转录因子_新型抗肿瘤药物作用靶点

©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(2):97-103,3(,210009),,,,,;;;;TR54116;Q786A1000-5048(2010)02-0097-07TranscriptionfactorsasnewtargetsforcancertherapyLIUNan,CHENYi2jun3LaboratoryofChemicalBiology,ChinaPharmaceuticalUniversity,Nanjing210009,ChinaAbstractMechanismstudiesinthegeneregulationintheeukaryoticcellsisoneofthemomentousareasinmo2lecularbiology1Regulationattranscriptionlevelisacomplexprogresswithmultiplestepswiththepresenceofthegenefunctions1Thereexistubiquitousoccurrenceoftranscriptionfactorsinmammaliantissuesandbiodiversityinthefactors1Thesetranscriptionfactorsarefoundtorelatecloselytovariouscarcinogeneses,includingcellprolifer2ation,apoptosis,invasionandangiogenesis1Understandingoftranscriptionfactorsandtheiractionmechanisms,throughtheactivationandinhibitionoftranscriptionfactors,wouldpotentiallyleadtothediscoveryofnewentitiesinthetargetingtreatmentandpreventionofthecancerdiseases1Keywordstranscriptionfactor;anti2tumor;NF2B;signaltransducerandactivatoroftranscription;nuclearfac2torofactivatedT2cells,,,(transcriptionfactor),,,1,2000[1]3,DNA(DNA2bindingdomain)(activationdomain),,,Darnell[2]DNA,[3]79320092122073Tel:[phone]E2mail:yjchen@cpu1edu1cn©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.[4]:,,,,,,DNA,3[2]:(1),(importin),,(2),(3),2,,DNA,Brivalou[5](1):(con2stitutivelyactivenuclearfactors)(regulato2rytranscriptionfactors),[21(activatorprotein21,AP21)](STATNF2BNFAT)211(nuclearfactorkappaB,NF2B)21111NF2BNF2BSen[6]1986B,BB,NF2B/Rel,[7-8],NF2B,,,,,(TNF2)1(IL21),NF2B,,,1HNF:;GR:;ER:;PR:NF2B,RelDNANF2B(inhibitorB,IB),[9]NF2B5:NF2B1(p50/p105)NF2B2(p52/p100)c2RelRelA(p65)RelBN300Rel(RHD)DNA,DNABIB,NF2BIBNF2B/IB,IB21112NF2BNF2B(canonicalpathway)(non2canonicalpathway)[10],,RelAp50IBNF2B/IBIB(IBkinase,IKK),IKK3(IKKIKKIKK)IKKIB,IBNF2B(RelA/p50),NF2B,B,,NF2BIB,NF2B(Nck2interactingkinases,NIK),NIKIKK,NF2B2Cp100,p100(proteasomes)p52RelB89©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(signaltransducerandacti2vatoroftranscription,STAT)21211STATSTAT,[4],7,STAT1STAT2STAT3STAT4STAT5aSTAT5bSTAT6STAT3,[11]STAT750900,6,NDNASH2C21212STATSTATJAK/STAT[12],,Src/JAK(Januskinase),(receptorproteintyrosinekinase),STAT,STATSH2STATSH2STAT,,,,STAT,,STATLee[13]RNASTAT3NF2BSTAT3p300RelA,NF2BNF2B,213T(nuclearfactorofactivatedT2cells,NFAT)21311NFAT1988NFAT1,TIL22[14]NFAT5,NFAT1(NFATp/NFATc2)NFAT2(NFATc1)NFAT3(NFATc4)NFAT4(NFATx/NFATc3)NFAT5NFAT[15],NFATIL22IL23IL24IL25TNF222(COX22),NFAT,Robbs[16]NFAT,A(CsA)FK506NFAT,(cyclophilinA,CyPA)12kDFK506(12kDFK5062bindingprotein,FKBP12),(CaN),NFAT21312NFAT,C(phospholipaseC,PLC)(phosphatidylinositol4,52bisphosphate,PIP2)(inositol1,4,52triphosphate,InsP3)(dia2cylglycerol,DAG)DAGRas/PKC,InsP3/InsP3,Ca2+,Ca2+,Ca2+CaN,(calm2odulin,CaM)CaN,CaNCaNNFATN(NFAThomologyre2gion,NHR),NFATDNA,NFAT,Ca2+,CaNNFAT,NFAT,[17](dualspecificitytyrosinephosphorylation2regulatedkinase,DYRK)[18-19],NFAT,DYRK21(caseinkinase1)NFATs,DYRK13(glycogensynthasekinase3)NFATs3311NF2BNF2B,T1(humanT2cellleukemia/lymphomavirustype1,HTLV21)TAXNF2BIKK,NF2B[20]NF2B,T,(AML)CD34+[21],NF2B(ataxiatelangiectasiamutated,ATM)ATMNF2B,ATMNF2BNF2B,NF2B,NF2B99©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(CLL)[22],NF2B,p65CLL,RelADNA[23]STAT,STAT3STAT5AML(ALL)(CML)[24],Harir[25]STAT5,PI32Kp85AKT/PKB;STAT5NFAT2BurkittBT[26-28],CaN,CaN,312(VEGF),,,VEGF,NFATSTATNF2BVEGFNFATCOX22[15]VEGF[29],NFAT,VEGF,,NFATVEGFR,NFAT[30-31],NFAT2,STAT3VEGFbFGF,[32],NF2B[33]Kisseleva[34]IB,,NF2B,NF2BNF2B313,,Rebouissou[35]GP130,IL262GP1302JAK2STAT3,,STAT3,,STAT3p300NF2B,,,[13]4,,,NF2B,STATNFAT411NF2BNF2B,4[10]:(1),;(2),BortezomibMG2132Bay1127082;(3),SN250;(4),IB,41111[36](dimethylaminoparthenolide,DMAPT,2),(acutemyeloidleukemia,AML)(parthe2nolide,2)10mol/L84%,IC50114mol/L,01169mmol/mL,,CrooksDMAPT,,,100,10mol/L93%,IC50117mol/L,70%,DMAPT[37],NF2B,p53,41112Bortezomib[38]Bortezomib(,PS2341,2)FDA,Bortezomib26S,IB,NF2B,412STATSTAT3[39]:(1)STATDNA;(2)STATSH2;(3)STATNSTAT,41211STAT3DNA(NSC295558,2)[40]STAT3DNA,STAT3,,(MDA2MB2231MDA2MB2435MDA2MB2453MDA2MB2468)001©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(Panc21)(DU145),STAT5STAT1NSC295558STAT3DNA,G0/G141212STATSH2S3I2201(NSC274859,2)[41]STAT3,,STAT3,STAT3,STAT3SH2STAT3,cyclinD1,bcl2xLSurvivinNSC274859Stattic(2)STAT3,[42]STAT3SH2,STAT3,STAT341213STATNSTAT3N130,8,,STAT3,STAT3STAT4NMR,STAT42STAT3N,STAT32,RQIKIWFPNRR2Nle2KWKK2NH2[43](IC5010mol/L)(MDA2MB2231MDA2MB2435MCF27),413NFATNFATCaN,FK506CsACaN,,FK506CsAMerckFK506L2732531[44],RocheCsAISATX47[45]CsA,,,,Noguchi[46]VIVIT,,VIVITCaNNFATNFAT,,,FK506CsA,2414,,:,,,,,,,,,,,,,,,,(),,,,101©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.