c-Jun as a pathophysiological regulator of EC death, TAM67, a dominant-negative mutant of c-Jun, was overexpressed in human umbilical vein ECs to abrogate endogenous c-Jun/activator protein-1 activation. H(2)O(2)-triggered apoptosis was largely attenuated in ECs overexpressing TAM67. Together, these results suggest that c-Jun, as a proapoptotic molecule, may play a role in mediating the cell death program in vascular endothelium.
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PMID:c-Jun triggers apoptosis in human vascular endothelial cells. 1047 68

We have previously demonstrated that the lungs of mice can exhibit increased programmed cell death or apoptosis after hyperoxic exposure in vivo. In this report, we show that hyperoxic exposure in vitro can also induce apoptosis in cultured murine macrophage cells (RAW 264.7) as assessed by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end-labeling, and nucleosomal assays. To further delineate the signaling pathway of hyperoxia-induced apoptosis in RAW 264.7 macrophages, we first show that hyperoxia can activate the mitogen-activated protein kinase (MAPK) pathway, the extracellular signal-regulated kinases (ERKs) p42/p44, in a time-dependent manner as assessed by increased phosphorylation of ERK1/ERK2 by Western blot analyses. Neither the c-Jun NH(2)-terminal kinase/stress-activated protein kinase nor the p38 MAPK was activated by hyperoxia in these cells. Chemical or genetic inhibition of the ERK p42/p44 MAPK pathway by PD-98059, a selective inhibitor of MAPK kinase, and dominant negative mutants of ERK, respectively, attenuated hyperoxia-induced apoptosis as assessed by DNA laddering and nucleosomal ELISAs. Taken together, our data suggest that hyperoxia can induce apoptosis in cultured murine macrophages and that the MAPK pathway mediates hyperoxia-induced apoptosis.
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PMID:Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells. 1048 67

The disruption of microtubules by treating bovine aortic endothelial cells with 10(-7)-10(-5) M colchicine caused apoptosis, as evidenced by DNA laddering and TdT-mediated dUTP nick end labeling fluorescence staining. Colchicine treatment also induced a sustained activation of c-Jun NH(2)-terminal kinase (JNK) that lasted for >/=12 h. The blockade of JNK activity by using the negative interfering mutant JNK(K-R) markedly decreased the apoptosis induced by colchicine. Exposure of bovine aortic endothelial cells to laminar shear stress (12 dyn/cm(2)) caused a transient (<2 h) activation of JNK, and there was no induction of apoptosis. The sustained activation of JNK may play a significant role in the apoptosis induced by colchicine.
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PMID:Sustained JNK activation induces endothelial apoptosis: studies with colchicine and shear stress. 1051 99

Three major mammalian mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal protein kinase (JNK), have been identified in the cardiomyocyte, but their respective roles in the heart are not well understood. The present study explored their functions and cross talk in ischemia/reoxygenation (I/R)-induced cardiac apoptosis. Exposing rat neonatal cardiomyocytes to ischemia resulted in a rapid and transient activation of ERK, p38, and JNK. On reoxygenation, further activation of all 3 mitogen-activated protein kinases was noted; peak activities increased (fold) by 5.5, 5.2, and 6.2, respectively. Visual inspection of myocytes exposed to I/R identified 18.6% of the cells as showing morphological features of apoptosis, which was further confirmed by DNA ladder and terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL). Myocytes treated with PD98059, a MAPK/ERK kinase (MEK1/MEK2) inhibitor, displayed a suppression of I/R-induced ERK activation, whereas p38 and JNK activities were increased by 70.3% and 55.0%, respectively. In addition, the number of apoptotic cells was increased to 33.4%. With pretreatment of cells with SB242719, a selective p38 inhibitor, or SB203580, a p38 and JNK2 inhibitor, I/R+PD98059-induced apoptotic cells were reduced by 42.8% and 63.3%, respectively. Hearts isolated from rats treated with PD98059 and subjected to global ischemia (30 minutes)/reoxygenation (1 hour) showed a diminished functional recovery compared with the vehicle group. Coadministration of SB203580 attenuated the detrimental effects of PD98059 and significantly improved cardiac functional recovery. The data taken together suggest that ERK plays a protective role, whereas p38 and JNK mediate apoptosis in cardiomyocytes subjected to I/R, and the dynamic balance of their activities is critical in determining cardiomyocyte fate subsequent to reperfusional injury.
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PMID:Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. 1074 92


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