Nucleo-Cytoplasmic Localization Domains Regulate Krüppel-Like Factor 6 (KLF6) Protein Stability and Tumor Suppressor Function 英文参考文献.docVIP

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Nucleo-Cytoplasmic Localization Domains Regulate Krüppel-Like Factor 6 (KLF6) Protein Stability and Tumor Suppressor Function 英文参考文献.doc

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Nucleo-Cytoplasmic Localization Domains Regulate Krüppel-Like Factor 6 (KLF6) Protein Stability and Tumor Suppressor Function 英文参考文献

Nucleo-CytoplasmicLocalizationDomainsRegulate Kru¨ppel-LikeFactor6(KLF6)ProteinStabilityandTumor SuppressorFunction Estefan?′aRodr?′guez1,NanaAburjania1,NolanM.Priedigkeit1,AnalisaDiFeo1,JohnA.Martignetti1,2* 1DepartmentofGeneticsandGenomicSciences,MountSinaiSchoolofMedicine,NewYork,NewYork,UnitedStatesofAmerica,2DepartmentofOncologicalSciences, MountSinaiSchoolofMedicine,NewYork,NewYork,UnitedStatesofAmerica Abstract Background:ThetumorsuppressorKLF6anditsoncogeniccytoplasmicsplicevariantKLF6-SV1representaparadigmin cancerbiologyinthattheirantagonisticcancerfunctionsareencodedwithinthesamegene.Asaconsequenceofsplicing, KLF6-SV1losesboththeC-terminusC2H2threezincfinger(ZF)domain,whichcharacterizesallKLFproteins,aswellasthe adjacent 59 basic region (5BR), a putative nuclear localization signal (NLS). It has been hypothesized that this NLS is a functionaldomaincriticaltodirectthedistinctsubcellularlocalizationofthetumorsuppressoranditssplicevariant. Methodology/PrincipalFindings:Inthisstudy,wedemonstrateusingEGFPfusionconstructsthatKLF6/KLF6-SV1nucleo- cytoplasmictransportisnotregulatedbythe59basicregionbutactivatedbyanovelNLSencodedwithintheZFdomain, andanuclearexportsignal(NES)locatedinthefirst16aminoacidsofthesharedN-terminussequence.Wedemonstrate KLF6nuclearexporttobeCrm1-dependent.Thedysregulationofnucleo-cytoplasmictransportwhendisruptingtheKLF6 NLSusingsite-directedmutagenesisshowedthatitsintegrityisnecessaryforappropriateproteinstability.Moreover,these mutationsimpairedtranscriptionalinductionoftwoKLF6well-characterizedtargetgenes,E-cadherinandp21,asshownby RT-PCRandluciferasepromoterassays.TheadditionoftheZFdomaintoKLF6-SV1resultsinitsnuclearlocalizationanda markedlydecreasedhalf-lifesimilartowildtypeKLF6. Conclusions/Significance: We describe the domains that control KLF6 nucleo-cytoplasmic shuttling and how these domainsplayaroleinKLF6proteinhalf-lifeandtumorsuppressorfunction.Theresultsbegintomechanisticallyexplain,at leastinpart,theopposingfunctionsofKL