UNIPROT:P05412 - FACTA Search

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)

Permanent or temporary disruption of cerebral blood flow rapidly depletes brain regions of their limited energy reserves (glycogen, glucose, oxygen, ATP) leading to an energy crisis. Tissue damage occurs due to the energy crisis. The central part of the damage, the ischaemic "core" region is surrounded by zones of the shell-like penumbra. Necrotic, as well as apoptotic cell death could be identified in the penumbra. Going away from the ischaemic core different neurochemical processes are occurring by space and time. "Immediate early response" genes (c-fos, fos-B, c-Jun, krox 20, 24) are activated, heatshock proteins (hsp 70, 72, HSF, HSE, HIF), cytokines (TNF-alpha, IL-1 beta), inflammatory factors (COX), adhesion and glial factors (ICAM-1, ELAM-1, P-selectin), vasoactive factors (IL-6, -10, PAF), reactive oxigen radicals and connected factors (O2, OH, NO, NOS, SOD) are produced within minutes and hours. Cell deaths, necrosis and apoptosis due to the activation of calpains, caspases and nucleases occur in days. In parallel, growth factors and plasticity proteins (BDNF, NGF, TGF-beta, VEGF, PDGF, GAP-43) are activated as a basis of functional rehabilitation.
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PMID:[Regulatory mechanisms in focal cerebral ischemia. New possibilities in neuroprotective therapy]. 1212 84

Sympathetic neurons depend on NGF binding to TrkA for their survival during vertebrate development. NGF deprivation initiates a transcription-dependent apoptotic response, which is suggested to require activation of the transcription factor c-Jun. Similarly, apoptosis can also be induced by selective activation of the p75 neurotrophin receptor. The transcriptional dependency of p75-mediated cell death has not been determined; however, c-Jun NH2-terminal kinase has been implicated as an essential component. Because the c-jun-null mutation is early embryonic lethal, thereby hindering a genetic analysis, we used the Cre-lox system to conditionally delete this gene. Sympathetic neurons isolated from postnatal day 1 c-jun-floxed mice were infected with an adenovirus expressing Cre recombinase or GFP and analyzed for their dependence on NGF for survival. Cre immunopositive neurons survived NGF withdrawal, whereas those expressing GFP or those uninfected underwent apoptosis within 48 h, as determined by DAPI staining. In contrast, brain-derived neurotrophic factor (BDNF) binding to p75 resulted in an equivalent level of apoptosis in neurons expressing Cre, GFP, and uninfected cells. Nevertheless, cycloheximide treatment prevented BDNF-mediated apoptosis. These results indicate that whereas c-jun is required for apoptosis in sympathetic neurons on NGF withdrawal, an alternate signaling pathway must be induced on p75 activation.
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PMID:c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation. 1216 68

NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) are protein molecules (MW 26 and 13.6 kDa, respectively) that are neuroprotective in the middle cerebral artery occlusion (MCAO) rat stroke model. Their mechanism of action involves the activation of transcription factor AP-1 that turns on neuronal growth genes. In our ongoing studies we are designing short peptides that mimic some of the properties of full-length neurotrophic factors. We have synthesized a neuroprotective 14-amino acid peptide (CMX-9236) with an N-terminal docosahexaenoic acid (DHA). DHA enhances entry through the blood-brain barrier. Using primary rat brain cortical cultures and a fluorescent assay we found that CMX-9236 can counteract the excitotoxic effects of glutamate or kainate, reversing the intracellular accumulation of Ca(2+) to normal levels. Administration (i.v.) of CMX-9236 post initiation of ischemia reduced the lesion volumes from 178+/-50 to 117+/-55 mm(3) in the temporary rat MCAO model (90 min), and from 216+/-58 to 127+/-57 mm(3) in the permanent (24 h) model for stroke, corresponding to 34+/-28% (P=0.01) and 41+/-19% (P=0.038) reductions of the infarct volumes. Neurological behavior scores showed 57 and 47% improvements for treated temporary and permanent models, respectively. Dose-response studies indicated a 60-fold activation of AP-1 transcription factor in cells treated with 100 ng/ml of the peptide. These studies illustrate that a small peptide can function as a neuroprotective agent and an activator of a beneficial signal transduction pathway.
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PMID:Neuroprotective effects of a new synthetic peptide, CMX-9236, in in vitro and in vivo models of cerebral ischemia. 1256 Jan 27

