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

In adult rats, the expression of transcription factor proteins c-Jun and CREB and their colocalization with tyrosine hydroxylase (TH) were investigated in neurons of the substantia nigra compacta (SNC) axotomized by stereotaxic unilateral transection of the medial forebrain bundle (MFB). Axotomized SNC neurons were identified by injection of the retrograde tracer horseradish-peroxidase-coupled-gold (HRP-gold) into the ipsilateral striatum 5 days prior to MFB transection. Nuclear c-Jun immunoreactivity (IR) appeared 36 h after MFB transection in SNC neurons, was maximal after 5 days, and declined after 10 days. c-Jun-IR was visible in HRP-gold-labeled SNC neurons, demonstrating that c-Jun is in fact expressed in axotomized neurons. The constitutively expressed CREB (calcium/cAMP response element-binding protein, syn. CREB-1) was present in apparently all neuronal and glial cells in the brains of untreated rats including those SNC neurons that coexpressed TH. Three days following MFB transection, the nuclear CREB-IR disappeared in the axotomized SNC neurons labeled by TH-IR and was almost completely absent after 20 days in this neuronal population. The TH-IR rapidly declined 5 days after MFB transection, and 10 and 100 days post-axotomy the number of TH-labeled neurons was reduced by 52 and 80%, respectively. During this period, the majority of surviving TH positive neurons coexpressed c-Jun but were immunonegative for CREB. Between 3 and 60 days following MFB transection, the number of CREB-labeled glial cell nuclei increased in the ipsilateral substantia nigra by about 80%. Concomitantly, expression of GFAP, a marker protein for astrocytes, was also enhanced whereas nuclear c-Jun-, JunD-, and c-Fos-IR did not change in glial cells. These findings demonstrate that c-Jun can be expressed in axotomized neurons during the absence of CREB and suggest a role of c-Jun in the transcriptional control of the TH gene.
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PMID:Induction of c-Jun and suppression of CREB transcription factor proteins in axotomized neurons of substantia nigra and covariation with tyrosine hydroxylase. 782 Mar 66

Stress stimulates the sympathoadrenal system, causing activation of the catecholamine biosynthetic enzymes. Here we examine the changes of gene expression of tyrosine hydroxylase (TH; EC 1.14.16.2), the initial enzyme of catecholamine biosynthesis, with stress. A single immobilization of rats led to a large transient elevation in TH mRNA and a small elevation in TH immunoreactive protein and activity. Repeated daily immobilizations triggered more sustained changes in TH mRNA levels. After two immobilizations, the levels remained elevated even 3 days later. The rise in TH mRNA was followed by increased immunoreactive protein but only a small elevation in activity. With seven repeated immobilizations, the animals did not appear to adapt and still manifested a further rise in TH mRNA. TH activity was markedly elevated and returned to control levels 7 days after the immobilization. The rise in TH mRNA with a single immobilization occurred even in adrenals of hypophysectomized rats that underwent splanchnic nerve section. Immobilization for 30 min was sufficient to increase TH mRNA. The effect was abolished by the transcriptional inhibitor actinomycin D. Mobility gel-shift assays revealed increased binding of c-Fos and c-Jun to the AP-1 transcription factor site after a single immobilization, and the binding was not further elevated with repeated stress. This study shows that a single immobilization can activate TH gene expression by a nonneuronal nonpituitary-mediated pathway associated with increased binding of AP-1 transcription factors.
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PMID:Induction of tyrosine hydroxylase gene expression by a nonneuronal nonpituitary-mediated mechanism in immobilization stress. 791 37

