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

The use of model systems derived from cell lines has been a valuable tool in understanding the molecules and cellular processes that govern differentiation processes (T.R. Breitman, S.E. Selonick, S.J. Collins, Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid, Proc. Natl. Acad. Sci. USA 77 (1980) 2936-2940 [2]; N. Gomez, S. Traverse, P. Cohen, Identification of a MAP kinase in phaeochromocytoma (PC12) cells, FEBS Lett. 314 (1992) 461-465 [4]). The use of such systems provides an inexpensive, quick and simple way to identify and test molecules that can be further studied in more complex in vivo experiments. Some cell lines such as embryonic stem cells can be induced to differentiate in vitro, however, the differentiation is difficult to control and most often leads to the generation of a wide variety of cell types. Cell lines derived from sources committed to a restricted cell fate provide an opportunity to examine cell growth and differentiation within a specific cell type (G.M. Keller, In vitro differentiation of embryonic stem cells, Curr. Opin. Cell Biol. 7 (1995) 862-869 [10]). In this article we describe a simple system for the differentiation of the human neuroblastoma cell line LA-N-5 into cholinergic neurons using all-trans retinoic acid (G. Han, B. Chang, M.J. Connor, N. Sidell, Enhanced potency of 9-cis versus all-trans retinoic acid to induce the differentiation of human neuroblastoma cells, Differentiation, 59 (1995) 61-69 [5]; D.P. Hill, K.R. Robertson, Characterization of the cholinergic neuronal differentiation of the human neuroblastoma cell line LA-N-5 after treatment with retinoic acid, Dev. Brain Res. 102 (1997) 53-67 [6]; J.A. Robson, N. Sidell, Ultrastructural features of a human neuroblastoma cell line treated with retinoic acid, Neuroscience 14 (1985) 1149-1162 [12]; N. Sidell, C.A. Lucas, G.W. Kreutzberg, Regulation of acetylcholinesterase activity by retinoic acid in a human neuroblastoma cell line, Exp. Cell Res. 155 (1984) 305-309 [14]). These cells provide a setting for the study of cholinergic neuronal differentiation and of the factors that influence that process. We also discuss procedures that can be used to study gene expression in LA-N-5 cells by immunohistochemistry and reporter gene analysis.
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PMID:Differentiation of LA-N-5 neuroblastoma cells into cholinergic neurons: methods for differentiation, immunohistochemistry and reporter gene introduction. 950 16

Chlorpyrifos oxon (CPO) activates extracellular signal-regulated kinase (ERK 44/42) in Chinese hamster ovary (CHOK1) cells but the mechanism is not defined. This study tests the hypothesis that diacylglycerol (DAG) is the secondary messenger responsible for CPO-induced ERK 44/42 activation. It is known that DAG is sequentially hydrolyzed by DAG lipase and monoacylglycerol (MAG) lipase, both of which are organophosphate sensitive. Inhibition of these enzymes might therefore lead to the accumulation of DAG and MAG, of which only DAG is a secondary messenger. The experiments show that treatment of CHOK1 cells with CPO significantly inhibits DAG/MAG lipase activity and elevates cellular DAG levels. Pretreatment of CHOK1 cells with CPO or a carbamate known to be a DAG lipase inhibitor, followed by treatment with a cell-permeable DAG (1,2-dihexanoyl-sn-glycerol), results in synergistic activation of ERK 44/42. CPO-potentiated DAG-induced ERK 44/42 activation is both time and concentration dependent. This activation is blocked by inhibitors of protein kinase C and mitogen-activated protein kinase kinase, suggesting that these enzymes are important in CPO/DAG cellular signaling. Activation by a stable DAG analogue (phorbol ester) was not altered by CPO, suggesting that DAG metabolism is the probable target for CPO-potentiated DAG-induced ERK 44/42 activation. These observations support the hypothesis that CPO potentiates DAG signaling in CHOK1 cells by inhibiting a CPO-sensitive DAG lipase, thereby providing a potential mechanism of toxicity not associated with acetylcholinesterase inhibition.
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PMID:Chlorpyrifos oxon potentiates diacylglycerol-induced extracellular signal-regulated kinase (ERK 44/42) activation, possibly by diacylglycerol lipase inhibition. 1178 Oct 77