Ependymin (EPN) is a goldfish brain neurotrophic factor previously shown to function in a variety of cellular events related to long-term memory formation and neuronal regeneration. CMX-8933, an 8-amino-acid synthetic peptide fragment of EPN, was designed for aiding an investigation of the biological properties of this glycoprotein. We reported from previous studies that treatment of mouse neuroblastoma (NB2a) cultures with CMX-8933 promotes activation of transcription factor AP-1, a characteristic previously associated with the following full-length neurotrophic factors: nerve growth factor, neurotropin-3, and brain-derived neurotrophic factor. The CMX-8933-activated AP-1 specifically bound an AP-1 consensus probe and appeared to contain c-Jun and c-Fos protein components in antibody supershift experiments. Because AP-1 influences a variety of positive and negative cellular processes, determined in part by its exact protein composition and mechanism of activation, we extended these initial AP-1 observations in the current study to confirm the identity of the CMX-8933-activated c-Jun and c-Fos components. CMX-8933 increases the enzymatic activity of c-Jun N-terminal kinase (JNK), increases the phosphorylation of JNK and c-Jun proteins, and increases the cellular titers of c-Jun and c-Fos mRNAs. Furthermore, the AP-1 activated by CMX-8933 is functional, insofar as it transactivates both synthetic and natural AP-1-dependent reporter plasmids. Inhibition studies indicate that activation of the 8933-induced AP-1 occurs via the mitogen-activated protein kinase pathway. These data are in agreement with the recently proposed model for the conversion of short- to long-term synaptic plasticity and memory, in which a JNK-activated transcription factor AP-1, containing c-Jun and c-Fos components, functions at the top of a hierarchy of transcription factors known to regulate long-term neural plasticity.
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PMID:A peptide fragment of ependymin neurotrophic factor uses protein kinase C and the mitogen-activated protein kinase pathway to activate c-Jun N-terminal kinase and a functional AP-1 containing c-Jun and c-Fos proteins in mouse NB2a cells. 1269 7

In the present study, we examined the effects of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin growth factor (IGF-1) on adult motoneuron survival following spinal root avulsion. The expression of neuronal nitric oxide synthase (nNOS), c-Jun, and the low-affinity neurotrophin receptor (P75) following treatment with these neurotrophic factors was also examined. In control animals, approximately 80% of spinal motoneurons were nNOS positive at 3 weeks following the lesion, whereas in GDNF or BDNF treated animals no nNOS positive motoneurons were found at the same time point. Following injury and treatment with GDNF and BDNF increased numbers of motoneurons were c-Jun and P75 positive. By 6 weeks following the lesion, only approximately 28% of motoneurons persisted in control animals whereas about 90% of motoneurons survived injury following treatment with either GDNF or BDNF. In contrast, CNTF and IGF-1 were ineffective in either inhibiting nNOS expression or preventing motoneuron death. Our results provide in vivo evidence that the survival of injured adult mammalian motoneurons can be promoted by specific neurotrophic factors, and that this effect is associated with inhibition of nNOS expression and up-regulation of c-Jun and P75 expression.
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PMID:GDNF and BDNF alter the expression of neuronal NOS, c-Jun, and p75 and prevent motoneuron death following spinal root avulsion in adult rats. 1290 44

