BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines 英文参考文献.docVIP

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BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines 英文参考文献.doc

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BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines 英文参考文献

BRAFV600ENegativelyRegulatestheAKTPathwayin MelanomaCellLines BrendenChen,ChristineTardell,BrianHiggins,KathrynPackman,JohnF.Boylan,HuifengNiu* DiscoveryOncology,Hoffmann-LaRocheInc.,Nutley,NewJersey,UnitedStatesofAmerica Abstract Cross-feedbackactivationofMAPKandAKTpathwaysisimplicatedasaresistancemechanismforcancertherapeuticagents targetingeitherRAF/MEKorPI3K/AKT/mTOR.Itisthusimportanttohaveabetterunderstandingofthemolecularresistance mechanismstoimprovepatientsurvivalbenefitfromtheseagents.HereweshowthatBRAFV600Eisanegativeregulatorof the AKT pathway. Expression of BRAFV600E in NIH3T3 cells significantly suppresses MEK inhibitor (RG7167) or mTORC1 inhibitor (rapamycin) induced AKT phosphorylation (pAKT) and downstream signal activation. Treatment-induced pAKT elevation is found in BRAF wild type melanoma cells but not in a subset of melanoma cell lines harboring BRAFV600E. Knock-downofBRAFV600EinthesemelanomacellselevatesbasalpAKTanddownstreamsignals,whereasknock-downof CRAF, MEK1/2 or ERK1/2 or treatment with a BRAF inhibitor have no impact on pAKT. Mechanistically, we show that BRAFV600E interacts with rictor complex (mTORC2) and regulates pAKT through mTORC2. BRAFV600E is identified in mTORC2afterimmunoprecipitationofrictor.Knock-downofrictorabrogatesBRAFV600EdepletioninducedpAKT.Knock- down of BRAFV600E enhances cellular enzyme activity of mTORC2. Aberrant activation of AKT pathway by PTEN loss appearstooverridethenegativeimpactofBRAFV600EonpAKT.Takentogether,ourfindingssuggestthatinasubsetof BRAFV600E melanoma cells, BRAFV600E negatively regulates AKT pathway in a rictor-dependent, MEK/ERK and BRAF kinase-independentmanner.Ourstudyrevealsanovelmolecularmechanismunderlyingtheregulationoffeedbackloops betweentheMAPKandAKTpathways. Citation: Chen B, Tardell C, Higgins B, Packman K, Boylan JF, et al. (2012) BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines. PLoS ONE7(8):e42598.doi:10.1371/journal.pone.0042598 Editor:SoumitroPal,Children’sH