Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ciliary neurotrophic factor (CNTF) exhibits multiple biological effects during vertebrate retinal development, including regulating the differentiation of photoreceptor cells and promoting the survival and axonal growth of ganglion cells. We report here that in addition to affecting the differentiation of retinal neurons, CNTF also promotes Muller glia genesis in the postnatal mouse retina. In both retinal monolayer and explant cultures, CNTF increases the number of progenitor cells adopting the Muller cell fate. Exogenous CNTF induces phosphorylation of signal transducers and activators of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) among neonatal progenitor cells and newborn Muller cells. In addition, increased levels of endogenous STAT3 and ERK phosphorylation have been observed at around postnatal day 5, coinciding with the peak of Muller glia genesis. Perturbation of STAT and ERK signaling using protein kinase inhibitors and a dominant-negative STAT3 mutant demonstrates that both CNTF-induced STAT and ERK activation are involved in promoting Muller cell production. Moreover, absorbing epidermal growth factor (EGF) signals with a neutralizing antibody did not affect CNTF-induced Muller glial genesis, indicating that the effect of CNTF is not mediated by the known Muller-enhancing activity of EGF. Together, these results support a novel function of CNTF-like cytokines in retinal gliogenesis.
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PMID:Ciliary neurotrophic factor promotes muller glia differentiation from the postnatal retinal progenitor pool. 1585 65

In the present study, we investigated if the previously observed JNK-mediated activation of c-Jun and induction of ATF3 could be ascribed to axonal transport of JNK signaling components, or if axonal transport of the transcription factors themselves contributes to the nuclear changes in injured sensory neurons. We observed retrograde axonal transport of a number of JNK upstream kinases in ligated rat sciatic nerve. In these preparations, axonal transport of JNK/p-JNK, the JNK scaffolding protein JIP, and the transcription factors ATF3 and ATF2/p-ATF2 was also found. No or little retrograde transport of c-Jun and p-c-Jun was found, whereas an anterograde transport of Hsp27, a protein previously reported in the context of p-c-Jun and ATF3, was observed. In separate experiments, we found that in vitro inhibition of axonal transport or axonal inhibition of JNK reduced the number of p-c-Jun- and ATF3-positive neuronal nuclei. The results suggest that retrograde axonal transport of JNK signaling components contributes to the injury induced c-Jun phosphorylation and ATF3 induction.
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PMID:Retrograde axonal transport of JNK signaling molecules influence injury induced nuclear changes in p-c-Jun and ATF3 in adult rat sensory neurons. 1591 51

Chronic administration of high doses of nicotine results in axonal degeneration in the central core of the fasciculus retroflexus, a fiber tract connecting the habenulae (Hb) to the interpeduncular nucleus (IPN). An important part of this connection is cholinergic and neurons of origin are located in the medial Hb. We have undertaken the present investigation in order to ascertain whether the cholinergic Hb-IPN neurons are the actual target of nicotine toxicity and to begin studying molecular correlates of this action. In the present report, we demonstrate that 7-day-long continuous administration of nicotine through osmotic minipumps, results in a significant (-13%) decrease in the volume of the medial Hb, where cholinergic neurons projecting to the IPN are located, and in a drop of a specific marker for cholinergic neurons, choline acetyltransferase (ChAT), in Hb (-36%) and IPN (-28%). At various intervals (2-6 days) during continuous nicotine administration, some apoptotic neurons were visualized in the medial Hb by the TUNEL technique. The chronic nicotine treatment also resulted, after 2 days of continuous administration in significant activation of the transcription factor CREB and the ERK/MAPK survival kinase in the Hb, suggesting that these alterations in expression are in some way related to the neurodegenerative/neuroreparative process. The present observations demonstrate that the cholinergic Hb-IPN neurons are a target for nicotine neurotoxicity and confirm the usefulness of the experimental model used here not only to study the consequences of chronic stimulant abuse, but also to study the neurochemistry of the affected neural systems and the role of signaling factors in neurodegenerative and repair mechanisms. Medical relevance of the data on unique vulnerability of the Hb-IPN connection to nicotine in relation to heavy smoking habits, is briefly discussed.
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PMID:Neurochemical correlates of nicotine neurotoxicity on rat habenulo-interpeduncular cholinergic neurons. 1593 16

