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1、ARTICLEJournalofCellularJournalofCellularBiochemistry113:2597–2606(2012)BiochemistrySp1,AcetylatedHistone-3andp300RegulateTRAILTranscription:MechanismsofPDGF-BB-MediatedVSMCProliferationandMigration1,2,311NorSaadahM.Azahri,BelindaA.DiBartolo,LevonM.Khachigian,and1,2*MaryM.Kavurma1Cent
2、reforVascularResearch,UniversityofNewSouthWales,Sydney,NSW2052,Australia2SchoolofMedicalSciences,UniversityofNewSouthWales,Sydney,NSW2052,Australia3FacultyofAlliedHealthSciences,DepartmentofBiomedicalSciences,InternationalIslamicUniversityMalaysia,25200Pahang,MalaysiaABSTRACTWerecentl
3、yreportedthatTNF-relatedapoptosis-inducingligand(TRAIL)isimportantinatherogenesis,sinceitcaninducevascularsmoothmusclecell(VSMC)proliferationandarterialthickeningfollowinginjury.HereweshowthefirstdemonstratethatTRAILsiRNAreducesplatelet-derivedgrowthfactor-BB(PDGF-BB)-stimulatedVSMCpro
4、liferationandmigration.PDGF-BB-inducibleVSMCproliferationwas/completelyinhibitedinVSMCsisolatedfromaortasofTRAILmice;whereasinduciblemigrationwasblockedcomparedtocontrolVSMCs.TRAILtranscriptionalcontrolmediatingthisresponseisnotestablished.TRAILmRNA,proteinandpromoteractivitywasincr
5、easedbyPDGF-BBandsubsequentlyinhibitedbydominant-negativeSp1,suggestingthatthetranscriptionfactorSp1playsarole.Sp1boundmultipleSp1sitesontheTRAILpromoter,includingtwoestablished(Sp1-1and-2)andtwonovelSp1-5/6and-7sites.PDGF-BB-inducibleTRAILpromoteractivitybySp1wasmediatedthroughtheses
6、ites,sincetransversemutationstoeachabolishedinducibleactivity.PDGF-BBstimulationincreasedacetylationofhistone-3(ac-H3)andexpressionofthetranscriptionalco-activatorp300,implicatingchromatinremodelling.p300overexpressionincreasedTRAILpromoteractivity,whichwasblockedbydominant-negativeSp
7、1.Furthermore,PDGF-BBtreatmentincreasedthephysicalinteractionofSp1,p300andac-H3,whilechromatinimmunoprecipitationstudiesrevealedSp1,p300andac-H3enrichmentontheTRAILpromoter.Takentogether,ourstudiesdemonstrateforthefirsttimethatPDGF-BB-inducedTRAILtranscriptionalactivityrequiresthecoope
8、ratio
