北大細胞生物學課件13細胞凋亡

Chapter13CellapoptosisExtracellular

cotrolofcelldivision,cellgrowth,andapoptosisMitogensstimulateG1-CdkandG1/S-CdkactivitiesPRIZED

Horvitz,andSulstonsharePhysiologyorMedicineNobel（2002）

“fortheirdiscoveriesconcerninggeneticregulationoforgandevelopmentandprogrammedcelldeath”1090–131=959(cells)機體結構細胞增殖細胞分化細胞凋亡細胞信號轉導染色體（DNA與蛋白質的相互作用）衰老

AsimplifiedmodelofonewaythatmitogensstimulatecelldivisionHumancellshaveabuilt-inlimitationonthenumberoftimestheycandivideThecelldivisioniscotrollednotonlybyextracellularmitogensbutalsobyintracellularmechanismsthatcanlimitcellproliferation.Cell-cyclearrestorapoptosisinducedbyexcessivestimulationofmitogenicpathways.ExtracellulargrowthfactorsstimulatecellgrowthActivationofcell-surfacereceptorsActivationofPI3-kinaseActivationofelF4E(translationinitiationfactor)andS6kinase(phosphorylatesribosomalproteinS6)Increasingproteinsynthesisandcellgrowth2.Apoptosis,Programmedcelldeath

Biologicalfunctionsofapoptosis

Indevelopment,homeostasis,tumorsurveillance,andthefunctionoftheimmunesystem.

細胞凋亡是多細胞生物在發(fā)育過程中，一種由基因控制的主動的細胞生理性自殺行為。

Morphologicalandbiochemicalcharacteristicsofapoptosis

Morphologichanges:

Early:Chromosomecondensation,cellbodyshrink

Later:BlebbingandNucleusandcytoplasmfragment—Apoptoticbodies

Atlast:PhagocytosedA、NormalcellB、Apoptosis:Apoptoticbodies

Biochemicalcharacteristicsofapoptosis

:ApoptosisinducedbyCytoCLane1．0h2．1h3．2h4．3h5．4h6．Control7．Marker

2.0kbp1.00.50.2180~200bpDNAladder,AccumulationoftTG,PSflip-flopContrastofApoptosisandnecrosisApoptosisNecrosisDeathbyapoptosisisaneat,orderlyprocess3.MolecularmechanismsofapoptosisEarlyresearches(MIT:RobertHorrid,1986)C.

elegans:1090cells,TheFindingofCED3mutantWithoutlosinganyoftheircellstoapoptosis.CED3geneplayacrucialroleintheprocessofapoptosis.Celegans:amillimeterlong,transparentbodyonlyafewcelltypes,fromzygotetomatureadultonlyin3.5days.131cellsdeath.線蟲體細胞凋亡研究：PCD相關基因15個，分為四組：1、與PCD有關的基因，負責PCD控制：ced-3、ced-4和ced-9。2、與PCD過程吞噬作用有關：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所必須。4、影響特異細胞類型PCD的基因：ces-1、ces-2、cgl-1、和her-1.保守性高，在哺乳動物中有相應同源物：Ced-3=ICE,Ced-4=Apaf-1,Ced-9=Bcl-2.Mammalian:CED3isrelatedtomammalianinterleukin-1?–convertingenzyme(ICEorcaspase-1)Apoptosisiscarriedoutbyaproteolyticsystem—

caspase

(1)Whycalledcaspase?Activesite:CysteineCleavagesite:Asparaticacid

CysteineAsparaticacidspecificproteaseAps-Xxx天冬氨酸特異性的半光氨酸蛋白水解酶Apoptosiscanbedividedintotwophases：

Activationphase：Thecellrespondsto“deathsignals”thatcommitittoundergoingself-destruction.

Executionphase：

Thedeathsentenceiscarriedout.Apoptosiscellsarerecognizedbyphagocytesbecausetheycarryexposedmarkers,called“