Calcineurin Inhibitor-Induced and Ras-Mediated Overexpression of VEGF in Renal Cancer Cells Involves mTOR through the Regulation of PRAS40 英文参考文献.docVIP

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Calcineurin Inhibitor-Induced and Ras-Mediated Overexpression of VEGF in Renal Cancer Cells Involves mTOR through the Regulation of PRAS40 英文参考文献.doc

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Calcineurin Inhibitor-Induced and Ras-Mediated Overexpression of VEGF in Renal Cancer Cells Involves mTOR through the Regulation of PRAS40 英文参考文献

CalcineurinInhibitor-InducedandRas-Mediated OverexpressionofVEGFinRenalCancerCellsInvolves mTORthroughtheRegulationofPRAS40 AnindaBasu1,2,PallaviBanerjee1,2,AlanG.Contreras1,2,EvelynFlynn1,2,SoumitroPal1,2 * 1DivisionofNephrologyandTransplantationResearchCenter,Children’sHospital,Boston,Massachusetts,UnitedStatesofAmerica,2DepartmentofPediatrics,Harvard MedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract Malignancyisamajorprobleminpatientstreatedwithimmunosuppressiveagents.Wehavedemonstratedthattreatment withcalcineurininhibitors(CNIs)caninducetheactivationofproto-oncogenicRas,andmaypromotearapidprogressionof humanrenalcancerthroughtheoverexpressionofvascularendothelialgrowthfactor(VEGF).Interestingly,wefoundthat CNI-inducedVEGFoverexpressionandcancercellproliferationwasinhibitedbyrapamycintreatment,indicatingpotential involvementofthemammaliantargetofrapamycin(mTOR)pathwayinthistumorigenicprocess.Here,weexaminedthe roleofmTORpathwayinmediatingCNI-andRas-inducedoverexpressionofVEGFinhumanrenalcancercells(786-0and Caki-1).Wefoundthattheknockdownofraptor(usingsiRNA)significantlydecreasedCNI-inducedVEGFpromoteractivity as observed by promoter-luciferase assay, suggesting the role of mTOR complex1 (mTORC1) in CNI-induced VEGF transcription.ItisknownthatmTORbecomesactivatedfollowingphosphorylationofitsnegativeregulatorPRAS40,which is a part of mTORC1. We observed that CNI treatment and activation of H-Ras (through transfection of an active H-Ras plasmid) markedly increased the phosphorylation of PRAS40, and the transfection of cells using a dominant-negative plasmid of Ras, significantly decreased PRAS40 phosphorylation. Protein kinase C (PKC)-f and PKC-d, which are critical intermediarysignalingmoleculesforCNI-inducedtumorigenicpathway,formedcomplexwithPRAS40;andwefoundthat theCNItreatmentincreasedthecomplexformationbetweenPRAS40andPKC,particularly(PKC)-f.InhibitionofPKCactivity using pharmacological inhibitor markedly decreased H-Ras-induced phosphoryla