p27/Kip1regulatesthecellcyclebyinhibitingthecheckpointkinasecdk2/cyclinEandblockingcellcycleprogressionthroughtheG1-Stransition.Cancercellsinsomecaseshavereducedlevelsofp27,supportingtheimportanceofp27incellcycleregulation.Theactivityofp27isregulatedbyphosphorylation,synthesisanddegradation.Phosphorylationofp27atthreonine-187bycdk2causesp27toassociatewithanSCFcomplexthattargetsp27forproteolyticdegradation.TheFboxproteinSkp2bindsspecificallytothreonine-187phosphorylatedp27,recruitingittotheSCFcomplexfordegradation.Othercomponentsofthep27ubiquitinligasecomplexincludeSkp1,Cul1,andRoc1/Rbx-1.Cks-1hasalsobeenidentifiedinareconstitutedsystemasanessentialcomponentforrecruitmentofp27fordegradationbytheSCFcomplex.Signalingbycytokinesmaymodulatecellsurvival,proliferation,orapoptosisthroughmodulationofp27expression.CytokineandAKTsignalingpathwaysactivateforkheadtranscriptionfactorsthatinducep27expressionatthetranscriptionallevel.

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REFERENCES:Carrano,A.C.etal.(1999)SKP2isrequiredforubiquitin-mediateddegradationoftheCDKinhibitorp27.Nat.Cell.Biol.1(4),193-9Dijkers,P.F.,(2000)ForkheadtranscriptionfactorFKHR-L1modulatescytokine-dependenttranscriptionalregulationofp27(KIP1).Mol.Cell.Biol.20(24),9138-48Ganoth,D.etal.(2001)Thecell-cycleregulatoryproteinCks1isrequiredforSCF(Skp2)-mediatedubiquitinylationofp27.Nat.Cell.Biol.3(3),321-4Malek,N.P.etal.(2001)Amouseknock-inmodelexposessequentialproteolyticpathwaysthatregulatep27Kip1inG1andSphase.Nature413(6853),323-7Podust,V.N.etal.(2000)ANedd8conjugationpathwayisessentialforproteolytictargetingofp27Kip1byubiquitination.ProcNatlAcadSciUSA97(9),4579-84VlADImirN.Podust,etal.ANedd8ConjugationPathwayisEssentialforProteolyticTargetingofp27^Kip1byUbiquitination.PNAS,Vol97,April2000,4579-4584.

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