ER Stress Activates NF-κB by Integrating Functions of Basal IKK Activity, IRE1 and PERK 英文参考文献.docVIP

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ER Stress Activates NF-κB by Integrating Functions of Basal IKK Activity, IRE1 and PERK 英文参考文献.doc

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ER Stress Activates NF-κB by Integrating Functions of Basal IKK Activity, IRE1 and PERK 英文参考文献

ERStressActivatesNF-kBbyIntegratingFunctionsof BasalIKKActivity,IRE1andPERK ArvinB.Tam1,EllenL.Mercado2,AlexanderHoffmann2,MahoNiwa1* 1DivisionofBiologicalSciences,SectionofMolecularBiology,UniversityofCalifornia,SanDiego,LaJolla,California,UnitedStatesofAmerica,2DepartmentofChemistry Biochemistry,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract NF-kB, atranscription factor,becomesactivated during theUnfolded Protein Response (UPR),anendoplasmic reticulum (ER)stressresponsepathway.NF-kBisnormallyheldinactivebyitsinhibitor,IkBa.MultiplecellularpathwaysactivateIKK (IkBaKinase)whichphosphorylateIkBaleadingtoitsdegradationandNF-kBactivation.Here,wefindthatIKKisrequired formaximumactivationofNF-kBinresponsetoERstress.However,unlikecanonicalNFkBactivation,IKKactivitydoesnot increaseduringERstress,butratherthelevelofbasalIKKactivityiscriticalfordeterminingtheextentofNF-k Bactivation. Furthermore, a key UPR initiator, IRE1, acts to maintain IKK basal activity through IRE1’s kinase, but not RNase, activity. InputsfromIRE1andIKK,incombinationwithtranslationrepressionbyPERK,anotherUPRinitiator,leadtomaximalNF-kB activation during the UPR. These interdependencies have a significant impact in cancer cells with elevated IKK/NF-kB activitysuchasrenalcellcarcinomacells(786-0).InhibitionofIKKbyanIKKinhibitor,whichsignificantlydecreasesNF-kB activity,isoverriddenbyUPRinduction,arguingfortheimportanceofconsideringUPRactivationincancertreatment. Citation: Tam AB, Mercado EL, Hoffmann A, Niwa M (2012) ER Stress Activates NF-kB by Integrating Functions of Basal IKK Activity, IRE1 and PERK. PLoS ONE7(10):e45078.doi:10.1371/journal.pone.0045078 Editor:MarianneKoritzinsky,UniversityHealthNetwork,Canada ReceivedJanuary16,2012;AcceptedAugust16,2012;PublishedOctober26,2012 Copyright:?2012Tametal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricted use,distribution,andreproductioninanymedium,providedt