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)

A unilateral hypoxia-ischaemia (HI) 21-day-old rat preparation was used to assess the effects of HI on the expression of the immediate-early gene proteins (IEGPs) c-Fos/FRAs, Fos B, c-Jun, Jun B, Jun D, Krox 20, Krox 24, and on the mRNA for the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Moderate HI (15 min hypoxia) produced delayed, selective neuronal death and was associated with a rapid induction of c-Fos, Fos B, Jun B, Jun D, and c-Jun proteins, but not Krox 20 protein or BDNF mRNA, in neurons on the side of HI and also a delayed expression of c-Jun (and to a lesser extent c-Fos/FRA's and Fos B) 24-48 h after HI in neurons that underwent delayed neuronal death. Krox 24 showed an initial induction followed by a long-lasting suppression of its expression in regions undergoing cell loss. Severe HI (60 min hypoxia) resulted in seizures and rapid neuronal loss and infarction (necrotic cell death) on the side of HI, and was associated with early induction of c-Fos, Fos B, c-Jun, Jun B, Jun D, Krox 20 and Krox 24 protein and BDNF mRNA in neurons on the non-ligated side of the brain. Fos, c-Jun, Jun B, Jun D and Krox 24, but not Krox 20, Fos B, or BDNF mRNA, were also induced in non-nerve cells on the damaged side of the brain after both moderate and severe HI, and many of these cells appeared to be dividing. Thus, moderate HI induces IEGP's in neurons and non-nerve cells in damaged regions, whereas severe HI induces IEGP's and BDNF in non-damaged regions. c-Jun (and to a lesser extent c-Fos/FRA's) showed a prolonged expression in neurons undergoing delayed, but not necrotic, cell death suggesting that they may be involved in the biochemical cascade that causes selective delayed neuronal death. BDNF was not induced by HI, and therefore, does not appear to play an endogenous neuroprotective role in the CNS.
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PMID:Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain. 798 48

During development, sympathetic neurons are critically dependent on nerve growth factor (NGF) for survival. Neurons isolated from the superior cervical ganglia (SCG) of embryonic rodents and maintained for 1 week in vitro undergo programmed cell death in response to NGF deprivation. As the cells mature in vitro and in vivo, however, these neurons develop a resistance to NGF deprivation and become much less acutely dependent on NGF for survival. Using an in vitro model of neuronal maturation, we confirmed that SCG neurons maintained in culture for 3-4 weeks did not experience a dramatic loss in viability after NGF removal, yet they did undergo the initial biochemical and genetic changes elicited by NGF deprivation of young neurons. NGF deprivation of mature neurons produced rapid decreases in glucose uptake and protein and RNA synthesis rates, increased phosphorylation of c-Jun, and an increase in c-jun mRNA. Mature neurons, however, experienced a block in the cell death program before the final stages of the pathway activated in young neurons, which includes the induction of c-fos mRNA and characteristic apoptotic nuclear changes. This maturation-induced block was indistinguishable by these criteria from the block produced by Bax deficiency. Expression of Bax in mature neurons restored the apoptotic pathway, such that after NGF removal, Bax-overexpressing mature neurons resumed the apoptotic program, including the induction of c-Fos and passage through a caspase checkpoint. Thus, a block in the apoptotic program at or near the BAX checkpoint accounts for the decreased dependence of mature neurons on neurotrophic factor to maintain survival.
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PMID:Analysis of the mechanism of loss of trophic factor dependence associated with neuronal maturation: a phenotype indistinguishable from Bax deletion. 939 Oct 20

Mammalian mitogen-activated protein kinases include the extracellular signal-regulated protein kinase, the c-Jun amino-terminal kinase, and the p38 subgroups. Sustained activation of Jun kinase and p38 have been shown to precede apoptosis of PC12 pheochromocytoma cells induced by withdrawal of trophic factors. To investigate the possible role of p38 in neuronal apoptosis, we tested the effect of two selective p38 inhibitors, the pyridinyl imidazole compounds SB203580 and SB202190, on different populations of chick embryonic neurons in vitro. Both substances promoted the in vitro survival of sensory, sympathetic, ciliary and motor neurons in a dose-dependent fashion. When assayed in nerve growth factor-stimulated PC12 cells, SB203580 pretreatment inhibited the activation of both ribosomal S6 kinases-1 and -2 with the same IC50 (approximately 30 microM) that inhibited apoptosis in primary neurons. Thus, p38 inhibitor-sensitive pathways may be involved in apoptosis of neurotrophic factor-deprived primary neurons, and in activation of ribosomal S6 kinases.
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PMID:Inhibitors of p38 mitogen-activated protein kinase promote neuronal survival in vitro. 958 93