Nav1.6 is the major sodium channel isoform at nodes of Ranvier in myelinated axons and, additionally, is distributed along unmyelinated C-fibers of sensory neurons. Thus, modulation of the sodium current produced by Nav1.6 might significantly impact axonal conduction. Mitogen-activated protein kinases (MAPKs) are expressed in neurons and are activated after injury, for example, after sciatic nerve transection and hypoxia. Although the role of MAPK in signal transduction and in injury-induced regulation of gene expression is well established, the ability of these kinases to phosphorylate and modulate voltage-gated sodium channels has not been reported. Sequence analysis shows that Nav1.6 contains a putative MAP kinase-recognition module in the cytoplasmic loop (L1), which joins domains 1 and 2. We show in this study that sodium channels and p38 MAP kinase colocalize in rat brain tissue and that activated p38alpha phosphorylates L1 of Nav1.6, specifically at serine 553 (S553), in vitro. None of the other cytoplasmic loops and termini of the channel are phosphorylated by activated p38alpha in these assays. Activation of p38 in the neuronal ND7/23 cell line transfected with Nav1.6 leads to a significant reduction in the peak Nav1.6 current amplitude, without a detectable effect on gating properties. The substitution of S553 with alanine within L1 of the Nav1.6 channel prevents p38-mediated reduction of Nav1.6 current density. This is the first demonstration of MAPK phosphorylation and modulation of a voltage-gated sodium channel, and this modulation may represent an additional role for MAPK in regulating the neuronal response to injury.
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PMID:Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. 1601 23

The mechanisms regulating the outgrowth of neurites during development, as well as after injury, are key to the understanding of the wiring and functioning of the brain under normal and pathological conditions. The amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease (AD). However, its physiological role in the central nervous system is not known. Many physical interactions between APP and intracellular signalling molecules have been described, but their functional relevance remains unclear. We show here that human APP and Drosophila APP-Like (APPL) can induce postdevelopmental axonal arborization, which depends critically on a conserved motif in the C-terminus and requires interaction with the Abelson (Abl) tyrosine kinase. Brain injury induces APPL upregulation in Drosophila neurons, correlating with increased post-traumatic mortality in appl(d) mutant flies. Finally, we also found interactions between APP and the JNK stress kinase cascade. Our findings suggest a role for APP in axonal outgrowth after traumatic brain injury.
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PMID:Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. 1605 9

This study investigates whether the immediate early gene (IEG) products c-Fos and c-Jun are activated in vivo in monkeys with experimental glaucoma, and in vitro in cultured human ONH astrocytes exposed to hydrostatic pressure (HP). Three Rhesus monkeys with mild glaucomatous damage (mean intraocular pressure (IOP) 27 +/- 1.3 mm Hg approximately 42 weeks) and three with moderate glaucomatous damage (mean IOP 44 +/- 6.7% mm Hg approximately 11 weeks) were used for this study; the contralateral eye served as normal control (mean IOP 18.6 +/- 1.7 mm Hg). ONH tissues were stained with GFAP, DAPI, and c-Jun or c-Fos, and transcription factor positive and negative nuclei were counted to determine nuclear localization. Cultured human normal and glaucomatous ONH astrocytes exposed to elevated HP served as the in vitro model of elevated pressure. Activation and nuclear localization of c-Fos and c-Jun increased significantly in the monkeys with elevated IOP. These data correlated with axonal loss, reactive astrocytes, and remodeling of the optic disc. Cultured human ONH astrocytes showed increased nuclear localization of c-Fos and c-Jun under exposure to HP. Immunohistochemistry demonstrated that the upstream regulators of c-Fos and c-Jun, ERK-MAPK and MAPKp38 localized to the nuclei of ONH astrocytes in monkeys with experimental glaucoma. Taken together, these results demonstrate c-Fos and c-Jun activation in ONH astrocytes in vivo and in vitro, and that activation of both transcription factors is associated with ERK and MAPKp38 activation in experimental glaucoma, suggesting that activation of transcription factors may participate in the induction and maintenance of the reactive astrocyte phenotype in glaucomatous optic neuropathy.
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PMID:Long-term activation of c-Fos and c-Jun in optic nerve head astrocytes in experimental ocular hypertension in monkeys and after exposure to elevated pressure in vitro. 1608 Oct 55

Neurturin (NTN) is an important neurotrophic factor for parasympathetic neurons; however, no studies to date have investigated the signalling mechanisms downstream of GFRalpha2 and Ret activation underlying this neurotrophic support. This is particularly important for pelvic parasympathetic neurons, which are prone to injury during surgical procedures such as prostatectomy, and where there are no current therapies for axonal regeneration. To address this issue we have cultured dissociated adult rat pelvic ganglion neurons and also examined the structural changes in pelvic ganglion neurons after axotomy. Axotomised penile neurons deprived of target-derived support had smaller somata than intact neurons. Studies of cultured adult pelvic ganglion neurons also demonstrated that NTN stimulated soma growth. Further experiments showed that NTN reduced the up-regulation of tyrosine hydroxylase expression in cultured pelvic parasympathetic neurons. NTN stimulated the extension of neurites in cultured parasympathetic, but not sympathetic, pelvic ganglion neurons. Inhibition of phosphatidylinositol 3-kinase prevented initiation of neurite outgrowth, whereas inhibition of the mitogen-activated protein kinase and the Src family kinase pathways disrupted NTN-stimulated microtubule assembly. Surprisingly, NTN did not activate the transcription factor cAMP-response element binding protein (CREB), which is typically involved in neurotrophic signalling in sympathetic neurons. This is the first study to identify signalling pathways activated by NTN in adult parasympathetic neurons. Our results may lead to a better understanding of regenerative mechanisms in parasympathetic neurons, especially for those innervating urogenital organs. Our results also indicate that neurotrophic signalling in parasympathetic neurons is different from that in other types of peripheral neurons.
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PMID:Neurturin has multiple neurotrophic effects on adult rat sacral parasympathetic ganglion neurons. 1610 41

