Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR 英文参考文献.docVIP

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Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR 英文参考文献.doc

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Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR 英文参考文献

ProteomicAnalysisShowsSyntheticOleanane TriterpenoidBindstomTOR MarkM.Yore1,ArminjaN.Kettenbach2,3,MichaelB.Sporn1*.,ScottA.Gerber2,3.,KarenT.Liby1. 1DepartmentofPharmacology,DartmouthMedicalSchool,Hanover,NewHampshire,UnitedStatesofAmerica,2DepartmentofGenetics,DartmouthMedicalSchool, Hanover,NewHampshire,UnitedStatesofAmerica,3NorrisCottonCancerCenter,Lebanon,NewHampshire,UnitedStatesofAmerica Abstract New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatmentofmanydiseases.Newsyntheticoleananetriterpenoids(SO),suchasCDDO(2-cyano-3,12-dioxooleana-1,9-dien- 28-oicacid)anditsderivatives,aremultifunctionalcompoundsoriginallydevelopedforthepreventionandtreatmentof inflammationandoxidativestress.However,theproteinbindingpartnersandmechanismsofactionoftheseSOarenotyet fullyunderstood.HerewecharacterizetheputativetargetprofileofoneSO,CDDO-Imidazolide(CDDO-Im),bycombining affinitypurificationwithmassspectroscopicproteomicanalysistoidentify577candidatebindingproteinsinwholecells. ThisSOpharmaco-interactomeconsistsofadiversebutinterconnectedsetofsignalingnetworks;bioinformaticanalysisof theproteininteractomeidentifiedcanonicalsignalingpathwaystargetedbytheSO,includingretinoicacidreceptor(RAR), estrogenreceptor(ER),insulinreceptor(IR),januskinase/signaltransducersandactivatorsoftranscription(JAK/STAT),and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition,wenowshowforthefirsttimethatthemammaliantargetofrapamycin(mTOR)isadirecttargetofCDDO-Im.We alsoshowthatCDDO-Imblocksinsulin-inducedactivation ofthispathwaybybindingtomTORandinhibitingitskinase activity.OurbasicstudiesconfirmthattheSO,CDDO-Im,actsonaproteinnetworktoelicititspharmacologicalactivity. Citation: Yore MM, Kettenbach AN, Sporn MB, Gerber SA, Liby KT (2011) Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR. PLoS ONE6(7):e22862.doi:10.1371/journal.p