The epidermal growth factor (EGF) receptor plays an important role in epithelial cells by controlling cell proliferation and survival. Keratinocytes also express another class of receptor tyrosine kinases, the neurotrophin receptors. To analyze the biological role of the neurotrophin brain-derived neurotrophic factor (BDNF) in keratinocytes, we expressed the BDNF receptor TrkB in immortalized human HaCaT keratinocytes. Stimulation of HaCaT-TrkB cells with BDNF induced DNA synthesis and increased mitochondrial reduction capacities, both indications of proliferating cells. An analysis of the signal transduction cascade revealed that the activated TrkB receptor effectively utilized components of the EGF receptor signaling pathway to control cell proliferation. Mitogenic signaling induced by BDNF or EGF was completely abrogated by the MAP kinase kinase inhibitor PD-98059, whereas inhibition of phosphatidylinositol 3-kinase by wortmannin only delayed the proliferative response. The importance of the extracellular signal-regulated kinase signaling pathway for growth of HaCaT keratinocytes was further demonstrated with HaCaT cells engineered to express an inducible A-Raf-estrogen receptor fusion protein (DeltaA-Raf:ER). Despite differences in the amplitude and duration of extracellular signal-regulated kinase activation, HaCaT cells expressing DeltaA-Raf:ER proliferated after activation of mutant A-Raf protein kinase. Proliferation was completely inhibited by PD-98059. Proliferation of HaCaT cells induced by EGF, BDNF, or DeltaA-Raf:ER was also accompanied by biosynthesis of the transcription factors Egr-1 and c-Jun, suggesting that these proteins may be part of the mitogenic signaling cascade.
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PMID:Brain-derived neurotrophic factor-, epidermal growth factor-, or A-Raf-induced growth of HaCaT keratinocytes requires extracellular signal-regulated kinase. 1507 11

Visual cortex ablation in newborn rats causes a rapid and almost complete degeneration of neurones in the dorsal lateral geniculate nucleus (dLGN), as a consequence of the axotomy of geniculo-cortical fibres. Death of dLGN neurones occurs by apoptosis and is partially prevented (approximately 50%) by intraocular delivery of brain-derived neurotrophic factor (BDNF). Here we investigated the molecular mechanisms of BDNF-mediated neuroprotection. We found that exogenous administration of BDNF partially decreases (approximately 50%) the up-regulation of apoptotic proteins (phosphorylated c-Jun, cytochrome C and cleaved caspase 3), that occurs in dLGN neurones following visual cortex ablation at postnatal day 7. These results demonstrate that the neuroprotective action of BDNF on axotomised dLGN neurones involves the partial blockade of well-characterised apoptotic pathways.
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PMID:BDNF down-regulates the caspase 3 pathway in injured geniculo-cortical neurones. 1548 79

Small-molecule mixed-lineage kinase (MLK) inhibitors, such as CEP-1347 [3,9-bis[(ethylthio)methyl]-(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H, 11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one] and CEP-11004 [3,9-bis-[(isopropylthio)methyl]-(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one], prevent c-Jun NH(2)-terminal kinase (JNK) pathway activation as well as the consequent neuronal cell death in many cell culture and animal models. In the cell culture model of nerve growth factor (NGF)-deprived sympathetic neurons, we find that CEP-11004 induced a approximately 3-fold increase in the mRNA and protein levels of TrkA, the NGF receptor. This resulted in ligand-independent activation of the TrkA receptor and the downstream phosphatidylinositol 3-kinase (PI3-kinase) pathway. Addition of the Trk inhibitor K252a [(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)-trinden-1-one] or the PI3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] significantly decreased the protein synthesis rates, mitochondrial function, and neuronal survival maintained by CEP-11004. In contrast to sympathetic neurons, MLK inhibitors maintain only short-term survival of potassium- and serum-deprived rat cerebellar granule neurons (CGNs), despite continuous inhibition of the JNK pathway. We found that similar to sympathetic neurons, CEP-11004 increased the levels of the Trk receptor expressed in CGNs, TrkB. However, CGNs required the addition of the exogenous ligand brain-derived neurotrophic factor (BDNF) to activate the PI3-kinase pathway and to maintain long-term survival. BDNF activated TrkB, but caused rapid down-regulation of activated receptors and maintained only minimal survival. Therefore, increase in TrkB levels by CEP-11004 mediated a synergism with BDNF resulting in long-term survival in response to the combined treatment of CEP-11004 and BDNF. Taken together, our studies suggest that in addition to the direct inhibition of the JNK pathway, the indirect activation of the PI3-kinase pathway via Trk activation is important for MLK inhibitor-mediated neuronal survival and trophism.
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PMID:Mixed-lineage kinase inhibitors require the activation of Trk receptors to maintain long-term neuronal trophism and survival. 1552 94

