Regulation of Gene Expression in Hepatic Cells by the Mammalian Target of Rapamycin (mTOR) 英文参考文献.docVIP

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Regulation of Gene Expression in Hepatic Cells by the Mammalian Target of Rapamycin (mTOR) 英文参考文献.doc

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Regulation of Gene Expression in Hepatic Cells by the Mammalian Target of Rapamycin (mTOR) 英文参考文献

RegulationofGeneExpressioninHepaticCellsbythe MammalianTargetofRapamycin(mTOR) RosaH.Jimenez1,Ju-SeogLee2,MirkoFrancesconi3,GastoneCastellani3,NicolaNeretti4,5,JenniferA. Sanders1,JohnSedivy5,PhilipA.Gruppuso1* 1DepartmentofPediatrics,RhodeIslandHospitalandBrownUniversity,Providence,RhodeIsland,UnitedStatesofAmerica,2MolecularTherapeutics,UniversityofTexas MDAndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica,3InterdepartmentalCenter‘‘L.Galvani’’,BolognaUniversity,Bologna,Italy,4InstituteforBrain andNeuralSystems,BrownUniversity,Providence,RhodeIsland,UnitedStatesofAmerica,5DepartmentofMolecularBiology,CellBiologyandBiochemistryandCenter forGenomicsandProteomics,BrownUniversity,Providence,RhodeIsland,UnitedStatesofAmerica Abstract Background:WeinvestigatedmTORregulationofgeneexpressionbystudyingrapamycineffectintwohepaticcelllines, thenon-tumorigenicWB-F344cellsandthetumorigenicWB311cells.Thelatterareresistanttothegrowthinhibitoryeffects of rapamycin, thus providing us with an opportunity to study the gene expression effects of rapamycin without confoundingeffectsoncellproliferation. Methodology/PrincipalFindings:Thehepaticcellswereexposedtorapamycinfor24hr.MicroarrayanalysisontotalRNA preparationsidentifiedgenesthatwereaffectedbyrapamycininbothcelllinesand,therefore,modulatedindependentof growtharrest.FurtherstudiesshowedthatthepromoterregionsofthesegenesincludedE-box-containingtranscription factor binding sites at higher than expected rates. Based on this, we tested the hypothesis that c-Myc is involved in regulation of gene expression by mTOR by comparing genes altered by rapamycin in the hepatic cells and by c-Myc inductioninfibroblastsengineeredtoexpressc-mycinaninduciblemanner.Resultsshowedenrichmentforc-Myctargets among rapamycin sensitive genes in both hepatic cell lines. However, microarray analyses on wild type and c-myc null fibroblastsshowedsimilarrapamycineffect,withthesetofrapamycin-sensitivegenesbeingenrichedforc-Myctargetsin bothcases. Conclu