考研资料：北京大学细胞生物学 第十三章+细胞凋亡与衰老.ppt

Chapter13 Cellapoptosis Extracellularcotrolofcelldivision cellgrowth andapoptosis MitogensstimulateG1 CdkandG1 S Cdkactivities PRIZEDHorvitz andSulstonsharePhysiologyorMedicineNobel 2002 fortheirdiscoveriesconcerninggeneticregulationoforgandevelopmentandprogrammedcelldeath 1090 131 959 cells 机体结构 细胞增殖 细胞分化 细胞凋亡 细胞信号转导 染色体 DNA与蛋白质的相互作用 衰老 Asimplifiedmodelofonewaythatmitogensstimulatecelldivision Humancellshaveabuilt inlimitationonthenumberoftimestheycandivide Thecelldivisioniscotrollednotonlybyextracellularmitogensbutalsobyintracellularmechanismsthatcanlimitcellproliferation Cell cyclearrestorapoptosisinducedbyexcessivestimulationofmitogenicpathways Extracellulargrowthfactorsstimulatecellgrowth Activationofcell surfacereceptors ActivationofPI3 kinase ActivationofelF4E translationinitiationfactor andS6kinase phosphorylatesribosomalproteinS6 Increasingproteinsynthesisandcellgrowth 2 Apoptosis Programmedcelldeath Biologicalfunctionsofapoptosis Indevelopment homeostasis tumorsurveillance andthefunctionoftheimmunesystem 细胞凋亡是多细胞生物在发育过程中 一种由基因控制的主动的细胞生理性自杀行为 Morphologicalandbiochemicalcharacteristicsofapoptosis Morphologichanges Early Chromosomecondensation cellbodyshrinkLater BlebbingandNucleusandcytoplasmfragment ApoptoticbodiesAtlast Phagocytosed A Normalcell B Apoptosis Apoptoticbodies Biochemicalcharacteristicsofapoptosis ApoptosisinducedbyCytoCLane1 0h2 1h3 2h4 3h5 4h6 Control7 Marker 2 0kbp 1 0 0 5 0 2 180 200bpDNAladder AccumulationoftTG PSflip flop ContrastofApoptosisandnecrosis Apoptosis Necrosis Deathbyapoptosisisaneat orderlyprocess 3 Molecularmechanismsofapoptosis Earlyresearches MIT RobertHorrid 1986 C elegans 1090cells TheFindingofCED3mutantWithoutlosinganyoftheircellstoapoptosis CED3geneplayacrucialroleintheprocessofapoptosis Celegans amillimeterlong transparentbodyonlyafewcelltypes fromzygotetomatureadultonlyin3 5days 131cellsdeath 线虫体细胞凋亡研究 PCD相关基因15个 分为四组 1 与PCD有关的基因 负责PCD控制 ced 3 ced 4和ced 9 2 与PCD过程吞噬作用有关 ced 1 ced 2 ced 5 8和ced 10 3 核酸酶基因 nuc 1 控制DNA降解 但非PCD所必须 4 影响特异细胞类型PCD的基因 ces 1 ces 2 cgl 1 和her 1 保守性高 在哺乳动物中有相应同源物 Ced 3 ICE Ced 4 Apaf 1 Ced 9 Bcl 2 Mammalian CED3isrelatedtomammalianinterleukin 1 convertingenzyme ICEorcaspase 1 Apoptosisiscarriedoutbyaproteolyticsystem caspase 1 Whycalledcaspase Activesite CysteineCleavagesite Asparaticacid CysteineAsparaticacidspecificprotease Aps Xxx 天冬氨酸特异性的半光氨酸蛋白水解酶 Apoptosiscanbedividedintotwophases Activationphase Thecellrespondsto deathsignals thatcommitittoundergoingself destruction Executionphase Thedeathsentenceiscarriedout Apoptosiscellsarerecognizedbyphagocytesbecausetheycarryexposedmarkers called eatme signals Thebeststudied eatme signalisthepresenceofphosphatidylserinemoleculesintheouterleafletofPMofapoptoticcells byflop flipase Howtoactivatecaspases Allcaspasesexpressedasproenzymes Procaspases Procaspase NH2 terminalprodomain Highlyvariable Largesubunit 20kD Smallsubunit 10kD Howareprocaspasesactivatedtoinitiatethecaspasecascade Theactivationistriggeredbyadaptorproteinsthatbringmultiplecopiesofspecificprocaspases 3groupsofcaspase 1 apoptoticinitiators caspase 2 caspase 8 caspase 9andcaspase 102 apoptoticexecutioners caspase 3 caspase 6 caspase 7and14 morphologychange 3 inflammatorymediateors caspase 1 andcaspase 11 Procaspasesareactivatedbybindingtoadaptorproteins ThecaspasecascadeinvolvedinapoptosisProcaspaseactivationbyproteolyticcleavage Caspasecascade Thetargetproteinsofcaspasearethefollowing Morethanadozenproteinkinase includingFAK PKC andRaf1 FAK disruptcelladhesionfortheapoptoticcell Lamins Cleavageoflaminsleadstothedisassemblyofthenuclearlaminaandshrinkageofthenucleus Proteinsrequiredforcellstructure SuchasIF actin andgelsilin Cleavageandinactivationoftheseproteinsleadtochangesincellshape Inducecelldisplaysignalsmarkeditforphagocytosis TheinhibitorofCAD Caspase activatedDnase anendonuclease CleavageofCADinhibitorleadtoactivationofCAD onceactivated CADtranslocatesfromthecytosoltothenucleusseveringDNAintofragments EnzymesinvolvedinDNArepair Whichareinactivatedbycaspasecleavage DNArepairisahomeostaticactivitythatisinappropriateinanapoptoticcell Molecularpathwaysofapoptosis Twoprinciplepathways Extrinsicpathway Intrinsicpathway 1 Extrinsicpathway FasSignalingPathway Fas alsocalledApo 1orCD95 isamemberofthetumornecrosisfactorreceptor TNFR superfamily Receptor mediatedpathwayofapoptosis Bcl 2Family cytoplasmicfactors Bad Bid andbax promoteapoptosis Bcl X Bcl w andBcl 2 preventapoptosis Internalstimuli DNAdamage highCa2 Oxidativestress 2 Intrinsicpathway Mitochondrialpathway Themitochondria mediatedpathwayofapoptosis Varioustypesofcellularstress Bcl 2family BadorBaxtobec