The nerve growth factor (NGF)-potentiating effect of K vitamins on PC12D cells was investigated. Treatment of PC12D cells with vitamin K(1) or K(2) in the presence of NGF significantly enhanced the proportion of neurite-bearing cells and acetylcholinesterase activity compared with NGF treatment alone. The K vitamins-enhanced neurite outgrowth on PC12D cells was completely blocked by a protein kinase A (PKA) inhibitor or mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059, whereas a protein kinase C inhibitor chelerythrine chloride did not significantly inhibit the enhancing effect of the K vitamins. These results suggest that the K vitamins enhance neurite outgrowth via the activation of PKA and MAPK-mediated signaling pathways in PC12D cells.
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PMID:Novel effect of vitamin K(1) (phylloquinone) and vitamin K(2) (menaquinone) on promoting nerve growth factor-mediated neurite outgrowth from PC12D cells. 1191 78

A primary therapeutic strategy for Alzheimer's disease includes acetylcholinesterase (AChE) inhibitors with the goal of enhancing cholinergic transmission. Stimulation of muscarinic acetylcholine receptors (mAChRs) by elevated levels of ACh plays a role in the effects of AChE inhibitors on cognition and behavior. However, AChE inhibitors only demonstrate modest symptomatic improvements. Chronic treatment with these drugs may cause mAChR downregulation and consequently limit the treatment efficacy. AChE knockout (-/-) mice were utilized in this study as a model for investigating the effects of selective, complete, and chronic diminished AChE activity on mAChR expression and function. In AChE -/- mice, the M(1), M(2), and M(4) mAChRs showed strikingly 50 to 80% decreased expression in brain regions associated with memory. In addition, mAChRs showed decreased presynaptic, cell surface, and dendritic distributions and increased localization to intracellular puncta. Furthermore, mAChR agonist-induced activation of extracellular signal-regulated kinase, a signaling pathway associated with synaptic plasticity and amyloidogenesis, is diminished in the hippocampus and cortex of AChE -/- mice. Therefore, chronic diminished ACh metabolism produces profound effects on mAChR expression and function. The alterations of mAChRs in AChE -/- mice suggest that mAChR downregulation may contribute to the limited efficacy of AChE inhibitors in Alzheimer's disease treatment.
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PMID:Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice. 1278 26

At the vertebrate neuromuscular junction ATP is known to stabilize acetylcholine in the synaptic vesicles and to be co-released with it. We have shown previously that a nucleotide receptor, the P2Y1 receptor, is localized at the junction, and we propose that this mediates a trophic role for synaptic ATP there. Evidence in support of this and on its mechanism is given here. With the use of chick or mouse myotubes expressing promoter-reporter constructs from genes of acetylcholinesterase (AChE) or of the acetylcholine receptor subunits, P2Y1 receptor agonists were shown to stimulate the transcription of each of those genes. The pathway to activation of the AChE gene was shown to involve protein kinase C and intracellular Ca 2+ release. Application of dominant-negative or constitutively active mutants, or inhibitors of specific kinases, showed that it further proceeds via some of the known intermediates of extracellular signal-regulated kinase phosphorylation. In both chick and mouse myotubes this culminates in activation of the transcription factor Elk-1, confirmed by gel mobility shift assays and by the nuclear accumulation of phosphorylated Elk-1. All of the aforementioned activations by agonist were amplified when the content of P2Y1 receptors was boosted by transfection, and the activations were blocked by a P2Y1-selective antagonist. Two Elk-1 binding site sequences present in the AChE gene promoter were jointly sufficient to drive ATP-induced reporter gene transcription. Thus ATP regulates postsynaptic gene expression via a pathway to a selective transcription factor activation.
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PMID:ATP acts via P2Y1 receptors to stimulate acetylcholinesterase and acetylcholine receptor expression: transduction and transcription control. 1280 85

Exposure of rat pheochromocytoma PC12 cells to Cuscuta chinensis glycoside induced neuronal differentiation with resulting outgrowth of neurites and increase of acetylcholinesterase activity. A specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, PD98059, prevented this effect of C. chinensis on PC12 cells. These results suggested that C. chinensis glycoside induced neuronal differentiation in PC12 cells linked to the mitogen-activated protein kinase signaling cascade.
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PMID:Effect of Cuscuta chinensis glycoside on the neuronal differentiation of rat pheochromocytoma PC12 cells. 1285 61

