细胞周期信号转导通路

Progressintheeukaryoticcellcycleisdrivenbyoscillations(振动)intheactivitiesofCDKs(Cyclin-DependentKinases).CDKactivityiscontrolledbyperiodicsynthesis（周期复合体）anddegradationofpositiveregulatorysubunits（调节亚基）,Cyclins,aswellasbyfluctuationsinlevelsofnegativeregulators,byCKIs(CDKInhibitors),andbyreversiblephosphorylation.Themammaliancellcycleconsistsoffourdiscretephases:S-phase,inwhichDNAisreplicated;M-phase,inwhichthechromosomesareseparatedovertwonewnucleiintheprocessofmitosis.Thesetwophasesareseparatedbytwosocalled“Gap”phases,G1andG2,inwhichthecellpreparesfortheupcomingeventsofSandM,respectively(Ref.1).ThedifferentCyclins,specificfortheG1-,S-,orM-phasesofthecellcycle,accumulateandactivateCDKsattheappropriatetimesduringthecellcycleandthenaredegraded,causingkinaseinactivation.LevelsofsomeCKIs,whichspecificallyinhibitcertainCyclin/CDKcomplexes,alsoriseandfallatspecifictimesduringthecellcycle(Ref.2).Abreakdownintheregulationofthiscycleleadstouncontrolledgrowthandcontributetotumorformation.Defectsinmanyofthemoleculesthatregulatethecellcyclealsoleadtotumorprogression.Keyamongthesearep53,theCKIs(p15(INK4B),p16(INK4A),p18(INK4C),p19(INK4D),p21,p27(KIP1)),andRb(RetinoblastomaSusceptibilityProtein),allofwhichacttokeepthecellcyclefromprogressinguntilallrepairstodamagedDNAhavebeencompleted.Inmammaliancells,differentCyclin-CDKcomplexesareinvolvedinregulatingdifferentcellcycletransitions:Cyclin-D-CDK4/6forG1progression,Cyclin-E-CDK2fortheG1-Stransition,Cyclin-A-CDK2forS-phaseprogression,andCyclin-A/B-CDC2forentryintoM-phase.Apartfromthesewell-knownrolesinthecellcycle,severalCyclinsandCDKsareinvolvedinprocessesnotdirectlyrelatedtothecellcycle.Cyclin-Dbindsandactivatestheestrogenreceptor.(Ref.6).TheCyclin-H-CDK7complexisacomponentofboththeCDK-activatingkinaseandthebasaltranscriptionfactorTFIIHandcanphosphorylateCDKs.OtherCyclinsandCDKs(Cyclin-C-CDK8,Cyclin-T-CDK9,andCyclin-K)arealsoassociatedwithRNAPolymerase-IIandphosphorylatethecarboxyl-terminalrepeatdomain.Cyclin-G,atargetofp53,recruitsPP2A(ProteinPhosphatase2A)todephosphorylateMDM2(MouseDoubleMinute2)(Ref.3).CyclinsassociatewithCDKstoregulatetheiractivityandtheprogressionofthecellcyclethroughspecificcheckpoints.DisruptionofCyclinactionleadstoeithercellcyclearrest,ortouncontrolledcellcycleproliferation.MitogenicsignalsthatarereceivedbycellsurfacereceptorscommunicatetothenuclearcellcyclemachinerytoinducecelldivisionthroughgrowthfactorreceptorsthattargetRas,whichsignalstoanumberofcytoplasmicsignalingcascadessuchasPI3K(Phosphatidylinositiol–3Kinase),RafandRho.TheseproteinsconnecttothenuclearcellcyclemachinerytomediateexitfromGointoG1andS-phaseofthecellcycle.ActivationofRasleadstotranscriptionalinductionofCyclin-D1inearlyG1throughaRas-responsiveelementintheCyclin-D1genepromoter.Cyclin-DassociateswithCDK4andCDK6toformactiveCyclin-D/CDK4(or-6)complexes.ThiscomplexisresponsibleforthefirstphosphorylationoftumorsuppressorRbinG1(Ref.1).Subsequently,Cyclin-Eissynthesized.WhenCyclin-EisabundantitinteractswiththecellcyclecheckpointkinaseCDK2andallowprogressionofthecellcyclefromG1toS-phase.OneofthekeytargetsofactivatedCDK2complexedwithCyclin-EisRb.WhendephosphorylatedinG1,RbcomplexeswithandblockstranscriptionalactivationbyE2Ftranscriptionfactors.ButwhenCDK2/Cyclin-EphosphorylatesRb,itdissociatesfromE2F,allowingE2FtoactivatethetranscriptionofgenesrequiredforS-phase.E2FactivityconsistsofaheterodimericcomplexofanE2FpolypeptideandaDP1protein(Ref.5).OneofthegenesactivatedbyE2FisCyclin-Eitself,leadingtoapositivefeedbackcycleasCyclin-Eaccumulates.InS-phase,Cyclin-Aismade,whichincomplexwithDK2addsfurtherphosphatestoRb.Cyclin-BismadeinG2andM-phasesofthecellcycle(Ref.4).ItcombineswithCDK1(alsocalledCDC2orCDC28)toformthemajormitotickinaseMPF(M-phasePromotingFactor).MPFcausesentryofcellsintomitosisand,afteralag,activatesthesystemthatdegradesitsCyclinsubunit.MPFinactivation,causedbythedegradationofCyclin-B,isrequiredforexitfrommitosis(Ref.2).14-3-3sbindtothephosphorylatedCDC2–Cyclin-Bkinaseandexportsitfromthenucleus.DuringG2-phase,CDC2ismaintainedinaninactivestatebythekinasesWee1andMyt1(MyelinTranscriptionFactor1).AscellsapproachM-phase,thephosphataseCDC25isactivatedbyPLK(Polo-LikeKinase).CDC25thenactivatesCDC2,establishingafeedbackamplificationloopthatefficientlydrivesthecellintomitosis.AllCyclinsaredegradedbyubiquitin-mediatedprocesses,andthemodebywhichthesesystemsareconnectedtothecell-cycleregulatoryphosphorylationnetwork,aredifferentformitoticandG1Cyclins(Ref.2).ThedecisionbythecelltoeitherremaininG1orprogressintoS-phaseistheresultinpartofthebalancebetweenCyclin-Eproductionandproteolyticdegradationintheproteosome.Cyclin-EistargetedfordestructionbytheproteosomethroughubiquitinationwhenassociatedwithacomplexofproteinscalledtheSCForFboxcomplex.DuringG1-phase,theRb-HDACs(HistoneDeacetylases)repressorcomplexbindstotheE2F-DP1transcriptionfactors,inhibitingthedownstreamtranscription.ManydifferentstimuliexertcheckpointcontrolincludingTGF-Beta,DNAdamage,contactinhibition,replicativesenescenceandgrowthfactor