1 We investigated the neuritogenic action of nitric oxide (NO)-generating agents and their mechanisms of action in a subclone of rat pheochromocytoma, PC12h cells. 2 NO donors such as sodium nitroprusside (SNP, 0.05-1 microM), NOR1 (5-100 microM), NOR2 (5-20 microM), NOR3 (5-20 microM), NOR4 (5-100 microM), or S-nitroso-N-acetyl-DL-penicillamine (SNAP, 10-100 microM) significantly induced neurite outgrowth. 3 NOR4-induced neurite outgrowth was accompanied by expression of neurofilament 200 kDa subunit (NF200) protein, an axonal marker, and was significantly inhibited by an NO scavenger, a soluble GC inhibitor, and a PKG inhibitor: 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (carboxy-PTIO, 20-100 microM), 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 100 microM) and KT5823 (0.2-1 microM), respectively. 4 The intracellular cGMP concentration of cells was markedly increased by treatment with NOR4 (100 microM). 5 A mitogen-activated protein kinase (MAPK) kinase inhibitor, PD98059 (10-50 microM), abolished the NOR4-induced neurite outgrowth. In agreement with this observation, NOR4 did phosphorylate extracellular signal-regulated kinase (ERK) 1 and 2, substrates of MAPK kinase. 6 A membrane-permeable cGMP analog, 8-Br-cGMP (1 mM) also induced significant neurite outgrowth. The 8-Br-cGMP-induced neurite outgrowth was almost completely inhibited by both KT5823 (0.5 microM) and PD98059 (50 microM). Moreover, sustained ERK phosphorylation was observed in the 8-Br-cGMP-treated PC12h cells. 7 These results suggest that NO itself has the ability to induce neurite outgrowth and that NO-induced ERK activation involves the NO-cGMP-PKG signaling pathway in PC12h cells.
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PMID:Fundamental role of nitric oxide in neuritogenesis of PC12h cells. 1611 90

We investigated the functional outcome of c-Jun activation in sympathetic and sensory neurons of neonatal rat superior cervical ganglion (SCG) and dorsal root ganglion (DRG), respectively. Distinctly different roles of c-Jun activation have been suggested for these two types of neurons. In dissociated sympathetic neurons, c-Jun has been demonstrated to promote apoptosis, whereas in sensory neurons it stimulates axonal outgrowth. In organ-cultured ganglia, we found that c-Jun was activated within 24 h of explantation in both types of neurons, and that the JNK inhibitor SP600125 could mitigate this response. In both types of neurons, c-Jun activation was also reduced by NGF treatment. Inhibition of c-Jun activation did not affect the viability of sympathetic neurons, whereas the number of apoptotic sensory neurons increased. Furthermore, inhibition of c-Jun reduced axonal outgrowth from both SCG and DRG. Thus, in organ culture, c-Jun activation may be required for axonal outgrowth and, at least in sensory neurons, it promotes survival. The role of ATF3, a neuronal marker of injury and a c-Jun dimerization partner, was also examined. We found an ATF3 induction in both SCG and DRG neurons, a response, which was reduced by JNK inhibition. The reduction of ATF3 upon JNK inhibition was much larger in DRG than in SCG, a result which might account for the higher number of apoptotic neurons in JNK inhibitor exposed DRG. Taken together, and contrary to our expectations, neonatal sympathetic and sensory neurons seem to respond to axonal injury similarly with respect to c-Jun activation, and in no case was this activation pro-apoptotic.
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PMID:The Janus role of c-Jun: cell death versus survival and regeneration of neonatal sympathetic and sensory neurons. 1612 1

c-Jun activation has been implicated not only in neuronal apoptosis, but also in survival and regeneration. This Janus facet of c-Jun activation could be related to neuronal cell type or to the developmental stage of the neuron. We investigated c-Jun activation in E18 sensory neurons. Cultures of rat dorsal root ganglia neurons were maintained with or without the addition of nerve growth factor or the c-Jun N-terminal kinase inhibitor, (D)-JNKI1. Few dorsal root ganglia neurons survived nerve growth factor deprivation, whereas neurons supplied with nerve growth factor survived and exhibited extensive axonal outgrowth. Activated c-Jun was present in the nuclei of neurons with regenerating axons, but not in apoptotic neurons. c-Jun N-terminal kinase inhibition reduced the number of p-c-Jun immunoreactive and regenerating neurons, and increased cell death. Thus, activation of c-Jun seems to be required for survival and regeneration of developing sensory neurons.
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PMID:The role of p-c-Jun in survival and outgrowth of developing sensory neurons. 1618 72


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