ER Stress-Inducible Factor CHOP Affects the Expression of Hepcidin by Modulating CEBPalpha Activity 英文参考文献.docVIP

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ER Stress-Inducible Factor CHOP Affects the Expression of Hepcidin by Modulating CEBPalpha Activity 英文参考文献.doc

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ER Stress-Inducible Factor CHOP Affects the Expression of Hepcidin by Modulating CEBPalpha Activity 英文参考文献

ERStress-Inducible Factor CHOPAffects theExpression ofHepcidin byModulating C/EBPalpha Activity SusanaJ.Oliveira1,2,JorgeP.Pinto1,Gonc?aloPicarote1,2,VeraM.Costa3,Fe′lixCarvalho3 ,Maria Rangel2,4,MariadeSousa1,2*,Se′rgioF.deAlmeida1¤ 1IrongenesandtheImmuneSystem,InstitutodeBiologiaMoleculareCelular,UniversidadedoPorto,Porto,Portugal,2InstitutodeCie?nciasBiome′dicasdeAbelSalazar, Porto,Portugal,3REQUIMTE,ToxicologyDepartment,FaculdadedeFarma′cia, UniversidadedoPorto,Porto,Portugal,4REQUIMTE,InstitutodeCie?ncias Biome′dicas de AbelSalazar,UniversidadedoPorto,Porto,Portugal Abstract Endoplasmic reticulum (ER) stress induces a complex network of pathways collectively termed the unfolded protein response(UPR).TheclarificationofthesepathwayshaslinkedtheUPRtotheregulationofseveralphysiologicalprocesses. However,itscrosstalkwithcellularironmetabolismremainsunclear,whichpromptedustoexaminewhetheranUPRaffects theexpressionofrelevantiron-relatedgenes.Forthatpurpose,theHepG2celllinewasusedasmodelandtheUPRwas activated by dithiothreitol (DTT) and homocysteine (Hcys). Here, we report that hepcidin, a liver secreted hormone that shepherdsironhomeostasis,exhibitsabiphasicpatternofexpressionfollowingUPRactivation:itslevelsdecreasedinan early stage and increased with the maintenance of the stress response. Furthermore, we show that immediately after stressingtheER,thestress-inducibletranscriptionfactorCHOPdepletesC/EBPaproteinpool,whichmayinturnimpacton theactivationofhepcidintranscription.InthelaterperiodoftheUPR,CHOPlevelsdecreasedprogressively,enhancingC/ EBPa-bindingtothehepcidinpromoter.Inaddition,analysisofferroportinandferritinHrevealedthatthetranscriptlevels oftheseiron-genesareincreasedbytheUPRsignalingpathways.Takentogether,ourfindingssuggestthattheUPRcan haveabroadimpactonthemaintenanceofcellularironhomeostasis. Citation:OliveiraSJ,PintoJP,PicaroteG,CostaVM,CarvalhoF,etal.(2009)ERStress-Inducible FactorCHOPAffectstheExpression ofHepcidinbyModulating C/EBP