高级细胞生物学课件

Caspase-mediatedprogrammedcelldeathpathwaysaspotentialtherapeutictargetsincancer,PCD:程序性细胞死亡Atgs:自噬相关基因IAPs:细胞凋亡抑制剂TNF:肿瘤坏死因子DD:死亡结构域DISC:死亡诱导信号复合体DED:死亡效应结构域TNFR:肿瘤坏死因子受体TRAIL:TNF相关调亡诱导配体,简写,introduction,Thecaspasefamilyiswellcharacterizedasplayingacrucialroleinmodulationofprogrammedcelldeath(PCD),whichisageneticallyregulated,evolutionarilyconservedprocesswithnumerouslinkstomanyhumandiseases,mostnotablycancer.,introduction,Therearetwotypesofapoptoticcaspases:initiatorcaspasesandexecutionercaspases.,Initiatorcaspases:casp2,casp8,casp9andcasp10,executionercaspases:casp3,casp6,casp7,caspases,introduction,Caspasesareinvolvedintwodifferentapoptoticpathways:thedeath-receptorpathway(extrinsic),whichistriggeredbyligationofdeathreceptorsandsubsequentcaspase-8activation.(ii)themitochondrialpathway(intrinsic),whichisinitiatedbyintracellularstress,andsubsequent-lyactivatedbycaspase-9.,Caspase-mediatedapoptosisincancerTumournecrosisfactorreceptorsBcl-2familyOtherapoptoticmodulators:cytochromec,Apaf-1andIAPsCaspase-mediatedautophagyincancerTargetedcaspasesandtheirsubstratesfordrugdiscoveryCaspase-8,-9and-3PARP-1andBeclin-1,1Caspase-mediatedapoptoticpathwaysincancer,1.1Tumournecrosisfactorreceptors,Duringthisprocess,Fasligand(FasL),whichtriggerstrimerizationofreceptorsandaggregationofintra-cellulardeathdomains(DDs),leadstoformationofadeath-inducingsignalingcomplex(DISC).ThedeathadaptorproteinFADDandphotolyticenzymecaspase-8arerecruitedtoFas.,TheBcl-2familyispivotalforregulationofapoptosis,andincludesbothanti-andpro-apoptoticproteins.,1.2Bcl-2family,1.2Bcl-2family,截图2,1.3Otherapoptoticmodulators,上图,2Caspase-mediatedautophagyincancer,3Targetedcaspasesandtheirsubstratesfordrugdiscovery,TNF-anditsfamilymembersofdeathligandsCD95Lprovokesevereadverseeffects.TRAILisaratherpromisinganti-cancercytokineasithasbeenshowntoexertselectivityamongstvariouscancercells.,3.1caspase-8,-3,-7,Caspase-8isnotonlyanapicalcaspasewhichtriggersapoptosisfollowingdeathreceptorligation,butalsoahighlyversatilemoleculethatimpactsoncellularsignaling.Wecanenhancedeath-inducingfunctionsofcaspase-8byelevatingitsexpression.,3.1caspase-8,-3,-7,Caspase-9istheinitiatorcaspaseassociatedwiththeintrinsicormitochondrialpathwayofapoptosis.Onceactivated,caspase-9cleavesandactivatesdownstreameffectorcaspases-3and-7,thusresultinginapoptosis.,3.1caspase-8,-3,-7,Caspase-3,theexecutionercaspase,isabletodirectlydegrademultiplesubstratesincludingstructuralandregulatoryproteins.,3.2PARP-1andBeclin-1,PARP-1workastheguardianangelofDNA.ThePARP-1-mediatedpathwayisamajormechanismforDNArepairincancercells,thusleadingtodrugresistanceandcontinuedtumorgrowth,3.2PARP-1andBeclin-1,Beclin-1isanovelsubstrateofcaspases-3,-7and-8,suggestingitscrucialroleincrosstalkbetweenapoptosisandautophagy.,concluding,Cancerisacomplex,multi-stepgene-deriveddiseasewithastonishinglynumerouslinkstoPCDapoptosisandautophagy.Anynewtherapeuticstrategyshouldconsidercombinationofapoptosisandautophagyincancertreatment.Currently,considerableeffortisneededtofurtherdeterminethemolecularmechanismsofapoptosisandautophagyincancer.anewtherapeuticstrategywouldbecarriedforwardfordrugdiscover