p63 Promotes Cell Survival through Fatty Acid Synthase 英文参考文献.docVIP

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p63 Promotes Cell Survival through Fatty Acid Synthase 英文参考文献.doc

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p63 Promotes Cell Survival through Fatty Acid Synthase 英文参考文献

p63PromotesCellSurvivalthroughFattyAcidSynthase VenkataSabbisetti1,2,AriannaDiNapoli1,ApryleSeeley1,2,AngelaM.Amato1,EstherO’Regan4 ,Musie Ghebremichael3,MassimoLoda1,2,SabinaSignoretti1,2 * 1Department of Pathology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America, 2DepartmentofMedicalOncology,Dana-FarberCancerInstitute,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3DepartmentofBiostatistics andComputationalBiology,Dana-FarberCancerInstitute,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,4St.James’shospital,Dublin,Ireland Abstract Thereisincreasingevidencethatp63,andspecificallyDNp63,playsacentralroleinbothdevelopmentandtumorigenesis bypromotingepithelialcellsurvival.However,fewstudieshaveaddressedthemolecularmechanismsthroughwhichsuch important function is exerted. Fatty acid synthase (FASN), a key enzyme that synthesizes long-chain fatty acids and is involvedinbothembryogenesisandcancer,hasbeenrecentlyproposedasadirecttargetofp53familymembers,including p63andp73.HereweshowthatknockdownofeithertotalorDN-specificp63isoformsinsquamouscellcarcinoma(SCC9) orimmortalizedprostateepithelial(iPrEC)cellscausedadecreaseincellviabilitybyinducingapoptosiswithoutaffecting the cell cycle. p63 silencing significantly reduced both the expression and the activity of FASN. Importantly, stable overexpressionofeitherFASNormyristoylatedAKT(myr-AKT)wasabletopartiallyrescuecellsfromcelldeathinducedby p63 silencing. FASN induced AKT phosphorylation and asignificant reduction in cell viability was observed when FASN- overexpressingSCC9cellsweretreatedwithanAKTinhibitorafterp63knockdown,indicatingthatAKTplaysamajorrolein FASN-mediated survival. Activated AKT did not cause any alteration in the FASN protein levels but induced its activity, suggestingthattherescuefromapoptosisdocumentedinthep63-silencedcellsexpressingmyr-AKTcellsmaybepartially mediatedbyFASN.Finally,wedemon