Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity 英文参考文献.docVIP

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Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity 英文参考文献.doc

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Gamma-Secretase-Dependent and -Independent Effects of Presenilin1 on β-Catenin·Tcf-4 Transcriptional Activity 英文参考文献

Gamma-Secretase-Dependentand-IndependentEffects ofPresenilin1onb-Catenin?Tcf-4TranscriptionalActivity ImmaRaurell1.,MontserratCodina1,2.,DavidCasagolda1,BeatrizdelValle1,JosepBaulida2 ,Antonio Garc?′adeHerreros2,3*,MireiaDun?ach1* 1Unitat de Biof?′sica-CEB, Departament de Bioqu?′mica i Biologia Molecular, Facultat Medicina, Universitat Auto`noma de Barcelona, Bellaterra, Spain, 2Programa de RecercaenCa`ncer, IMIM-HospitaldelMar,Barcelona,Spain,3DepartamentdeCie`ncies ExperimentalsidelaSalut,UniversitatPompeuFabra,Barcelona,Spain Abstract Presenilin1(PS1)isacomponentofthec-secretasecomplexmutatedincasesofFamilialAlzheimer’sdisease(FAD).PS1is synthesizedasa50kDapeptidesubsequentlyprocessedtotwo29and20kDasubunitsthatremainassociated.Processing of PS1 is inhibited by several mutations detected in FAD patients. PS1 acts as negative modulator of b-catenin?Tcf-4 transcriptionalactivity.Inthisarticleweshowthatinmurineembryonicfibroblasts(MEFs)themechanismsofactionofthe processed and non-processed forms of PS1 on b-catenin?Tcf-4 transcription are different. Whereas non-processed PS1 inhibitsb-catenin?Tcf-4activitythroughamechanismindependentofc-secretaseandassociatedwiththeinteractionofthis protein with plakoglobin and Tcf-4, the effect of processed PS1 is prevented by c-secretase inhibitors, and requires its interactionwithE-orN-cadherinandthegenerationofcytosolicterminalfragmentsofthesetwocadherins,whichinturn destabilizetheb-catenintranscriptionalcofactorCBP.Accordingly,thetwoformsofPS1interactdifferentlywithE-cadherin or b-catenin and plakoglobin: whereas processed PS1 binds E-cadherin with high affinity and b-catenin or plakoglobin weakly,thenon-processedformbehavesinversely.Moreover,contrarilytoprocessedPS1,thatdecreasesthelevelsofc-fos RNA,non-processedPS1inhibitstheexpressionc-myc,aknowntargetofb-catenin?Tcf-4,anddoesnotblocktheactivityof other transcriptional factors requiring CBP. These results indicate that prevention of PS1 processing in FAD affects the me