The responses of the central (CNS) and peripheral (PNS) nervous system to axotomy differ in a number of ways; these differences can be observed in both the cell body responses to injury and in the extent of regeneration that occurs in each system. The cell body responses to injury in the PNS involves the upregulation of genes that are not upregulated following comparable injuries to CNS neurons. The expression of particular genes following injury may be essential for regeneration to occur. In the present study, we have evaluated the hypothesis that expression of the inducible transcription factor c-Jun is associated with regrowth of axotomized CNS neurons. In these experiments, we compared c-Jun expression in axotomized brainstem neurons after thoracic spinal cord hemisection alone (a condition in which no regrowth occurs) and in groups of animals where hemisections were combined with treatments such as transplants of fetal spinal cord tissue and/or application of neurotrophic factors to the lesion site. The latter conditions enhance the capacity of the CNS for regrowth. We have demonstrated that hemisections alone do not upregulate expression of c-Jun, indicating that this particular cell body response is not a direct result of axotomy. However, c-Jun expression is upregulated in animals that received application of transplants and neurotrophins. Because these interventions also promote sprouting and regrowth of CNS axons after spinal cord lesions, we suggest that transplants and exogenous neurotrophic factor application activate a cell body response consistent with a role for c-Jun in axonal growth.
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PMID:Fetal spinal cord transplants and exogenous neurotrophic support enhance c-Jun expression in mature axotomized neurons after spinal cord injury. 991 6

This review primarily discusses work that has been performed in our laboratories and that of our direct collaborators and therefore does not represent an exhaustive review of the current literature. Our aim is to further discuss the role that gene expression plays in neuronal plasticity and pathology. In the first part of this review we examine activity-dependent changes in the expression of inducible transcription factors (ITFs) and neurotrophins with long-term potentiation (LTP) and kindling. This work has identified particular ITFs (Krox-20 and Krox-24) and neurotrophin systems (particularly the brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase-B, Trk-B system) that may be involved in stabilizing long-lasting LTP (i.e. LTP3). We also show that changes in the expression of other ITFs (Fos, Jun-D and Krox-20) and the BDNF/trkB neurotrophin system may play a central role in the development of hippocampal kindling, an animal model of human temporal lobe epilepsy. In the next part of this review we examine changes in gene expression after neuronal injuries (ischemia, prolonged seizure activity and focal brain injury) and after nerve transection (axotomy). We identify apoptosis-related genes (p53, c-Jun, Bax) whose delayed expression selectively increases in degenerating neurons, further suggesting that some forms of neuronal death may involve apoptosis. Moreover, since overexpression of the tumour-suppressor gene p53 induces apoptosis in a wide variety of dividing cell types we speculate that it may perform the same function in post-mitotic neurons following brain injuries. Additionally, we show that neuronal injury is associated with rapid, transient, activity-dependent expression of neurotrophins (BDNF and activinA) in neurons, contrasting with a delayed and more persistent injury-induced expression of certain growth factors (IGF-1 and TGFbeta) in glia. In this section we also describe results linking ITFs and neurotrophic factor expression. Firstly, we show that while BDNF and trkB are induced as immediate-early genes following injury, the injury-induced expression of activinA and trkC may be regulated by ITFs. We also discuss whether loss of retrograde transport of neurotrophic factors such as nerve growth factor following nerve transection triggers the selective and prolonged expression of c-Jun in axotomized neurons and whether c-Jun is responsible for regeneration or degeneration of these axotomized neurons. In the last section we further examine the role that gene expression may play in memory formation, epileptogenesis and neuronal degeneration, lastly speculating whether the expression of various growth factors after brain injury represents an endogenous neuroprotective response of the brain to injury. Here we discuss our results which show that pharmacological enhancement of this response with exogenous application of IGF-1 or TGF-beta reduces neuronal loss after brain injury.
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PMID:Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system. 1008 Mar 84

