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)

Sphingosine-1-phosphate (SPP), a bioactive sphingolipid metabolite, suppresses apoptosis of many types of cells, including rat pheochromocytoma PC12 cells. Elucidating the molecular mechanism of action of SPP is complicated by many factors, including uptake and metabolism, as well as activation of specific G-protein-coupled SPP receptors, known as the endothelial differentiation gene-1 (EDG-1) family. In this study, we overexpressed type 1 sphingosine kinase (SPHK1), the enzyme that converts sphingosine to SPP, in order to examine more directly the role of intracellularly generated SPP in neuronal survival. Enforced expression of SPHK1 in PC12 cells resulted in significant increases in kinase activity, with corresponding increases in intracellular SPP levels and concomitant decreases in both sphingosine and ceramide, and marked suppression of apoptosis induced by trophic factor withdrawal or by C(2)-ceramide. NGF, which protects PC12 cells from serum withdrawal-induced apoptosis, also stimulated SPHK1 activity. Surprisingly, overexpression of SPHK1 had no effect on activation of two known NGF-stimulated survival pathways, extracellular signal regulated kinase ERK 1/2 and Akt. However, trophic withdrawal-induced activation of the stress activated protein kinase, c-Jun amino terminal kinase (SAPK/JNK), and activation of the executionary caspases 2, 3 and 7, were markedly suppressed. Moreover, this abrogation of caspase activation, which was prevented by the SPHK inhibitor N,N-dimethylsphingosine, was not affected by pertussis toxin treatment, indicating that the cytoprotective effect was likely not mediated by binding of SPP to cell surface G(i)-coupled SPP receptors. In agreement, there was no detectable release of SPP into the culture medium, even after substantially increasing cellular SPP levels by NGF or sphingosine treatment. In contrast to PC12 cells, C6 astroglioma cells secreted SPP, suggesting that SPP might be one of a multitude of known neurotrophic factors produced and secreted by glial cells. Collectively, our results indicate that SPHK/SPP may play an important role in neuronal survival by regulating activation of SAPKs and caspases.
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PMID:Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. 1123 41

Sympathetic neurons require nerve growth factor for survival and die by apoptosis in its absence. Key steps in the death pathway include c-Jun activation, mitochondrial cytochrome c release, and caspase activation. Here, we show that neurons rescued from NGF withdrawal-induced apoptosis by expression of dominant-negative c-Jun do not release cytochrome c from their mitochondria. Furthermore, we find that the mRNA for BIM(EL), a proapoptotic BCL-2 family member, increases in level after NGF withdrawal and that this is reduced by dominant-negative c-Jun. Finally, overexpression of BIM(EL) in neurons induces cytochrome c redistribution and apoptosis in the presence of NGF, and neurons injected with Bim antisense oligonucleotides or isolated from Bim(-/-) knockout mice die more slowly after NGF withdrawal.
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PMID:Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. 1130 Oct 23

Members of the Egr family of transcription factors are rapidly and robustly induced by neurotransmitters and neurotrophins and have been implicated in mediating enduring changes in neuronal function elicited by these stimuli. Because we have found in previous studies that a dominant negative inhibitor of Egr action, the Egr zinc finger domain (ZnEgr), blocks NGF-induced neurite outgrowth in PC12 cells, we have used this preparation to help identify the downstream targets of Egr proteins involved in plasticity. Our investigation into the mechanism of action of ZnEgr indicates that it blocks NGF-induced neurite outgrowth by suppressing activation of c-Jun, a critical step in the signaling pathway mediating this response. Although we had assumed that ZnEgr exerts its effects by binding to the Egr response element (ERE) and thereby blocking target gene regulation by Egr proteins, this classical mode of action appears to be too slow to mediate the effects of Egr proteins on c-Jun activation. In evaluating alternative ERE-independent mechanisms of Egr (and ZnEgr) action, we found that Egr1 and c-Jun coprecipitate and that ZnEgr disrupts formation of the Egr1/c-Jun complex. Furthermore, mutations of ZnEgr that greatly impair or abolish its ability to bind to the ERE do not block its ability to suppress c-Jun activation or neurite outgrowth induced by NGF. Accordingly, our studies indicate that Egr and ZnEgr proteins regulate c-Jun activation via a novel mechanism, protein-protein interaction with c-Jun, rather than via their classical mode of action, binding to the ERE.
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PMID:A dominant negative Egr inhibitor blocks nerve growth factor-induced neurite outgrowth by suppressing c-Jun activation: role of an Egr/c-Jun complex. 1201 3

