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Article: Upstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/Threonine Protein Kinase in β-Amyloid Peptide Neurotoxicity

TitleUpstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/Threonine Protein Kinase in β-Amyloid Peptide Neurotoxicity
Authors
Issue Date2003
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2003, v. 278 n. 50, p. 49819-49827 How to Cite?
AbstractOne of the hallmarks of Alzheimer's disease is extracellular accumulation of senile plaques composed primarily of aggregated β-amyloid (Aβ) peptide. Treatment of cultured neurons with Aβ peptide induces neuronal death in which apoptosis is suggested to be one of the mechanisms. We have demonstrated previously that Aβ peptide induces activation of double-stranded RNA-dependent serine/threonine protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2α (eIF2α) in neurons in vitro. Degenerating neurons in brain tissues from Alzheimer's disease patients also displayed high immunoreactivity for phosphorylated PKR and eIF2α. Our previous data have also indicated that PKR plays a significant role in mediating Aβ peptide-induced neuronal death, because neurons from PKR knockout mice and neuroblastoma SH-SY5Y cells stably transfected with dominant negative mutant of PKR are less susceptible to Aβ peptide toxicity. Therefore, it is important to understand how PKR is activated by Aβ peptide. We report here that inhibition of caspase-3 activity reduces phosphorylation of PKR and to a certain extent, cleavage of PKR and eIF2α in neurons exposed to Aβ peptide. Calcium release from the endoplasmic reticulum and activation of caspase-8 are the upstream signals modulating the caspase-3-mediated activation of PKR by Aβ peptide. Although in other systems HSP90 serves as a repressor for PKR, it is unlikely the candidate for caspase-3 to affect PKR activation in neurons after Aβ peptide exposure. Elucidation of the upstream pathways for PKR activation can help us to understand how this kinase participates in Aβ peptide neurotoxicity and to develop effective neuroprotective strategy.
Persistent Identifierhttp://hdl.handle.net/10722/149624
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSuen, KCen_US
dc.contributor.authorYu, MSen_US
dc.contributor.authorSo, KFen_US
dc.contributor.authorChang, RCCen_US
dc.contributor.authorHugon, Jen_US
dc.date.accessioned2012-06-26T05:56:13Z-
dc.date.available2012-06-26T05:56:13Z-
dc.date.issued2003en_US
dc.identifier.citationJournal Of Biological Chemistry, 2003, v. 278 n. 50, p. 49819-49827en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/149624-
dc.description.abstractOne of the hallmarks of Alzheimer's disease is extracellular accumulation of senile plaques composed primarily of aggregated β-amyloid (Aβ) peptide. Treatment of cultured neurons with Aβ peptide induces neuronal death in which apoptosis is suggested to be one of the mechanisms. We have demonstrated previously that Aβ peptide induces activation of double-stranded RNA-dependent serine/threonine protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2α (eIF2α) in neurons in vitro. Degenerating neurons in brain tissues from Alzheimer's disease patients also displayed high immunoreactivity for phosphorylated PKR and eIF2α. Our previous data have also indicated that PKR plays a significant role in mediating Aβ peptide-induced neuronal death, because neurons from PKR knockout mice and neuroblastoma SH-SY5Y cells stably transfected with dominant negative mutant of PKR are less susceptible to Aβ peptide toxicity. Therefore, it is important to understand how PKR is activated by Aβ peptide. We report here that inhibition of caspase-3 activity reduces phosphorylation of PKR and to a certain extent, cleavage of PKR and eIF2α in neurons exposed to Aβ peptide. Calcium release from the endoplasmic reticulum and activation of caspase-8 are the upstream signals modulating the caspase-3-mediated activation of PKR by Aβ peptide. Although in other systems HSP90 serves as a repressor for PKR, it is unlikely the candidate for caspase-3 to affect PKR activation in neurons after Aβ peptide exposure. Elucidation of the upstream pathways for PKR activation can help us to understand how this kinase participates in Aβ peptide neurotoxicity and to develop effective neuroprotective strategy.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshAmyloid Beta-Peptides - Chemistry - Metabolismen_US
dc.subject.meshAnimalsen_US
dc.subject.meshApoptosisen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshBrain - Embryology - Metabolismen_US
dc.subject.meshCho Cellsen_US
dc.subject.meshCalcium - Metabolismen_US
dc.subject.meshCaspase 3en_US
dc.subject.meshCaspase 8en_US
dc.subject.meshCaspase 9en_US
dc.subject.meshCaspases - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshCricetinaeen_US
dc.subject.meshEndoplasmic Reticulum - Metabolismen_US
dc.subject.meshEnzyme Activationen_US
dc.subject.meshEnzyme Inhibitors - Pharmacologyen_US
dc.subject.meshEukaryotic Initiation Factor-2 - Metabolismen_US
dc.subject.meshHsp90 Heat-Shock Proteins - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshMiceen_US
dc.subject.meshModels, Biologicalen_US
dc.subject.meshNeurons - Drug Effects - Metabolismen_US
dc.subject.meshPeptides - Chemistryen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshPrecipitin Testsen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshTransfectionen_US
dc.subject.meshEif-2 Kinase - Metabolismen_US
dc.titleUpstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/Threonine Protein Kinase in β-Amyloid Peptide Neurotoxicityen_US
dc.typeArticleen_US
dc.identifier.emailSo, KF:hrmaskf@hkucc.hku.hken_US
dc.identifier.emailChang, RCC:rccchang@hkucc.hku.hken_US
dc.identifier.authoritySo, KF=rp00329en_US
dc.identifier.authorityChang, RCC=rp00470en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1074/jbc.M306503200en_US
dc.identifier.pmid12975376-
dc.identifier.scopuseid_2-s2.0-0348010382en_US
dc.identifier.hkuros85196-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0348010382&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume278en_US
dc.identifier.issue50en_US
dc.identifier.spage49819en_US
dc.identifier.epage49827en_US
dc.identifier.isiWOS:000187068200023-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridSuen, KC=7004577222en_US
dc.identifier.scopusauthoridYu, MS=35346047600en_US
dc.identifier.scopusauthoridSo, KF=34668391300en_US
dc.identifier.scopusauthoridChang, RCC=7403713410en_US
dc.identifier.scopusauthoridHugon, J=7103202992en_US

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