resources肿瘤问题.ppt

1,顾健人,上海市肿瘤研究所癌基因及相关基因国家重点实验室,2,1.现有“生物信息学”的限制：“有眼不识泰山”第一外显子识别能力外显子内含子识别能力2.一个基因：不同剪切体Splicingform(Isoform)3.一个基因蛋白质切割：蛋白质1肽段,人基因组计划已经给了我们多少？,人基因有多少个？,10万3万？,3,4.同一个蛋白质细胞内的不同“定位”不同功能！5.98DNA序列：功能不明!（95）,细胞核,细胞质,线粒体,细胞膜,蛋白质移位Translocation,4,E1bE1aExon2Exon3,p16Ink4a,P14ARF(human)P19ARF(mouse),CrossTalkbetwerenOncogenesPKC4E-BPdissociation&releaseofelf-4Ecapdependentinitiationtranslationof5-UTR,37,P1(3)KdependentcyelinD3PhosphorylationofRbandp107E2FInvolvedinP1(3)KandAkttumorigenesisDependentonPhosphorylation&activationofp70S6K,RibosomalS6KinaseS6K1,S6K2,Regulatorofcellgrowth&proteintranslationp70S6KshortisoformofS6K1CytoplasicinlargepartActivationisblockedbyrapamycinMediatemTOReffectonprotein-translationPhosphorylationofS6subunit(40srsprotein)S6translationof5ter.Pyr-richtract(5-TOPmRNA),Alsoinvolvedincellcycle,38,WntPathway,WntWnt1=(int-1,mouseMMTVintegrationactivatedgene)Porcupine:AgeneforwntsecretionPolytopicmembraneproteinRelatedtoacyltransferaseFrizzled(Fz)WntReceptorDally:Co-receptorofWntGlypican-typeheparansulfateproteoglycanGlycosyl-PtdInsmoietymembraneb-catenin:inabsenceofWntDestabilizedbyaproteincomplexDishevelled(Dsh)activatedbyWnt-FzbindingAxinAPCGSK-3b(Glycogensynthasekinase)GSK-3b-b-catenin-bcatenindegradationWntFzbindingDshGSK-3bb-cateninstabilizedenternucleusNucleartranscriptionfactor:Tcf/LEF:activatedbyb-catenin,39,WntPathway,TCF/LEF,APC,GSK3b,TCF/LEF,b-catenin,LRP,Fz,40,HedgehogPothway,Hedgehog:EmbryonicdevelopmentinducerHh,hh:HumnaShh(Sonichh)Ihh(Indianhh)Dhh(Deserthh)19KDproteinCCholesterolesterNPalmitoylation(aftercholesteroladdition,enhancingsignaling)Secretionofhh:2genes:DispatchedrelatedtohhRPatchedhhreleaseToutvelu:enzyme,heparin-SO4synthesisfortransportandresponseofhhRececeptorofhhPatched(Ptc):Ts,12Span-transmembraneProton-drivenlipidtransportorSmoothened(Smo):Onc,7-transmembranep(Fzlike),41,1.hh(-):(inacomplex)hh(+):2.Smoactivated:coupledwithacomplex3.hh(-):(1)CiNter.transcriptionrepressor(Ci75)(2)Ciincytoplasm(Cos2/Fu/Su/Cicomplexanchoredonmicrotubule)4.hh(+):Costa/Fu/Su/CidissociatedfrommicrotubuleCi(Fulllength):entersnucleusTranscriptionofgenes(ptc,Hipandgrowthgenes),ActivationofhhPathway,hhPtcSmo*,hh-Ptc,Smo*,Smo*,Fu:Fused,S/TPKSu:SuppressorofFuCosta2(Cos.2):KinaselikeCi:Cubitusinteruptus,ZFTAGliinmammal,PKA,42,Su,Fused(Fu),Costa2,Smoothened(Smo),Patched(Prc),Hed