Membrane depolarization of PC12 cells using 50 mM KCl leads to induction of tyrosine hydroxylase (TH) mRNA. This induction of TH mRNA is apparently due to increased TH gene promoter activity mediated by the influx of Ca2+. In PC12 cells transiently transfected with a chimeric gene expressing chloramphenicol acetyltransferase (CAT) driven by the proximal TH gene 5'-flanking region, 50 mM KCl increases TH gene promoter activity 3-4-fold. Promoter analysis utilizing TH-CAT constructs containing mutagenized sequences indicates that this response to the depolarization-mediated influx of Ca2+ is primarily dependent on both the TH cAMP-responsive element (CRE) and TH activating protein-1 (AP1) site. Minimal promoter constructs that contain a single copy of either the TH CRE or TH AP1 site fused upstream of the TH gene basal promoter are only modestly responsive or nonresponsive, respectively, to depolarization. However, both these constructs are strongly responsive to the calcium ionophore, A23187. Gel shift assays indicate that TH AP1 complex formation is dramatically increased after treatment with either 50 mM KCl or A23187. Using antibodies to transcription factors of the Fos and Jun families, we show that the nuclear proteins comprising the inducible TH AP1 complex include c-Fos, c-Jun, JunB, and JunD. In cAMP-responsive element binding protein (CREB)-deficient cell lines that express antisense RNA complementary to CREB mRNA, the response of the TH gene promoter to cyclic AMP is dramatically inhibited, but the response to A23187 remains robust. This result indicates that transcription factors other than CREB can participate in the Ca2+-mediated regulation of the TH gene. In summary, our results support the hypothesis that regulation of the TH gene by Ca2+ is mediated by mechanisms involving both the TH CRE and TH AP1 sites and that transcription factors other than or in addition to CREB participate in this response.
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PMID:Tyrosine hydroxylase gene promoter activity is regulated by both cyclic AMP-responsive element and AP1 sites following calcium influx. Evidence for cyclic amp-responsive element binding protein-independent regulation. 903 29

The expression of c-Jun in the brains of young (8-week-old) and older (52-week-old) mice following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was investigated immunocytochemically. Both age groups exhibited reduction in the number of dopaminergic neurons in the substantia nigra after administration of MPTP. There was a significant difference in the magnitude of decrease in the number of dopaminergic neurons between the two groups, as has previously been reported, and the older mice exhibited more extensive loss of dopaminergic neurons in the substantia nigra after MPTP administration than did the young mice. Prolonged c-Jun expression was induced in the substantia nigra following administration of MPTP, and this induction was more prominent in the older mice than in the young mice. Maximum expression of c-Jun occurred on day 7 after the administration of MPTP in both groups. Double staining for tyrosine hydroxylase (TH; a dopaminergic neuron marker) and c-Jun revealed their co-localization indicating that the cells expressing c-Jun were dopaminergic neurons. Cytoplasmic volumes of strongly c-Jun positive cells were reduced, suggesting that they may have been degenerating. In situ end labeling revealed no apoptotic neurons after MPTP administration. These results suggest the existence of some cascade mechanism of nonapoptotic death of dopaminergic neurons following administration of MPTP.
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PMID:Expression of c-Jun in dopaminergic neurons of the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. 938 16

Neurotransmitter biosynthesis is regulated by environmental stimuli, which transmit intracellular signals via second messengers and protein kinase pathways. For the catecholamine biosynthetic enzymes, dopamine beta-hydroxylase and tyrosine hydroxylase, regulation of gene expression by cyclic AMP, diacyl glycerol, and Ca2+ leads to increased neurotransmitter biosynthesis. In this report, we demonstrate that the cAMP-mediated regulation of transcription from the dopamine beta-hydroxylase promoter is mediated by the AP1 proteins c-Fos, c-Jun, and JunD. Following treatment of cultured cells with cAMP, protein complexes bound to the dopamine beta-hydroxylase AP1/cAMP response element element change from consisting of c-Jun and JunD to include c-Fos, c-Jun, and JunD. The homeodomain protein Arix is also a component of this DNA-protein complex, binding to the adjacent homeodomain recognition sites. Transfection of a dominant negative JunD expression plasmid inhibits cAMP-mediated expression of the dopamine beta-hydroxylase promoter construct in PC12 and CATH.a cells. In addition to the role of c-Fos in regulating dopamine beta-hydroxylase gene expression in response to cAMP, a second pathway, involving Rap1/B-Raf is involved. These experiments illustrate an unusual divergence of cAMP-dependent protein kinase signaling through multiple pathways that then reconverge on a single element in the dopamine beta-hydroxylase promoter to elicit activation of gene expression.
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PMID:AP1 proteins mediate the cAMP response of the dopamine beta-hydroxylase gene. 972 25

