S Phase–Coupled E2f1 Destruction Ensures Homeostasis in Proliferating Tissues 英文参考文献.docVIP

S Phase–Coupled E2f1 Destruction Ensures Homeostasis in Proliferating Tissues 英文参考文献.doc

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S Phase–Coupled E2f1 Destruction Ensures Homeostasis in Proliferating Tissues 英文参考文献

SPhase–CoupledE2f1DestructionEnsuresHomeostasis inProliferatingTissues JeanM.Davidson1,RobertJ.Duronio1,2,3* 1DepartmentofBiology,TheUniversityofNorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica,2LinebergerComprehensiveCancerCenter, TheUniversityofNorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica,3PrograminMolecularBiologyandBiotechnology,TheUniversityof NorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica Abstract Precisecontrolofcellcycleregulatorsiscriticalfornormaldevelopmentandtissuehomeostasis.E2Ftranscriptionfactors areactivatedduringG1todrivetheG1-StransitionandaretheninhibitedduringSphasebyavarietyofmechanisms.Here, wegeneticallymanipulatethesingleDrosophilaactivatorE2F(E2f1)toexplorethedevelopmentalrequirementforSphase– coupled E2F down-regulation. Expression of an E2f1 mutant that is not destroyed during S phase drives cell cycle progression and causes apoptosis. Interestingly, this apoptosis is not exclusively the result of inappropriate cell cycle progression,becauseastableE2f1mutantthatcannotfunctionasatranscriptionfactorordrivecellcycleprogressionalso triggersapoptosis.ThisobservationsuggeststhattheinappropriatepresenceofE2f1proteinduringSphasecantrigger apoptosisbymechanismsthatareindependentofE2Factingdirectlyattargetgenes.TheabilityofSphase-stabilizedE2f1 totriggerapoptosisrequiresaninteractionbetweenE2f1andtheDrosophilapRbhomolog,Rbf1,andinvolvesinductionof the pro-apoptotic gene, hid. Simultaneously blocking E2f1 destruction during S phase and inhibiting the induction of apoptosisresultsintissueovergrowthandlethality.WeproposethatinappropriateaccumulationofE2f1proteinduringS phase triggers the elimination of potentially hyperplastic cells via apoptosis in order to ensure normal development of rapidlyproliferatingtissues. Citation: Davidson JM, Duronio RJ (2012) S Phase–Coupled E2f1 Destruction Ensures Homeostasis in Proliferating Tissues. PLoS Genet 8(8): e1002831. doi:10.1371/jo

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