TheG2/MDNAdamagecheckpointpreventsthecellfromenteringmitosis(Mphase)ifthegenomeisdamaged.TheCdc2-cyclinBkinaseispivotalinregulatingthistransition.DuringG2phase,Cdc2ismaintainedinaninactivestatebythekinasesWee1andMt1.AscellsapproachMphase,thephosphataseCdc25isactivated,perhapsbythepolo-kinasePik1.Cdc25thenactivatesCdc2,establishingafeedbackamplificationloopthatefficientlydrivesthecellintomitosis.DNAdamageactivatestheDNA-PK/ATM/ATRkinases,initiatingtwoparallelcascadesthatinactivateCdc2-cyclinB.Thefirstcascaderapidlyinhibitsprogressionintomitosis:theCHKkinasesphosphorylateandinactivateCdc25,whichcannolongeractivateCdc2.Thesecondcascadeisslower.Phosphorylationofp53dissociatesitfromMDM2,activatingitsDNAbindingactivity.Acetylationbyp300/PCAFfurtheractivatesitstranscriptionalactivity.Thegenesthatareturnedonbyp53constituteeffectorsofthissecondcascade.Theyinclude14-3-3s,whichbindstothephosphorylatedCdc2-cyclinBkinaseandexportsitfromthenucleus;GADD45,whichapparentlybindstoanddissociatestheCdc2-cyclinBkinase;andp21Cip1,aninhibitorofasubsetofthecyclin-dependentkinasesincludingCdc2(CDK1). Contributor:CellSignalingTechnology REFERENCES:
