Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.
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PMID:A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia. 1466 49

The transcription factor Elk-1 belongs to the ternary complex factor (TCF) subfamily of Ets proteins. TCFs interact with serum response factor to bind jointly to serum response elements in the promoters of immediate-early genes (IEGs). TCFs mediate the rapid transcriptional response of IEGs to various extracellular stimuli which activate mitogen-activated protein kinase signaling. To investigate physiological functions of Elk-1 in vivo, we generated Elk-1-deficient mice by homologous recombination in embryonic stem cells. These animals were found to be phenotypically indistinguishable from their wild-type littermates. Histological analysis of various tissues failed to reveal any differences between Elk-1 mutant and wild-type mice. Elk-1 deficiency caused no changes in the proteomic displays of brain or spleen extracts. Also, no immunological defects could be detected in mice lacking Elk-1, even upon infection with coxsackievirus B3. In mouse embryonic fibroblasts, Elk-1 was dispensable for c-fos and Egr-1 transcriptional activation upon stimulation with serum, lysophosphatidic acid, or tetradecanoyl phorbol acetate. However, in brains of Elk-1-deficient mice, cortical and hippocampal CA1 expression of c-fos, but not Egr-1 or c-Jun, was markedly reduced 4 h following kainate-induced seizures. This was not accompanied by altered patterns of neuronal apoptosis. Collectively, our data indicate that Elk-1 is essential neither for mouse development nor for adult life, suggesting compensatory activities by other TCFs.
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PMID:Mice deficient for the ets transcription factor elk-1 show normal immune responses and mildly impaired neuronal gene activation. 1467 63

Recent evidence has emphasized the importance of p38 mitogen-activated protein kinase (MAPK) in the induction of metabotropic glutamate receptor (mGluR)-dependent long term depression (LTD) at hippocampal CA3-CA1 synapses. However, the cascade responsible of mGluR to activate p38 MAPK and the signaling pathway immediately downstream from it to induce synaptic depression is poorly understood. Here, we show that transient activation of group I mGluR with the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) activates p38 MAPK through G protein betagamma-subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD. Furthermore, our data clearly show that an accelerating AMPA receptor endocytosis by stimulating the formation of guanyl nucleotide dissociation inhibitor-Rab5 complex is a potential downstream processing of p38 MAPK activation to mediate DHPG-LTD. These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors.
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PMID:Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. 1470 49

Genome-wide gene expression analysis of the hippocampal CA1 region was conducted in a rat global ischemia model for delayed neuronal death and induced ischemic tolerance using an oligonucleotide-based DNA microarray containing 8,799 probes. The results showed that expression levels of 246 transcripts were increased and 213 were decreased following ischemia, corresponding to 5.1% of the represented probe sets. These changes were divided into seven expression clusters using hierarchical cluster analysis, each with distinct conditions and time-specific patterns. Ischemic tolerance was associated with transient up-regulation of transcription factors (c-Fos, JunB Egr-1, -2, -4, NGFI-B), Hsp70 and MAP kinase cascade-related genes (MKP-1), which are implicated cell survival. Delayed neuronal death exhibited complex long-lasting changes of expression, such as up-regulation of proapoptotic genes (GADD153, Smad2, Dral, Caspase-2 and -3) and down-regulation of genes implicated in survival signaling (MKK2, and PI4 kinase, DAG/PKC signaling pathways), suggesting an imbalance between death and survival signals. Our study provides a differential gene expression profile between delayed neuronal death and induced ischemic tolerance in a genome-wide analysis, and contributes to further understanding of the complex molecular pathophysiology in cerebral ischemia.
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PMID:Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats. 1474 48

The pro-inflammatory cytokine tumor-necrosis factor-alpha (TNF-alpha) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF-alpha inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF-alpha prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68 +/- 5%, n = 6 versus control 175 +/- 7%, n = 6, P < 0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF-alpha as p38 MAPK has previously been shown to be involved in interleukin-1beta inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF-alpha led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 microM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF-alpha (SB/TNF-alpha 174 +/- 5%, n = 6 versus TNF-alpha 120 +/- 7%, n = 6, P < 0.001, 1 h post-tetanus) to values comparable to control LTP (control 175 +/- 7%, n = 6). Interestingly however, the depressive effects of TNF-alpha on late LTP (2-3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF-alpha 132 +/- 5%, n = 6 versus control LTP 175 +/- 7%, n = 6, P < 0.001, 3 h post-tetanus). This work suggests that TNF-alpha inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.
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PMID:Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. 1498 Mar 82

Transient global cerebral ischemia leads to delayed neuronal cell death in the hippocampal CA1, caudate putamen and neocortex. If preischemic hyperglycemia exists, the same duration of ischemia recruits additional brain structures, such as dentate gyrus to become damaged. The objective of the present study is to determine whether activation of mitogen-activated protein kinases (MAPKs) plays a role in hyperglycemia-mediated ischemic neuronal damage. Using phopho-specific antibodies against c-jun NH2-terminal kinase (JNK) and p38 MAPK, we studied activation of these two MAPKs in ischemia-vulnerable neocortex and ischemia-resistant dentate gyrus in rats subjected to 15 min of forebrain ischemia and followed by 0.5, 1 and 3 hr of recirculation under normo- and hyperglycemic conditions. The results showed that levels of phosphorylated JNK increased in both normo- and hyperglycemic brains following blood reperfusion for 0.5 hr and persisted up to 3 hr in the neocortex but not in the dentate gyrus, implying JNK may play a role in mediating neuronal cell death after ischemia. However, since hyperglycemia did not further increase phospho-JNK, JNK may not contribute to the detrimental effect of hyperglycemia on neuronal cell death. The amount of phospho-p38 was not altered by ischemia under both normo- and hyperglycemic conditions, suggesting that p38 MAPK may not play a major role in mediating neuronal damage in these two structures.
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PMID:Effects of hyperglycemic and normoglycemic cerebral ischemia on phosphorylation of c-jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). 1498 93

