UbiquitinligasesinoncogenictransformationandcancertherapyDanielaSenft1,JianfeiQi2,andZe'evA.Ronai1,31SanfordBurnhamPrebysMedicalDiscoveryInstitute,LaJolla,California92130,USA2UniversityofMarylandSchoolofMedicine,Baltimore,Maryland21201,USA3TechnionIntegratedCancerCenter,Technion,IsraelInstituteofTechnologyFacultyofMedicine,Haifa31096,IsraelAbstractThecellularresponsetoexternalstresssignalsandDNAdamagedependsontheactivityofubiquitinligases(E3s),whichregulatenumerouscellularprocesses,includinghomeostasis,metabolismandcellcycleprogression.E3srecognize,interactwithandubiquitylateproteinsubstratesinatemporallyandspatiallyregulatedmanner.Thetopologyoftheubiquitinchainsdictatesthefateofthesubstrates,markingthemforrecognitionanddegradationbytheproteasomeoralteringtheirsubcellularlocalizationorassemblyintofunctionalcomplexes.BothgeneticandepigeneticalterationsaccountforthederegulationofE3sincancer.Consequently,thestabilityand/oractivityofE3substratesarealsoaltered,insomecasesleadingtodownregulationoftumour-suppressoractivitiesandupregulationofoncogenicactivities.AbetterunderstandingofthemechanismsunderlyingE3regulationandfunctionintumorigenesisisexpectedtoidentifynovelprognosticmarkersandtoenablethedevelopmentofthenextgenerationofanticancertherapies.ThisReviewsummarizestheoncogenicandtumour-suppressorrolesofselectedE3sandhighlightsnovelopportunitiesfortherapeuticintervention.Theproteomeisthetruedriverormediatorofcellularfunctionsandisthereforethepreferredtargetofanticancertherapies.Mosttargetedtherapiesaredirectedagainstsignallingcircuitsthatarederegulatedincancer,exemplifiedbythetargetingofproteinkinases1.Alteredactivityofkeyregulatoryproteinscanbeduetogeneticorepigeneticmodifications,whichtakeplaceinthecourseofcelltransformation.Signallingproteinsareregulatedbyseveralsite-specificpost-translationalmodifications,ofwhichubiquitylationissecondonlytophosphorylationinabundance2.UbiquitylationisCorrespondencetoZ.A.R.zeev@ronailab.net.AuthorcontributionsD.S.andJ.Q.researchedth...
