ThecellcycletransitionfromG1toSphaseisakeyregulatorypointinthecellcycle.Thistransitionisregulatedbythecheckpointkinasecdk2thatactivatestheG1toStransitionwhenitisassociatedwithcyclinE.Cdk2/CyclinEcausestheG1toStransitionthroughphosphorylationofthetumorsuppressorRb,releasingthetranscriptionfactorE2F-1.OtherpathwaysactingthroughRac,RasandRhoalsoregulatetheG1toStransition.RasregulatescyclinD1expressiontoaffecttheG1toStransition.TransformingformsofRasorRafinducecyclinD1expressionandcauseearlyentryintoSphase.SignalingfromRastoRaftoMEKtoERKsinducesCyclinD1expression,allowingCyclinD1tocomplexwithCdk4andCdk6andphosphorylateRb.Rac-1andPAKappeartoinduceCyclinD1expressionandinducetheG1toStransitionprimarilythroughactivationofNF-kBtoactivatetheCyclinD1promoter.Rhoactivatescdk2andalsoinhibitsp21andp27toinducecyclinD1andstimulatetheG1toStransition.Rhorepressesp21expressiontoblockp21inductionbyRasandtoallowRasinducedprogressionfromG1toS.Cellsthatlackp21donotrequireRhoforRastoinducecellcycleprogressionfromG1toSphase.ThecooperativeactionofRas,RacandRhotoinduceCyclinD1expressionisakeycomponentofoncogenictransformation.

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