Avicin D, a Plant Triterpenoid, Induces Cell Apoptosis by Recruitment of Fas and Downstream Signaling Molecules into Lipid Rafts 英文参考文献.docVIP

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Avicin D, a Plant Triterpenoid, Induces Cell Apoptosis by Recruitment of Fas and Downstream Signaling Molecules into Lipid Rafts 英文参考文献.doc

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Avicin D, a Plant Triterpenoid, Induces Cell Apoptosis by Recruitment of Fas and Downstream Signaling Molecules into Lipid Rafts 英文参考文献

AvicinD,aPlantTriterpenoid,InducesCellApoptosisby RecruitmentofFasandDownstreamSignalingMolecules intoLipidRafts Zhi-XiangXu1,2*,TianDing3,4,ValsalaHaridas1,FionaConnolly1,JordanU.Gutterman1 1Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 2Division of Hematology and Oncology,TheUniversityofAlabamaatBirmingham,Birmingham,Alabama,UnitedStatesofAmerica,3DepartmentofMolecularPathology,TheUniversityofTexasM.D. AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica,4GenscriptInc.,Piscataway,NewJersey,UnitedStatesofAmerica Abstract Avicins,afamilyoftriterpeneelectrophilesoriginallyidentifiedaspotentinhibitorsoftumorcellgrowth,havebeenshown tobepleiotropiccompoundsthatalsopossessantioxidant,anti-mutagenic,andanti-inflammatoryactivities.Wepreviously showed that Jurkat cells, which express a high level of Fas, are very sensitive to treatment with avicins. Thus, we hypothesizedthatavicinsmayinducecellapoptosisbyactivationoftheFaspathway.Byusingaseriesofcelllinesdeficient in cell death receptors, we demonstrated that upon avicin D treatment, Fas translocates to the cholesterol- and sphingolipid-enriched membrane microdomains known as lipid rafts. In the lipid rafts, Fas interacts with Fas-associated deathdomain(FADD)andCaspase-8toformdeath-inducingsignalingcomplex(DISC)andthusmediatescellapoptosis. Interferingwithlipidraftorganizationbyusingacholesterol-depletingcompound,methyl-b-cyclodextrin,notonlyprevents theclusteringofFasanditsDISCcomplexbutalsoreducesthesensitivityofthecellstoavicinD.AvicinDactivatesFas pathwaysindependentoftheassociationbetweenextracellularFasligandsandFasreceptors.AdeficiencyinFasandits downstream signaling molecules leads to the resistance of the cells to avicin D treatment. Taken together, our results demonstrate that avicin D triggers the redistribution of Fas in the membrane lipid rafts, where Fas activates receptor- mediatedcelldeath. Citation: Xu Z-X, Ding T, Harid