An Atypical Unfolded Protein Response in Heat Shocked Cells 英文参考文献.docVIP

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An Atypical Unfolded Protein Response in Heat Shocked Cells 英文参考文献.doc

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An Atypical Unfolded Protein Response in Heat Shocked Cells 英文参考文献

AnAtypicalUnfoldedProteinResponseinHeatShocked Cells LonnekeHeldens,SanneM.M.Hensen,CarlaOnnekink,SiebeT.vanGenesen,RonP.Dirks¤,NicoletteH. Lubsen* DepartmentofBiomolecularChemistry,RadboudUniversityNijmegen,Nijmegen,TheNetherlands Abstract Background:Theheatshockresponse(HSR)andtheunfoldedproteinresponse(UPR)arebothactivatedbyproteotoxic stress, although in different compartments, and share cellular resources. How these resources are allocated when both responsesareactiveisnotknown.Insightinpossiblecrosstalkwillhelpunderstandingtheconsequencesoffailureofthese systemsin(age-related)disease. Results:InheatstressedHEK293cellssynthesisofthecanonicalUPRtranscriptionfactorsXBP1sandATF4wasdetectedas well as HSF1 independent activation of the promoters of the ER resident chaperones HSPA5 (BiP) and DNAJB9 (ERdj4). However,theheatstressactivationoftheDNAJB9promoter,aXBP1starget,wasnotblockedincellsexpressingadominant negativeIRE1amutant,andthusdidnotrequireXBP1s.Furthermore,theDNAelementrequiredforheatstressactivationof theDNAJB9promoterisdistinctfromtheATF4andATF6targetelements;eventhoughinhibitionofeIF2aphosphorylation resultedinadecreasedactivationoftheDNAJB9promoteruponheatstress,suggestingaroleforaneIF2aphosphorylation dependentproduct. Conclusions:TheinitialstepintheUPR,synthesisoftranscriptionfactors,isactivatedbyheatstressbutthesecondstep, transcriptional transactivation by these factors, is blocked and these pathways of the UPR are thus not productive. ExpressionofcanonicalERchaperonesispartoftheresponseofheatstressedcellsbutanothersetoftranscriptionfactors hasbeenrecruitedtoregulateexpressionoftheseERchaperones. Citation: Heldens L, Hensen SMM, Onnekink C, van Genesen ST, Dirks RP, et al. (2011) An Atypical Unfolded Protein Response in Heat Shocked Cells. PLoS ONE6(8):e23512.doi:10.1371/journal.pone.0023512 Editor:SueCotterill,St.GeorgesUniversityofLondon,UnitedKingdom ReceivedJanuary20,2011;AcceptedJuly19,2011;PublishedAugust10,2011 Copyright: ? 2011 Heldens et