The effects of the beta-amyloid peptide (Abeta) fragment 25-35 were investigated on hippocampal synaptic transmission and long-term potentiation (LTP) in vitro. Abeta([25-35]) was found to impair both post-tetanic potentiation (PTP) and LTP in the hippocampal CA1. The anthra[1,9-cd]pyrazol-6(2H)-one, SP600125, was used to inhibit c-Jun N-terminal kinase (JNK) activity, which is believed to mediate cell death. Prior application of SP600125 attenuated the Abeta([25-35])-mediated impairment of PTP and LTP, when measured from the pre-drug baseline. In the presence of SP600125 alone, we observed an increase in baseline synaptic transmission and reduction in paired-pulse facilitation, consistent with an increase in synaptic transmission. There was no alteration in the level of PTP and LTP obtained, when measured from the pre-drug baseline. In the presence of both SP600125 and Abeta, however, PTP was greatly enhanced compared with controls. We therefore suggest that the activation of the JNK signalling pathway mediates the effects of Abeta on synaptic plasticity. Our data also indicate that endogenous JNK activity may regulate neurotransmitter release in the hippocampal CA1 in vitro.
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PMID:The role of c-Jun N-terminal kinase in the A beta-mediated impairment of LTP and regulation of synaptic transmission in the hippocampus. 1499 43

Brain-derived neurotrophic factor (BDNF) is a potent modulator of synaptic transmission and plasticity in the CNS, acting both pre- and postsynaptically. We demonstrated recently that BDNF/TrkB signaling increases dendritic spine density in hippocampal CA1 pyramidal neurons. Here, we tested whether activation of the prominent ERK (MAPK) signaling pathway was responsible for BDNF's effects on spine growth. Slice cultures were transfected with enhanced yellow fluorescent protein (eYFP) by particle-mediated gene transfer, and CA1 pyramidal neurons were imaged by laser-scanning confocal microscopy. We confirmed that BDNF (24 h) increases spine density in apical dendrites of CA1 neurons. The MEK (ERK kinase) inhibitors PD98059 and U0126 completely prevented the increase in spine density induced by BDNF, without having an effect on spine density by themselves. In contrast to its actions on cortical pyramidal neurons, BDNF had minor and rather localized effects on dendritic complexity in hippocampal pyramidal neurons, increasing the total length, but not the branching of apical dendrites within CA1 stratum radiatum, without affecting basal dendrites in stratum oriens. Our results support the hypothesis that the ERK-signaling pathway not only mediates long-term synaptic plasticity and hippocampal-dependent learning, but it is also involved in the structural remodeling of excitatory spine synapses triggered by neurotrophins.
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PMID:ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. 1505 32

Thyroid hormone activates extracellular signal-regulated kinases (ERK1 and ERK2), which are important in late long-term potentiation (L-LTP). The aim of this study was to determine the possible mechanism underlying the impairment of L-LTP as a result of hypothyroidism. We investigated the effect of hypothyroidism on L-LTP of the two associative pathways in the hippocampus: the Schaffer collateral synapses and the perforant path synapses. We also examined the effect of hypothyroidism on ERK1 and ERK2 levels in both the CA1 and dentate gyrus (DG) regions of the hippocampus. Electrophysiological recordings from hippocampi of anesthetized rats show that hypothyroidism impairs L-LTP in CA1 region, but not in the DG. Western blot analysis of the CA1 region shows that hypothyroidism decreases phosphorylated ERK1 and ERK2 levels without affecting their total levels. In the DG of the hypothyroid rat, however, there was no significant change in the levels of phosphorylated or total ERKs. The correlation between the effect of hypothyroidism on L-LTP and enzyme levels suggests that hypothyroidism-induced impairment of L-LTP in CA1 may be due to decreased levels of phosphorylated ERK1 and ERK2.
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PMID:Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement. 1505 81

The activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in the pathological changes accompanying inflammatory and apoptotic processes of various cell types including neurons. In a kainic acid (KA)-induced mouse seizure model, p38 MAPK is induced in reactive astrocytes in the CA3 region of the hippocampus where severe neuronal loss occurs. Here we report the delayed and protracted activation of p38 MAPK in the CA3 region of the hippocampus of mice treated with KA. In this model, the inhibition of p38 MAPK isoforms by SB203580, a specific inhibitor, attenuated neuronal loss in the CA3 and CA1 regions of the hippocampus, which was accompanied by the suppression of the p38 MAPK activation as well as astrogliosis. Thus, the delayed and sustained induction of p38 MAPK plays a crucial role in the neuronal damage of KA-induced brain seizures.
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PMID:Inhibition of delayed induction of p38 mitogen-activated protein kinase attenuates kainic acid-induced neuronal loss in the hippocampus. 1506 51


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