Stress activated protein kinases (SAPK) are key enzymes mediating the cellular response to stressful stimuli. While they are intensively studied in cultured cells, little is known about their physiological role in vivo, or relevance to pathological conditions. Therefore we examined the effect of various times of immobilization on c-Jun N-terminal protein kinase (JNK) activity in several rat stress responsive tissues and in a number of other locations. The abundance and relative distribution of JNK isoforms, the basal levels, time course and relative magnitude of stress induced JNK activity differed among tissues and regions of the brain of the same animal. JNK immunoreactive proteins were most abundant in the brain, especially in the hippocampus, hypothalamus and frontal cortex. Marked activation in response to immobilization stress was observed in adrenal medulla, adrenal cortex, aorta and hippocampus, less pronounced in locus coeruleus. JNK was not affected in superior cervical ganglia, pituitary, hypothalamus, frontal cortex and cerebellum. In adrenal medulla, the activation of JNK by single immobilization stress is correlated with increased transcription of stress-responsive genes, tyrosine hydroxylase and dopamine beta-hydroxylase. These data suggest a potential role of JNK signal transduction pathway in mediating the long term adaptation to stressful stimuli in vivo.
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PMID:Selective in vivo stimulation of stress-activated protein kinase in different rat tissues by immobilization stress. 987 60

The immunophilin ligand FK506 (Tacrolimus) is used for prevention of graft rejection following organ transplantation. FK506 is a high-affinity ligand for FK506-binding proteins, an immunophilin subgroup of peptidyl-prolyl-cis/trans-rotamases abundant in the mammalian brain. Here, we demonstrate that FK506 is a potent survival factor that prevents neuronal cell death following axotomy of central intrinsic neurons. Administration of FK506 (2 mg/kg, s.c., per day for two days pre-axotomy and for up to eight days post-axotomy) effectively delayed and reduced the death of axotomized neurons in the substantia nigra pars compacta following transection of the medial forebrain bundle. In saline-treated controls, 75%, 89% and 92% of nigral neurons died after 25, 50 and 60 days post-axotomy, respectively. In contrast, application of FK506 resulted in survival of 46%, 44% and 28% of the axotomized nigral neurons, and the majority of these surviving neurons showed continuous expression of tyrosine hydroxylase, the pacemaker enzyme for dopamine synthesis. Moreover, FK506 significantly reduced the expression of the inducible transcription factor c-Jun and its N-terminal phosphorylation and prevented the axotomy-induced suppression of the constitutive transcription factor ATF-2 in neurons of the substantia nigra and mammillary body. The latter is also axotomized by the coincident transection of the mammillothalamic tract, but the mammillary neurons survive the axotomy. In contradistinction to FK506, the non-immunosuppressive FK506-binding protein ligand GPI-1046 (25 or 12.5 mg/kg, applied once or twice per day for two days pre-axotomy and for eight days post-axotomy) was completely ineffective for all these parameters investigated. Finally, FK506, but not GPI-1046, impressively accelerated the recovery from surgery. Our data provide the first evidence that FK506 acts as a neuroprotective molecule that rescues axotomized otherwise degenerating central intrinsic neurons in the adult mammalian brain by mechanisms that interfere with the transcriptional program of the axotomy-induced cell body response, such as activating transcription factor-2 suppression and c-Jun expression and phosphorylation.
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PMID:The immunophilin ligand FK506, but not GPI-1046, protects against neuronal death and inhibits c-Jun expression in the substantia nigra pars compacta following transection of the rat medial forebrain bundle. 1067 Apr 42

