SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability 英文参考文献.docVIP

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SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability 英文参考文献.doc

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SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability 英文参考文献

SIRT1PromotesN-MycOncogenesisthroughaPositive FeedbackLoopInvolvingtheEffectsofMKP3andERKon N-MycProteinStability GlennM.Marshall1,2.,PeiY.Liu1.,SamueleGherardi3,ChristopherJ.Scarlett4,AntonioBedalov5 ,Ning Xu1,NuncioIraci3,EmanueleValli3,DoraLing1,WayneThomas1,MargovanBekkum1,EricSekyere1, KacperJankowski1,TobyTrahair1,KarenL.MacKenzie1,MichelleHaber1,MurrayD.Norris1,AndrewV. Biankin4,GiovanniPerini3,TaoLiu1* 1Children’s Cancer Institute Australia for Medical Research, Randwick, Australia, 2The Centre for Children’s Cancer and Blood Disorders, Sydney Children’s Hospital, Randwick, Australia, 3Department of Biology, University of Bologna, Bologna, Italy, 4Garvan Institute of Medical Research, Darlinghurst, Australia, 5Fred Hutchinson CancerResearchCentre,UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica Abstract The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms convertingalow-leveltoahigh-levelN-Mycexpression.N-MycproteinisstabilizedwhenphosphorylatedatSerine62by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcriptionoftheclassIIIhistonedeacetylaseSIRT1,whichinturnincreasedN-Mycproteinstability.SIRT1bindstoMyc BoxIdomainofN-Mycproteintoformanoveltranscriptionalrepressorcomplexatgenepromoterofmitogen-activated proteinkinasephosphatase3(MKP3),leadingtotranscriptionalrepressionofMKP3,ERKproteinphosphorylation,N-Myc proteinphosphorylationatSerine62,andN-Mycproteinstabilization.Importantly,SIRT1wasup-regulated,MKP3down- regulated,inpre-cancerouscells,andpreventativetreatmentwiththeSIRT1inhibitorCambinolreducedtumorigenesisin TH-MYCNtransgenicmice.OurdatademonstratetheimportantrolesofSIRT1inN-MyconcogenesisandSIRT1inhibitorsin thepreventionandtherapyofN-Myc–inducedneuroblastoma. Citation:MarshallGM,LiuPY,GherardiS,ScarlettCJ,BedalovA,etal.(2011)SIRT1PromotesN-MycOncogenesisthroughaPositiveFeedbackLoopInvolvingthe EffectsofMKP3andE