Schedule-dependent interaction between anticancer treatments

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1、RESEARCH

2、REPORTSCANCERBIOLOGYfoundinthenoncancerousprimarylineRPE1(fig.S2),suggestingthattheseMDMX-mediateddynamicsarenotlimitedtocancercells.TheSchedule-dependentinteractionp53postmitoticpulseappearedinRPE1within20hours,whichisconsistentwiththeirshorterbetweenanticancertreatmentscellc

3、yclelength(fig.S1B).Thep53oscillationsduringthesecondphaseoftheresponseresemblethep53oscillationsthat121Sheng-hongChen,WilliamForrester,GalitLahavoccurinresponsetoDNAdouble-strandbreaks(DSBs)(14).Althoughthep53oscillationsresult-TheoncogeneMDMXisoverexpressedinmanycancers,leadingtosupp

4、ressioningfromMDMXdepletionhadloweramplitudeofthetumorsuppressorp53.InhibitorsoftheoncogeneproductMDMXthanthoseinducedbyDSBs(MCF7:Fig.1,Gandthereforemighthelpreactivatep53andenhancetheefficacyofDNA-damagingL;RPE1:fig.S2,CandH),bothsharedaremark-drugs.However,wecurrentlylackaquantitativ

5、eunderstandingofhowMDMXablysimilarperiod(Fig.1Kandfig.S2G).Weinhibitionaffectsthep53signalingpathwayandcellsensitivitytoDNAdamage.thereforesuggestthatMDMX-mediatedp53oscil-LivecellimagingshowedthatMDMXdepletiontriggeredtwodistinctphasesoflationsresultfromthecorenegativefeedbackloopp53a

6、ccumulationinsinglecells:aninitialpostmitoticpulse,followedbybetweenp53andMdm2,aswaspreviouslysug-low-amplitudeoscillations.TheresponsetoDNAdamagewassharplydifferentgestedafterDNAdamage[Fig.1Mand(14)].inthesetwophases;inthefirstphase,MDMXdepletionwassynergisticwithMdm2suppressionledtoc

7、ompletelydifferentDNAdamageincausingcelldeath,whereasinthesecondphase,depletionofnon-oscillatoryp53dynamics(fig.S3),strength-MDMXinhibitedcelldeath.ThusaquantitativeunderstandingofsignaleningthemodelthatMdm2isrequiredforp53dynamicsandcellularstatesisimportantfordesigninganoptimalschedu

8、leofoscillationsafterDNAdamageandMDMXsup-dual-drugadministration.pression.Thesimilarityinoscillationperiodledustoaskwhetherthep53oscillationsafterMDMXfficientkillingofcancercellsoftenrequirescandidateinhibitorsarestillunderstudy.WeknockdownresultfromactivationoftheDNA-combinationsofd