北大細(xì)胞生物學(xué)課件13細(xì)胞凋亡

Chapter13CellapoptosisExtracellular

cotrolofcelldivision,cellgrowth,andapoptosisMitogensstimulateG1-CdkandG1/S-CdkactivitiesPRIZED

Horvitz,andSulstonsharePhysiologyorMedicineNobel（2002）

“fortheirdiscoveriesconcerninggeneticregulationoforgandevelopmentandprogrammedcelldeath”1090–131=959(cells)機(jī)體結(jié)構(gòu)細(xì)胞增殖細(xì)胞分化細(xì)胞凋亡細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)染色體（DNA與蛋白質(zhì)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(xì)胞凋亡是多細(xì)胞生物在發(fā)育過(guò)程中，一種由基因控制的主動(dòng)的細(xì)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(chóng)體細(xì)胞凋亡研究：PCD相關(guān)基因15個(gè)，分為四組：1、與PCD有關(guān)的基因，負(fù)責(zé)PCD控制：ced-3、ced-4和ced-9。2、與PCD過(guò)程吞噬作用有關(guān)：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(xì)胞類型PCD的基因：ces-1、ces-2、cgl-1、和her-1.保守性高，在哺乳動(dòng)物中有相應(yīng)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“