转录因子MEF2对多种信号通路的调节及其生物学作用

ISSN100727626CN1123870PQChineseJournalofBiochemistryandMolecularBiology2004820(4):423427MEF23,(,,201203)2(myocyteenhancerfactor2,MEF2).,.MEF2,.MEF2,.,MEF2,(hepaticstellatecell,HSC).,,,Q51RegulationofTranscriptionalFactorMEF2toMultipleSignalConductionPathwaysandBiologicalFunctionsZHANGWen2wei3,XULie2ming(InstituteofLiverDiseasesandShuguangHospital,ShanghaiUniversityofTraditionalChineseMedicineandPharmacology,Shanghai201203,China)AbstractMyocyteenhancerfactor(MEF2)arespecifictranscriptionfactors,andarefascinatingduetotheirinvolvementindiversefunctionsofgeneregulationandthemultiplicityofregulatorymechanisms.TheapparentabilityofMEF2istocontrolthetranscriptionofgenesinmuscledifferentiation.Themainfunctionsaretomediatedifferentiationduringthedevelopmentofskeletal,cardiac,smoothmuscle.Ascalcium2regulatedfactors,MEF2playsanimportantroleintheneuronalsurvivalanddifferentiation.Recently,MEF2factorsareshowntoparticipateintheprocessofliverfibrosisandmaybeanimportantregulatoryfactorduringhepaticstellatecellactivation.Keywordsmyocyteenhancerfactor,regulation,transcriptionfactor,liverfibrosis:2003209209,:2003212222(No.30271657)3Tel:[phone],E2mail:[e-mail],,19769,Received:September9,2003;Accepted:December22,2003SupportedbyNationalNaturalScienceFoundationofChina(No.30271657)andCooperationwithBrownUniversity,USA3CorrespondingauthorTel:86221251322444,E2mail:[e-mail]2(myocyteenhancerfactor2,MEF2),DNA,(musclecreatinekinase,MCK)APTDNA[1].MEF2MADS2Box(:MCM1,;SRF,;agamousdeficiens,),4:MEF2AMEF2BMEF2CMEF2D[2].,MEF2.,,.1MEF2MEF2:N,MADS2box,MADS2boxMEF2.MEF2C(Fig11).MEF2MADS2box57DNA,,MADS2box,,DNA.APTDNAMADS2box.MEF2MEF2,MADS2box29.DNA,MEF2.MEF2C.MEF2MADS2box,,Fig.1StructurediagramsofMEF2[2]StructuresofthefourvertebrateMEF2geneproductsareshown.AlternativeexonsareindicatedintheC2terminaldomains,andthereareMADSboxandMEF2domainintheN2terminaldomains.,,MEF2.MEF2.MADS2box,MEF2,MADS2box.MEF2MADS2box.MEF2,C,50%,95%MADS2boxMEF2.,MEF2MADS2boxMEF2[2].DrosophilaMEF2,MEF2,MEF2[3,4].,MEF2MADS2box[1].MEF2C(P38,ERK5),,(TADS).MEF2C,,.MEF2,,.2MEF2MEF2,MEF2Ca2+,MKK6PP38CalcineurinPNFATPKC.,,MEF2[2].,MEF2Ca2+.MEF2(Fig.2).Fig.2SignalingpathwaysconvergedonMEF2EachofthesignalingpathwayscanaugmentthetranscriptionalactivityofMEF2andactivatecalcium2regulatedgenes[2].MKK6:mitogen2activatedproteinkinasekinase6PKC:proteinkinaseCNFAT:nuclearfactorofactivatedTcells2.1(mitogen2activatedproteinkinase,MAPK)MAPKMEF2.,MAPKP38,MEF2CC3,MEF2C[5].,MAPKPP38MEF2,[69].,MAPKBMK1PERK5,MEF2CSer2387,MEF2C42420c2jun[10].MEF2MEF2DNA,MEF2.2.2(calcineurin)calcineurin,MEF2.CalcineurinMEF2,MEF2T(nuclearfactorofactivatedTcells,NFAT)[2].T,NFAT.NFAT,NFAT,MEF2[11].MEF2T.Nur77()T,MEF2,MEF2.TMEF2DNA,[12].MEF2BZLF1().BZLF1EB(Epstein2Barrvirus,EBV),BZLF1MEF2,MEF2.BZLF1CsA()FK2506[13].2.3C(proteinkinaseC,PKC)PKCCa2+,Ca2+,PKC.PKC,MEF2,MEF2.,PKC,PKC,DNA,MEF2[14].2.4,MEF2.