生物细胞细胞凋亡与衰老幻灯片.ppt

生物细胞细胞凋亡与衰老第1页，共27页，编辑于2022年，星期一PRIZED Horvitz,and Sulston share Physiology or Medicine Nobel（2002）“for their discoveries concerning genetic regulation for their discoveries concerning genetic regulation of organ development and programmed cell death”of organ development and programmed cell death”1090 131=959(cells)第2页，共27页，编辑于2022年，星期一机体结构机体结构细胞增殖细胞增殖细胞分化细胞分化细胞凋亡细胞凋亡细胞信号转导细胞信号转导染色体染色体（DNADNA与蛋白质的相互作用）与蛋白质的相互作用）衰老衰老第3页，共27页，编辑于2022年，星期一第4页，共27页，编辑于2022年，星期一A simplified model of one way that mitogens stimulate cell division第5页，共27页，编辑于2022年，星期一Human cells have a built-in limitation on the number of times they can divideThe cell division is cotrolled not only by extracellular mitogens but also by intracellular mechanisms that can limit cell proliferation.Cell-cycle arrest or apoptosis induced by excessive stimulation of mitogenic pathways.第6页，共27页，编辑于2022年，星期一Extracellular growth factors stimulate cell growthActivation of cell-surface receptors Activation of PI 3-kinaseActivation of elF4E(translation initiation factor)and S6 kinase(phosphorylates ribosomal protein S6)Increasing protein synthesis and cell growth第7页，共27页，编辑于2022年，星期一2.Apoptosis,Programmed cell death Biological functions of apoptosis In development,homeostasis,tumor surveillance,and the function of the immune system.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。第8页，共27页，编辑于2022年，星期一第9页，共27页，编辑于2022年，星期一 Morphological and biochemical characteristics of apoptosis Morphologi changes:Early:Chromosome condensation,cell body shrink Later:Blebbing and Nucleus and cytoplasm fragment Apoptotic bodies At last:Phagocytosed第10页，共27页，编辑于2022年，星期一A、Normal cell B、Apoptosis:Apoptotic bodies第11页，共27页，编辑于2022年，星期一 Biochemical characteristics of apoptosis:Apoptosis induced by Cyto CLane 10 h 21 h 32 h 43 h 54 h 6Control 7Marker 2.0kbp1.00.50.2180200bp DNA ladder,Accumulation of tTG,PS flip-flop第12页，共27页，编辑于2022年，星期一Contrast ofApoptosis and necrosisApoptosisNecrosisDeath by apoptosis is a neat,orderly process第13页，共27页，编辑于2022年，星期一3.Molecular mechanisms of apoptosisEarly researches(MIT:Robert Horrid,1986)C.elegans:1090 cells,The Finding of CED3 mutantWithout losing any of theircells to apoptosis.CED3 gene play a crucial role in the process of apoptosis.C elegans:a millimeter long,transparent body only a few cell types,from zygote to mature adult only in 3.5days.131 cells death.第14页，共27页，编辑于2022年，星期一线虫体细胞凋亡研究：线虫体细胞凋亡研究：PCD相关基因相关基因15个，分为四组：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:CED3 is related to mammalian interleukin-1converting enzyme(ICE or caspase-1)第15页，共27页，编辑于2022年，星期一 Apoptosis is carried out by a proteolytic system caspase(1)Why called caspase?Active site:CysteineCleavage site:Asparatic acid Cysteine Asparatic acid specific proteaseAps-Xxx天冬氨酸特异性的半光氨酸蛋白水解酶第16页，共27页，编辑于2022年，星期一Apoptosis can be divided into two phases：Activation phase：The cell responds to“death signals”that commit it to undergoing self-destruction.Execution phase：The death sentence is carried out.Apoptosis cells are recognized by phagocytes because they carry exposed markers,called“eat me”signals.The best studied“eat me”signal is the presence of phosphatidylserine molecules in the outer leaflet of PM of apoptotic cells(by flop-flipase).第17页，共27页，编辑于2022年，星期一 How to activate caspases?All caspases expressed as proenzymes ProcaspasesProcaspaseNH2-terminal prodomain:Highly variableLarge subunit(20kD)Small subunit(10kD)How are procaspases activated to initiate the caspase cascade?The activation is triggered by adaptor proteins that bring multiple copies of specific procaspases.3 groups of caspase:1、apoptotic initiators:caspase-2,caspase-8,caspase-9 and caspase-10 2、apoptotic executioners:caspase-3,caspase-6，caspase-7 and 14(morphology change)3、inflammatory mediateors:caspase-1,and caspase-11 第18页，共27页，编辑于2022年，星期一Procaspases are activated by binding to adaptor proteinsThe caspase cascade involved in apoptosisA.Procaspase activation by proteolytic cleavage.B.Caspase cascade第19页，共27页，编辑于2022年，星期一The target proteins of caspase are the following:More than a dozen protein kinase,including FAK,PKC,and Raf1.FAK disrupt cell adhesion for the apoptotic cell.Lamins.Cleavage of lamins leads to the disassembly of the nuclear lamina and shrinkage of the nucleus.Proteins required for cell structure.Such as IF,actin,and gelsilin.Cleavage and inactivation of these proteins lead to changes in cell shape.Induce cell display signals marked it for phagocytosis.第20页，共27页，编辑于2022年，星期一The inhibitor of CAD(Caspase-activated Dnase,an endonuclease).Cleavage of CAD inhibitor lead to activation of CAD,once activated,CAD translocates from the cytosol to the nucleus severing DNA into fragments.Enzymes involved in DNA repair.Which are inactivated by caspase cleavage.DNA repair is a homeostatic activity that is inappropriate in an apoptotic cell.第21页，共27页，编辑于2022年，星期一 Molecular pathways of apoptosisTwo principle pathways Extrinsic pathwayIntrinsic pathway第22页，共27页，编辑于2022年，星期一(1)Extrinsic pathway:Fas Signaling PathwayFas(also called Apo-1 or CD95)is a member of the tumor necrosis factor receptor(TNFR)superfamily.Receptor-mediated pathway of apoptosisBcl-2 Family(cytoplasmic factors):Bad,Bid,and bax:promote apoptosis;Bcl-X,Bcl-w,and Bcl-2:prevent apoptosis.Internal stimuli:DNA damage,high Ca2+,Oxidative stress第23页，共27页，编辑于2022年，星期一第24页，共27页，编辑于2022年，星期一(2)Intrinsic pathway:Mitochondrial pathwayThe mitochondria-mediated pathway of apoptosisVarious types ofcellular stressBcl-2 family:Bad or Bax to become inserted into OM of MitRelease of cytochrome c from I-O space of Mit.Form a multisubunit complex;and Caspase Cascade,第25页，共27页，编辑于2022年，星期一Activation of caspase-2 is required for permeabilization of mitochondria,release of cytochrome c,and apoptosis第26页，共27页，编辑于2022年，星期一Pathways to cell death in C.elegans and mammals第27页，共27页，编辑于2022年，星期一