13 细胞凋亡与衰老

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Chapter13CellapoptosisExtracellularcotrolofcelldivision,cellgrowth,andapoptosisMitogensstimulateG1-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-inlimitationonthenumberoftimestheycandivideThecelldivisioniscotrollednotonlybyextracellularmitogensbutalsobyintracellularmechanismsthatcanlimitcellproliferation.Cell-cyclearrestorapoptosisinducedbyexcessivestimulationofmitogenicpathways. ExtracellulargrowthfactorsstimulatecellgrowthActivationofcell-surfacereceptorsActivationofPI3-kinaseActivationofelF4E(translationinitiationfactor)andS6kinase(phosphorylatesribosomalproteinS6)Increasingproteinsynthesisandcellgrowth 2.Apoptosis,ProgrammedcelldeathBiologicalfunctionsofapoptosis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、NormalcellB、Apoptosis:Apoptoticbodies Biochemicalcharacteristicsofapoptosis:ApoptosisinducedbyCytoCLane1．0h2．1h3．2h4．3h5．4h6．Control7．Marker2.0kbp1.00.50.2180~200bpDNAladder,AccumulationoftTG,PSflip-flop ContrastofApoptosisandnecrosisApoptosisNecrosisDeathbyapoptosisisaneat,orderlyprocess 3.MolecularmechanismsofapoptosisEarlyresearches(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-1ß–convertingenzyme(ICEorcaspase-1) Apoptosisiscarriedoutbyaproteolyticsystem—caspase(1)Whycalledcaspase?Activesite:CysteineCleavagesite:AsparaticacidCysteineAsparaticacidspecificproteaseAps-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—ProcaspasesProcaspaseNH2-terminalprodomain:HighlyvariableLargesubunit(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 ProcaspasesareactivatedbybindingtoadaptorproteinsThecaspasecascadeinvolvedinapoptosisProcaspaseactivationbyproteolyticcleavage.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. MolecularpathwaysofapoptosisTwoprinciplepathwaysExtrinsicpathwayIntrinsicpathway (1)Extrinsicpathway:FasSignalingPathwayFas(alsocalledApo-1orCD95)isamemberofthetumornecrosisfactorreceptor(TNFR)superfamily.Receptor-mediatedpathwayofapoptosisBcl-2Family(cytoplasmicfactors):Bad,Bid,andbax:promoteapoptosis;Bcl-X,Bcl-w,andBcl-2:preventapoptosis.Internalstimuli:DNAdamage,highCa2+,Oxidativestress (2)Intrinsicpathway:MitochondrialpathwayThemitochondria-mediatedpathwayofapoptosisVarioustypesofcellularstressBcl-2family:BadorBaxtobecomeinsertedintoOMofMitReleaseofcytochromecfromI-OspaceofMit.Formamultisubunitcomplex;andCaspaseCascade,… Activationofcaspase-2isrequiredforpermeabilizationofmitochondria,releaseofcytochromec,andapoptosis PathwaystocelldeathinC.elegansandmammals