Riluzole Increases the Amount of Latent HSF1 for an Amplified Heat Shock Response and Cytoprotection 英文参考文献.docVIP

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Riluzole Increases the Amount of Latent HSF1 for an Amplified Heat Shock Response and Cytoprotection 英文参考文献.doc

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Riluzole Increases the Amount of Latent HSF1 for an Amplified Heat Shock Response and Cytoprotection 英文参考文献

RiluzoleIncreasestheAmountofLatentHSF1foran AmplifiedHeatShockResponseandCytoprotection JingxianYang1,KristenBridges1,KuangYuChen2,AliceY.-C.Liu1* 1DepartmentofCellBiologyandNeuroscience,RutgersStateUniversityofNewJersey,Piscataway,NewJersey,UnitedStatesofAmerica,2DepartmentofChemistryand ChemicalBiology,RutgersStateUniversityofNewJersey,Piscataway,NewJersey,UnitedStatesofAmerica Abstract Background: Induction of the heat shock response (HSR) and increased expression of the heat shock proteins (HSPs) providemechanismstoensureproperproteinfolding,trafficking,anddisposition.TheimportanceofHSPsisunderscored by the understanding that protein mis-folding and aggregation contribute centrally to the pathogenesis of neurodegenerativediseases. Methodology/Principal Findings: We used a cell-based hsp70-luciferease reporter gene assay system to identify agents that modulate the HSR and show here that clinically relevant concentrations of the FDA-approved ALS drug riluzole significantly increased the heat shock induction of hsp70-luciferse reporter gene. Immuno-Western and -cytochemical analysisofHSF1showthatriluzoleincreasedtheamountofcytosolicHSF1toaffordagreateractivationofHSF1uponheat shock.TheincreasedHSF1contributedcentrallytothecytoprotectiveactivityofriluzoleashsf1geneknockoutnegatedthe synergisticactivityofriluzoleandconditioningheatshocktoconfercellsurvivalunderoxidativestress.Evidenceofapost- transcriptionalmechanismfortheincreaseinHSF1include:quantitationofmRNAhsf1byRT-PCRshowednoeffectofeither heat shock or riluzole treatment; riluzole also increased the expression of HSF1 from a CMV-promoter; analysis of the turnoverofHSF1bypulsechaseandimmunoprecipitationshowthatriluzoleslowedthedecayof[35S]labeled-HSF1.The effectofriluzoleonHSF1wasqualitativelydifferentfromthatofMG132andchloroquine,inhibitorsoftheproteasomeand lysosome, respectively, and appeared to involve the chaperone-mediated autophagy pathway as RNAi-mediated knockdownofCMAnegateditseffect. Conclusio