Cyclinsareproteinsthatassociatewithcyclin-dependentproteinkinasestoregulatetheiractivityandtheprogressionofthecellcyclethroughspecificcheckpoints.Disruptionofcyclinactioncanleadtoeithercellcyclearrest,ortouncontrolledcellcycleproliferation.Thecyclicalincreaseanddecreaseincyclinlevelsisakeytocellcycleregulation.WhencyclinEisabundantitinteractswiththecellcyclecheckpointkinasecdk2toactivatecdk2andallowprogressionofthecellcyclefromG1toSphase.Oneofthekeytargetsofactivatedcdk2complexedwithcyclinEisthetumorsuppressorRb.WhendephosphorylatedinG1,RbcomplexeswithandblockstranscriptionalactivationbyE2Ftranscriptionfactors.WhenRbisphosphorylatedbycdk2/CyclinE,itdissociatesfromE2f,allowingE2FtoactivatethetranscriptionofgenesrequiredforSphase.OneofthegenesactivatedbyE2FiscyclinEitself,leADIngtoapositivefeedbackcycleascyclinEaccumulates.ThedecisionbythecelltoeitherremaininG1orprogressintoSphaseistheresultinpartofthebalancebetweencyclinEproductionandproteolyticdegradationintheproteosome.CyclinEistargetedfordestructionbytheproteosomethroughubiquitinationwhenassociatedwithacomplexofproteinscalledtheSCForFboxcomplex.ProteinsincludedthiscomplexincludeanFboxproteinthattargetsspecificsubstratessuchasCyclinEfordegradation.InthecaseofcyclinEtheFboxproteinFbw7,alsocalledhCdc4,associateswithphosphorylatedfreecyclinEtorecruititintotheSCFcomplexfordegradation.SCFFbw7isaubiquitinligaserecruitedintothecomplexthatspecificallytargetscyclinE.Cul3,skp1,andRbx1alsoarepartofthecomplexthatdegradescyclinE.Theremayberedundancyforsomecomponentsofthecomplexsincecul1deletionalsodisruptscyclinEdegradation,andmultipleFboxproteinsmaycontributetocyclinEdegradation.TheinteractionofmultipledifferentfactorsincyclinEaccumulationintegratesdifferentsignalingpathwayswithcellcycleregulationandmayplayaroleintheunregulatedcellcycleprogressionofcancer.

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