Tumor necrosis factor-alpha (TNFalpha, 10-100 ng/ml) provokes a dramatic cell death in differentiated PC12 cells (dPC12), but it does not affect the viability and the proliferation of naive PC12 cells (nPC12). We have analyzed the molecular alterations of the TNFalpha-signal cascade underlying this developmental switch toward propagation of apoptosis. The transcriptional inhibitor actinomycin D rendered nPC12 responsive for TNFalpha-induced death, but was hardly effective in dPC12, suggesting that TNFalpha evokes its harmful action in dPC12 predominantly by posttranslational modification of existing molecules. This suggestion was supported by the finding that differentiation of PC12 per se went along with the increased expression of the proapoptotic TNFalpha-receptor I (p55) and its adapter protein Traf-2, whereas expression and phosphorylation of the antiapoptotic Akt (PKB) declined. We could demonstrate that the c-Jun N-terminal kinases (JNKs) mediate this enhanced capacity of apoptotic signaling in dPC12. TNFalpha induced in dPC12, but not nPC12, a biphasic activation of JNKs with a rapid transient JNK1 activation and a second persistent activation of JNK1 and JNK2 paralleled by phosphorylation of c-Jun; in contrast, TNFalpha did not activate p38 kinase. Block of JNKs by CEP-11004, a MLK antagonist and subsequently indirect inhibitor of JNK activation, or L-JNK11, a direct peptidergic inhibitor of JNK activity, almost completely rescued dPC12. Summarizing, the NGF-triggered formation of neurites during differentiation of PC12 includes the reinforced propensity for apoptosis, with JNK2 as the effector in JNK3-negative PC12. These findings offer novel insights into the increased risk of neuronal death, which is linked to the potential to regenerate.
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PMID:Fatal shift of signal transduction is an integral part of neuronal differentiation: JNKs realize TNFalpha-mediated apoptosis in neuronlike, but not naive, PC12 cells. 1209 55

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

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ(2) has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ(2) (0.2 to 1.6 microM) alone showed measurable neurite extension and expression of neurofilament, a marker of cell differentiation. However, a much greater extent of neurite extension and expression of neurofilament was observed in the presence of NGF (50 ng/ml). In parallel with its increasing effect on the neurite extension and expression of neurofilament, 15-deoxy-PGJ(2) enhanced NGF-induced p38 MAP kinase expression and its phosphorylation in addition to the activation of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting effect of 15-deoxy-PGJ(2) (0.8 microM) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ(2) on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ(2) did not occur through PPAR-gamma because synthetic PPAR-gamma agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ(2). In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-gamma was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD(2) and PGE(2)) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE(2) and PGD(2) receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ(2) on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ(2) may not be mediated by GPCR either. These data demonstrate that activation of p38 MAP kinase in conjunction with AP-1 signal pathway may be important in the promoting activity of 15-deoxy-PGJ(2) on the differentiation of PC-12 cells.
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PMID:Activation of p38 mitogen-activated protein kinase and activator protein-1 during the promotion of neurite extension of PC-12 cells by 15-deoxy-delta12,14-prostaglandin J2. 1260 68

The c-Jun N-terminal kinases (JNKs) are important mediators of neurodegeneration and their actions include the activation of genetic programs by phosphorylation of the nuclear transcription factor c-Jun/AP-1, the release of cytochrome c or the pro-inflammatory actions of microglia. Recent data, however, provide evidence for physiological functions of JNKs in particular JNK1, and this involves a role of JNKs in the development of the brain and the (functional and/or structural) integrity of the cytoskeleton. Here we summarize our findings on the cytoskeleton-associated actions of JNKs. Thus, JNKs the relevant MAP kinases for the NGF-induced formation and elongation of PC12 cells, and this process is also supported by JNK2 and JNK3 which are commonly considered as pro-apoptotic signal transducers. Importantly, JNK3 is also mandatory for the intact differentiation of neurons since the functional deletion of JNK3 caused apoptotic features such as activation of caspase 3 in untreated P0 primary hippocampal neurons and following glutamate excitotoxicity. Finally, we can visualize the presence of JNKs at the cytoskeleton, axon and growth cones of primary hippocampal neurons and PC12 cells, and this pattern changes following excitatory stimulation with glutamate. Thus, the functional role of JNKs during development and differentiation substantially differs from their degenerative actions in the adult brain.
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PMID:c-Jun N-terminal kinases (JNKs) and the cytoskeleton--functions beyond neurodegeneration. 1546 86

The p53 family member, p73, is essential for the survival of sympathetic neurons during the developmental period of naturally occurring neuronal death. Here, we have asked whether DeltaNp73, which is the only p73 isoform expressed in sympathetic neurons, mediates this survival by p53-dependent and/or p53-independent mechanisms. Initially, we used a genetic approach and crossed p53+/- and p73+/- mice. Quantitation of neurons in the sympathetic superior cervical ganglion during the period of naturally occurring cell death revealed that the loss of p53 partially rescued the death of neurons seen in p73-/- animals. Moreover, exogenous expression of DeltaNp73 in cultured p53-/- sympathetic neurons rescued these neurons from apoptosis after NGF withdrawal. Biochemical studies asking how DeltaNp73 inhibited NGF withdrawal-induced apoptosis in wild-type neurons demonstrated that it prevented the upregulation of the direct p53 targets p21 and Apaf-1 as well as cleavage of caspase-3. It also inhibited events at the mitochondrial apoptotic checkpoint, suppressing the induction of BimEL and the release of mitochondrial cytochrome c. Interestingly, DeltaNp73 expression also inhibited one very early event in the apoptotic cascade, the activation of c-Jun N-terminal protein kinase (JNK), likely by binding directly to JNK. Finally, we show that neuronal cell size is decreased in p73-/- mice, and that this decrease is not rescued by the lack of p53, suggesting a role for p73 in regulating cell size that does not involve interactions with p53. Thus, DeltaNp73 promotes neuronal survival via p53-dependent and -independent mechanisms, and it does so at multiple points, including some of the most proximal events that occur after NGF withdrawal.
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PMID:Evidence that DeltaNp73 promotes neuronal survival by p53-dependent and p53-independent mechanisms. 1548 36


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