The effect of cycloheximide (CHX; 5 mg/kg) on proenkephalin (proENK) and tyrosine hydroxylase (TH) mRNA expression in rat central and peripheral nervous systems was studied. CHX increased proENK and TH mRNA levels in the adrenal gland, but not in hippocampus, striatum, midbrain, brainstem, pituitary, and hypothalamus. The pretreatment with actinomycin D (0.5 mg/kg) significantly decreased CHX-induced proENK and TH mRNA expression, suggesting that the CHX-dependent increase of these mRNA levels may be caused by the increase of transcriptional activity rather than RNA stabilization. To investigate the factors involved in CHX-induced proENK and TH mRNA expression, the effect of CHX on activator protein-1 (AP-1), cAMP response element (CRE) binding protein (CREB), and glucocorticoid response element (GRE) was tested. In AP-1, the basal expression of Fra-2 and c-Jun proteins and AP-1 DNA binding activity in the adrenal medulla was higher than other tissues tested, but CHX reduced these protein levels and AP-1 DNA binding activity. In CREB, CHX time dependently increased the level of phospho-CREB without altering total CRE level and CRE DNA binding activity. Furthermore, phospho-CREB actively participated in CRE DNA binding activity. In GRE, although CHX increased plasma and adrenal corticosterone level, RU486 (10 mg/kg) reduced CHX-induced proENK, but not TH, mRNA level in a partial manner. These results suggest that the basal expression of proENK and TH mRNA transcription in the adrenal gland seems to be tonically inhibited by de novo protein synthesis. In addition, CHX-dependent increase of proENK and TH mRNA expression in the adrenal medulla is well correlated with phospho-CREB level, but not AP-1. Finally, glucocorticoid seems to be involved at least partially in CHX-dependent proENK, but not TH, mRNA expression in the adrenal medulla.
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PMID:Cycloheximide increases proenkephalin and tyrosine hydroxylase gene expression in rat adrenal medulla. 1082 88

The precise mechanisms by which beneficial responses to acute stress are transformed into long-term pathological effects of chronic stress are largely unknown. Western blot analyses revealed that members of the AP1 transcription factor family are differentially regulated by single and repeated stress in the rat adrenal medulla, suggesting distinct roles in establishing stress-induced patterns of gene expression in this tissue. The induction of c-fos was transient, whereas marked elevation of long-lasting Fos-related antigens, including Fra2, was observed after repeated immobilization. We investigated DNA protein interactions at the AP1-like promoter elements of two stress-responsive genes, tyrosine hydroxylase and dopamine beta-hydroxylase. Increased DNA-binding activity was displayed in adrenomedullary extract from repeatedly stressed rats, which was predominantly composed of c-Jun- and Fra2-containing dimers. The induction of Fra2 and increased AP1-like binding activity was reflected in sustained transcriptional activation of tyrosine hydroxylase and dopamine beta-hydroxylase genes after repeated episodes of stress. The functional link between Fra2 and regulation of tyrosine hydroxylase and dopamine beta-hydroxylase transcription was confirmed in PC12 cells coexpressing this factor and the corresponding promoter-reporter gene constructs. These studies emphasize the potential importance of stress-evoked increases in the expression of the Fra2 gene for in vivo adaptations of the adrenal catecholamine producing system.
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PMID:Fos-related antigen 2: potential mediator of the transcriptional activation in rat adrenal medulla evoked by repeated immobilization stress. 1090 2

The stress-activated protein kinase (SAPK) cascade serves a critical role in the apoptotic death of neuronal cells in response to a variety of cellular stresses. Recent in vitro and in vivo evidence has directly implicated this kinase in the death of dopaminergic nigral neurons in the MPTP model of Parkinson's disease (PD). To assess the involvement of c-Jun, a key transcription factor substrate of SAPK (also known as c-Jun N-terminal kinase, or JNK) in the MPTP-induced death of dopaminergic nigral neurons, we determined the ability of MPP+, the active toxin metabolite of MPTP, to induce the phosphorylated form of c-Jun in dopaminergic neurons in nigral (ventral mesencephalon) cultures. At a dose of MPP+ that specifically induces apoptotic changes in nuclear morphology in tyrosine hydroxylase-positive (dopaminergic) cells in these cultures, MPP+ induces nuclear phospho-c-Jun immunoreactivity (IR). The peak induction of phospho-c-Jun IR was observed 16h after beginning MPP+ exposure, and preceded the maximal induction of apoptotic nuclear changes by approximately 8h. These data support an important role for the SAPK/JNK pathway including its c-Jun transcriptional target in the apoptotic death of dopaminergic nigral neurons in the MPTP model of PD.
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PMID:The parkinsonian neurotoxin, MPP+ induces phosphorylated c-Jun in dopaminergric neurons of mesencephalic cultures. 1147 76


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