The mood stabilizing drug lithium has emerged as a robust neuroprotective agent in preventing apoptosis of neurons. Long-term treatment with lithium effectively protects primary cultures of rat brain neurons from glutamate-induced, NMDA receptor-mediated excitotoxicity. This neuroprotection is accompanied by an inhibition of NMDA-receptor-mediated calcium influx, upregulation of anti-apoptotic Bcl-2, downregulation of pro-apoptotic p53 and Bax, and activation of cell survival factors. Lithium treatment antagonizes glutamate-induced activation of c-Jun-N-terminal kinase (JNK), p38 kinase, and AP-1 binding, which has a major role in cytotoxicity, and suppresses glutamate-induced loss of phosphorylated cAMP responsive element binding protein (CREB). Lithium also induces the expression of brain-derived neurotrophic factor (BDNF) and subsequent activation TrkB, the receptor for BDNF, in cortical neurons. The activation of BDNF/TrkB signaling is essential for the neuroprotective effects of this drug. In addition, lithium stimulates the proliferation of neuroblasts in primary cultures of CNS neurons. Lithium also shows neuroprotective effects in rodent models of diseases. In a rat model of stroke, post-insult treatment with lithium or valproate, another mood stabilizer, at therapeutic doses markedly reduces brain infarction and neurological deficits. This neuroprotection is associated with suppression of caspase-3 activation and induction of chaperone proteins such as heat shock protein 70. In a rat model of Huntington's disease (HD) in which an excitotoxin is unilaterally infused into the striatum, both long- and short-term pretreatment with lithium reduces DNA damage, caspase-3 activation, and loss of striatal neurons. This neuroprotection is associated with upregulation of Bcl-2. Lithium also induces cell proliferation near the injury site with a concomitant loss of proliferating cells in the subventricular zone. Some of these proliferating cells display neuronal or astroglial phenotypes. These results corroborate our findings obtained in primary neuronal cultures. The neuroprotective and neurotrophic actions of lithium have profound clinical implications. In addition to its present use in bipolar patients, lithium could be used to treat acute brain injuries such as stroke and chronic progressive neurodegenerative diseases.
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PMID:Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? 1558 3

Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) are potent trophic factors for dorsal root ganglion cells. In addition, these factors are produced in subsets of dorsal root ganglion cells and transported anterogradely to their terminals in the superficial dorsal horn of the spinal cord, where they constitute the only source of GDNF and BDNF. We investigated the effect of 10 mug GDNF and BDNF injected by lumbar puncture on the expression of the immediate early gene (IEG) products c-Fos, c-Jun, and Krox-24 in the adult rat dorsal horn. In the dorsal horn of S1 spinal segments, GDNF and BDNF induced a strong increase in IEG expression, which was most pronounced in laminae I and II (2.9- to 4.5-fold). More distal from the injection site, in the dorsal horn of L1/L2 spinal segments, the increase in IEG expression was less pronounced, suggesting a concentration-dependent effect. In order to explain the effects of intrathecally injected GDNF, we investigated whether lumbo-sacral dorsal horn neurons expressed RET protein, the signal-transducing element of the receptor complex for GDNF. It was found that several of these neurons contained RET immunoreactivity and that some of the RET-labeled neurons had the appearance of nociceptive-specific cells, confirming their presumed role in pain transmission. Additionally, using double-labeling immunofluorescence combined with confocal microscopy, it was found that after intrathecal GDNF injection 35% of c-Fos-labeled cells were also labeled for RET. These results demonstrate that intrathecally administered GDNF and BDNF induce IEG expression in dorsal horn neurons in the adult rat, supposedly by way of their cognate receptors, which are present on these neurons. We further suggest that the endogenous release of GDNF and BDNF, triggered by nociceptive stimuli, is involved in the induction of changes in spinal nociceptive transmission as in various pain states.
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PMID:Intrathecal injection of GDNF and BDNF induces immediate early gene expression in rat spinal dorsal horn. 1589 62

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