(transforminggrowthfactor2,TGF)Smads()MEF2[15].,3(phosphoinositide232kinase,PI32K)MEF2[16,17].,(calciumPcalmodulin2dependentproteinkinase,CaMK)MEF2,MEF2MEF2[1821].3MEF23.1MEF2MEF2,DNA,[22,23].MEF2DNA[24].MEF222(basichelix2loop2helixprotein,BHLHprotein)MyoD,.,MEF2bHLH,bHLH[28].MEF2AMADS2boxbHLH3.,.MEF2,DNA,bHLH.,,MEF2bHLHMRF4(melanotropinreleasingfactor,MRF4).MRF4(),MEF2,MEF2MRF4[25].,,MAPKPp38MEF2,MEF2DNA[26].,MEF2MEF2C,MEF2BAD[27,28].,MEF2MEF2A,MEF2B,MEF2C,MEF2D,MEF2B.MEF2,(MEF2D),[29].MEF2[28,30,31].,MEF2A,5244:MEF2,MEF2[32].MEF2,.MEF2,MEF2,.,MEF2A,MEF2B,MEF2DmRNAs,,MEF2C,MEF2s[31].3.2MEF2MEF2.,MEF2,MEF2C[33,34].MEF2,,,.,MAPKPp38,MEF2.MEF2,.MEF2[9].,MEF2,,.,MEF2,MEF2A,[35].,MEF2AMEF2[9].,MEF2AMASH1(mammalianachaete2scutehomolog1)[36].MEF2C,.MEF2C.,MEF2C,.,,MEF2[9].,MEF2D,MEF2D,.,,MEF2D,MEF2D[37].3.3MEF2(hepaticstellatecell,HSC).,,.,MEF2HSCMEF2.MEF2[37],,,,,RT2PCRMEF2mRNA,WesternMEF2,MEF2AMEF2DmRNA.luciferaseEMSAMEF2,MEF2DNA.HSC2T6(matrigel),T6,T6,MEF2.MEF2,MEF22SMA,MEF2RNAi(smallinterferenceRNA)MEF2,2SMA.MEF2,.,MEF2,G0PG1SG2PM(2003811,).(References)1NigelJB.Moleculesinfocusmyocyteenhancerfactor2(MEF2).IntJBiochemCellBiol,1997,29(12):146714702BlackBL,OlsonEN.Transcriptionalcontrolofmuscledevelopmentbymyocyteenhancerfactor22(MEF2)proteins.AnnuRevCellDevBiol,1998,14:1671963LillyB,GalewskyS,FirulliAB,SchulzRA,OlsonEN.D2MEF2:aMADSboxtranscriptionfactorexpressedindifferentiatingmesodermandmusclecelllineagesduringDrosophilaembryogenesis.ProcNatlAcadSciUSA,1994,91(12):566256664NguyenHT,BodmerR,AbmayrSM,McdermottJC,SpoerelNA.62420D2mef2:aDrosophilamesoderm2specificMADSboxcontaininggenewithabiphasicexpressionprofileduringembryogenesis.ProcNatlAcadSciUSA,1994,91(16):752075245HanJ,JiangY,LiZ,KravchenkoW,UlevitchRJ.ActivationofthetranscriptionfactorMEF2CbytheMAPkinasep38ininflammation.Nature,1997,38(6):2962996LuJ,MckinseyTA,ZhangCL,OlsonEN.RegulationofskeletalmyogenesisbyassociationoftheMEF2transcriptionfactorwithclasshistonedeacetylases.MolCell,2000,6(2):2332447ZetserA,GredingerE,BengalE.p38mitogen2activatedproteinkinasepathwaypromotesskeletalmuscledifferentiation.ParticipationoftheMEF2Ctranscriptionfactor.JBiolCh