This study was designed to determine whether induction and phosphorylation of the transcription factor c-Jun is associated with lesion-induced death of dopaminergic neurons of the substantia nigra pars compacta, and if this cellular response is modulated by glial-cell-line-derived neurotrophic factor. In adult rats, delayed dopaminergic neuron cell death induced by intrastriatal 6-hydroxydopamine injection led to a marked increase in the number of both c-Jun- and phosphorylated c-Jun-immunoreactive nuclei in the substantia nigra pars compacta. The response was maximal before any significant loss of nigral neurons could be detected (on day 7 post lesion) and was confined to the dopaminergic neurons. Similarly, 6-hydroxydopamine lesion of the striatal dopaminergic terminals or excitotoxic lesion of the striatal target neurons in neonatal rats resulted in an increased number of c-Jun- and phosphorylated c-Jun-immunoreactive nigral nuclei that preceded the loss of nigral dopaminergic neurons. By contrast, after an excitotoxic lesion of the striatal target neurons in the adult rat, resulting in atrophy but not cell death of the nigral dopaminergic neurons, no upregulation of either c-Jun or phosphorylated c-Jun was found. A single injection of 10 microg of glial-cell-line-derived-neurotrophic factor given at day 3 after the intrastriatal 6-hydroxydopamine lesion reduced the number of c-Jun- and phosphorylated c-Jun-immunoreactive nuclei in the substantia nigra and protected the dopaminergic neurons from the ensuing cell death. We conclude that c-Jun induction and phosphorylation may be involved in the cellular events leading to death of nigral dopaminergic neurons in vivo and that this response can be modulated by glial-cell-line-derived-neurotrophic factor.
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PMID:Injury induced c-Jun expression and phosphorylation in the dopaminergic nigral neurons of the rat: correlation with neuronal death and modulation by glial-cell-line-derived neurotrophic factor. 1113 99

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

Pancreatic carcinoma cells exhibit a pronounced tendency to invade along and into intra- and extrapancreatic nerves, even at early stages of the disease. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) has been shown to promote pancreatic cancer cell invasion. Here, we demonstrate that pancreatic carcinoma cell lines, such as PANC-1, expressed the RET and GDNF family receptor alpha receptor components for GDNF and that primary pancreatic tumor samples, derived from carcinomas with regional lymph node metastasis, exhibited marked expression of the mRNA encoding the RET51 isoform. Moreover, GDNF was an efficacious and potent chemoattractant for pancreatic carcinoma cells as examined in in vitro and in vivo model systems. Treatment of PANC-1 cells with GDNF resulted in activation of the monomeric GTPases N-Ras, Rac1, and RhoA, in activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and in activation of the phosphatidylinositol 3-kinase/Akt pathway. Both inhibition of the Ras-Raf-MEK (mitogen-activated protein/ERK kinase)-ERK cascade by either stable expression of dominant-negative H-Ras(N17) or addition of the MEK1 inhibitor PD98059 as well as inhibition of the phosphatidylinositol 3-kinase pathway by LY294002 prevented GDNF-induced migration and invasion of PANC-1 cells. These results demonstrate that pancreatic tumor cell migration and possibly perineural invasion in response to GDNF is critically controlled by activation of the Ras-Raf-MEK-ERK and the phosphatidylinositol 3-kinase pathway.
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PMID:Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. 1528 35

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs). We have previously demonstrated that overexpression of GDNF in astrocytes of GFAP-GDNF mice promotes long-term survival of neonatal MNs after facial nerve axotomy. In the present study, we investigated whether astrocyte-derived GDNF could also have a neuroprotective effect on adult MNs following facial nerve avulsion. We also examined avulsion- and GDNF-induced changes in the expression pattern of several members of the AP-1 and ATF/CREB families of transcription factors, which are involved in the fate determination of neurons following injury. We demonstrated that GDNF promotes complete rescue of avulsed MNs for at least 4 months post-injury. Transgene GDNF significantly upregulates c-Jun expression in naive MNs, further upregulates injury-induced c-Jun expression in facial MNs, and results in its activation in most surviving MNs. No significant changes were found in c-Fos expression. We found that GDNF has an opposing effect on ATF2 and ATF3 expression. It dramatically downregulates increased levels of ATF3 in response to injury, whereas the expression of ATF2, which is normally reduced after injury, is completely preserved in GFAP-GDNF mice. Our data suggest that maintenance of high levels of ATF2 in injured MNs could be crucial in modulating c-Jun function, and c-Jun/ATF2 signaling could be involved in GDNF-mediated survival of mature MNs.
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PMID:Astrocyte-derived transgene GDNF promotes complete and long-term survival of adult facial motoneurons following avulsion and differentially regulates the expression of transcription factors of AP-1 and ATF/CREB families. 1649 98

Astrocytes are thought to be critical to neurons' surviving damage caused by ischemic stroke or other injury. Plasminogen activator inhibitor-1 is one of the active soluble factors released by astrocytes and regulates plasminogen activator-plasmin proteolytic sequence in the CNS as a serpin. In this study, we show that plasminogen activator inhibitor-1 can promote neurite outgrowth and survival of rat pheochromocytoma cells in serum-deprived conditions, and that this neuroprotective activity is correlated with enhanced activation of both extracellular signal-regulated kinases following a direct phosphorylation of nerve growth factor receptor, Trk A, and of c-Jun. Our results suggest that plasminogen activator inhibitor-1 can act as a neurotrophic factor, protecting neurons from serum deprivation-induced neuron death not only by compensating for nerve growth factor functions, but also by activating the c-Jun/activating protein-1 pathway.
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PMID:Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun pathways. 1667 72


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