F-Box Protein Specificity for G1 Cyclins Is Dictated by Subcellular Localization 英文参考文献.docVIP

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F-Box Protein Specificity for G1 Cyclins Is Dictated by Subcellular Localization 英文参考文献.doc

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F-Box Protein Specificity for G1 Cyclins Is Dictated by Subcellular Localization 英文参考文献

F-BoxProteinSpecificityforG1CyclinsIsDictatedby SubcellularLocalization BenjaminD.Landry1,2,JohnP.Doyle3,DavidP.Toczyski3,JenniferA.Benanti1,2* 1PrograminGeneFunctionandExpression,UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica, 2PrograminMolecular Medicine,UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica,3DepartmentofBiochemistryandBiophysics,Universityof CaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica Abstract LevelsofG1cyclinsfluctuateinresponsetoenvironmentalcuesandcouplemitoticsignalingtocellcycleentry.TheG1 cyclinCln3isakeyregulatorofcellsizeandcellcycleentryinbuddingyeast.Cln3degradationisessentialforpropercell cyclecontrol;however,themechanismsthatcontrolCln3degradationarelargelyunknown.HereweshowthattwoSCF ubiquitinligases,SCFCdc4 andSCFGrr1,redundantlytargetCln3fordegradation.WhiletheF-boxproteins(FBPs)Cdc4and Grr1werepreviouslythoughttotargetnon-overlappingsetsofsubstrates,wefindthatCdc4andGrr1eachbindtoall3G1 cyclinsincellextracts,yetonlyCln3isredundantlytargetedinvivo,dueinparttoitsnuclearlocalization.Therelatedcyclin Cln2iscytoplasmicandexclusivelytargetedbyGrr1.However,Cdc4caninteractwithCdk-phosphorylatedCln2andtarget itfordegradationwhencytoplasmicCdc4localizationisforcedinvivo.ThesefindingssuggestthatCdc4andGrr1mayshare additional redundant targets and, consistent with this possibility, grr1D cdc4-1 cells demonstrate a CLN3-independent synergisticgrowthdefect.OurfindingsdemonstratethatstructurallydistinctFBPsarecapableofinteractingwithsomeof thesamesubstrates;however,invivospecificityisachievedinpartbysubcellularlocalization.Additionally,theFBPsCdc4 and Grr1 are partially redundant for proliferation and viability, likely sharing additional redundant substrates whose degradationisimportantforcellcycleprogression. Citation:LandryBD,DoyleJP,ToczyskiDP,BenantiJA(2012)F-BoxProteinSpecificityforG1CyclinsIsDictatedbySubcellularLocalization.PLoSGenet8(