Chlorpyrifos, an acetylcholinesterase (AChE) inhibitor, is a widely used organophosphate pesticide. Recent concern has focused on its neurotoxicity that is not attributable to AChE inhibition. Here, we report that chlorpyrifos and chlorpyrifos-oxon, but not 3,5,6-trichloro-2-pyridinol (TCP; the breakdown product of chlorpyrifos and chlorpyrifos-oxon), induce apoptosis in primary cortical neurons cultured from embryonic day 17 or newborn rats. It is generally agreed that chlorpyrifos-oxon is approximately three orders of magnitude more potent than chlorpyrifos in inhibition of brain acetylcholinesterase activity. However, our data demonstrate that chlorpyrifos-oxon is only slightly more potent than chlorpyrifos in inducing apoptosis. This indicates that chlorpyrifos-induced apoptosis may occur independently of AChE inhibition, although AChE activity was not measured in this study. Furthermore, chlorpyrifos activates the ERK1/2 and p38 MAP kinases. Surprisingly, blocking ERK1/2 activation by the MEK inhibitor SL327 caused a small but statistically significant inhibition of apoptosis, while blocking p38 with SB202190 significantly accelerated apoptosis induced by chlorpyrifos. This suggests a pro- and anti-apoptotic role for ERK1/2 and p38, respectively. Although chlorpyrifos did not stimulate total JNK activity, it caused a sustained activation of a sub-pool of JNK in the nucleus and stimulated phosphorylation of c-Jun, a downstream target of JNK. Transient expression of a dominant negative c-Jun mutant inhibited chlorpyrifos-induced apoptosis, suggesting a role for JNK and JNK-mediated transcription in this cell death. Together, our data suggest apoptosis as a novel toxic endpoint of chlorpyrifos neurotoxicity in the brain that may be independent of AChE inhibition. Furthermore, activation of the ERK1/2 and JNK MAP kinases contributes to, while activation of the p38 MAP kinase counteracts chlorpyrifos-induced apoptosis in cortical neurons.
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PMID:Chlorpyrifos induces apoptosis in rat cortical neurons that is regulated by a balance between p38 and ERK/JNK MAP kinases. 1469 Dec 13

This was a small (approximately 50 people) focused meeting on neurodegenerative disorders, with most of the speakers being from biotechnology or major pharmaceutical companies. The meeting covered a range of topics including introductions to Alzheimer's disease and Parkinson's disease, examples of targeting particular receptors/pathways, animal models and preclinical studies, clinical trial design and the use of biomarkers and imaging modalities. The major focus in the Alzheimer's disease area was finding symptomatic treatments that are superior to acetylcholinesterase inhibitors and the extensive efforts that are ongoing to develop disease-modifying therapies. In terms of Parkinson's disease there are now several reports examining the effects of dopamine agonists versus 3,4-dihydroxyphenylalanine on disease progression, and ongoing work with growth factors (e.g., glial cell line-derived neurotrophic factor) and mixed lineage/c-Jun N-terminal kinase inhibitors, such as CEP-1347. Small molecules that enhance endogenous signalling and repair pathways were also discussed.
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PMID:SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer's and Parkinson's disease. 1546 66

The neuroprotective properties of bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 mum glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-tacrine treatment (0.01-1 mum) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 mum bis(7)-tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro-beta-erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-tacrine, suggesting that the neuroprotection of bis(7)-tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-d-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca(2+) imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-tacrine was found effectively to buffer the intracellular Ca(2+) increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [(3)H]MK-801 with an IC(50) value of 0.763 mum in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects.
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PMID:Novel dimeric acetylcholinesterase inhibitor bis7-tacrine, but not donepezil, prevents glutamate-induced neuronal apoptosis by blocking N-methyl-D-aspartate receptors. 1571 Jun 23

Our previous study demonstrated that huperzine A, a selective acetylcholinesterase inhibitor, stimulates the synthesis of nerve growth factor (NGF) in cultured rat cortical astrocytes. The present studies are designed to examine if huperzine A exerts its neuroprotective activity against oxidative stress damage through increasing the synthesis of NGF in SHSY5Y neuroblastoma cells. Transient exposure of the cells to 200 microM H2O2 triggered a significant reduction of cell viability and decreased the mRNA and protein levels of NGF, neurotrophin receptor P75 (P75NTR) receptor and tyrosine kinase A (TrkA) receptor. Incubation of cells with 10 microM huperzine A prior to H2O2 exposure significantly elevated their survival and restored the mRNA and protein levels of NGF, P75NTR receptor and TrkA receptor. These neuroprotective effects of huperzine A on H2O2-induced cytotoxicity were blocked by the TrkA receptor phosphorylation inhibitor K252alpha, and were antagonized by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) inhibitor, PD98059. The present results indicate that the cytoprotective effect of huperzine A is mediated at least partly by up-regulated NGF and NGF receptors. The results also show that the MAP/ERK kinase signal pathway is crucial for huperzine A to protect against H2O2-induced damage in SHSY5Y cells.
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PMID:Huperzine A protects SHSY5Y neuroblastoma cells against oxidative stress damage via nerve growth factor production. 1611 75


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