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1、细胞凋亡与双语教学,南京大学细胞生物学课程双语课程介绍,细胞生物学： 专业必修课，2学时，本科生2年级 细胞生物学实验：专业必修课，3学时，本科生2年级 分子细胞生物学：研究生选修课，4学时，研究生1年级 授 课 对 象： 生命科学学院、医学院、环境学院、强化部、 物理系、生物制药（合办）专业,课 程 情 况,课 程 定 位,细胞生物学： 是研究细胞基本生命活动规律的科学，是介于分子生物学和生理学、 普通生物学之间的一门综合性学科； 是联系分子生物学（即微观生物学）和生物学或医学的桥梁； 是近10年来飞速发展的学科。,夯实专业基础知识 + 提高专业兴趣和信心,1基础知识与学科发展相结合； 2细
2、胞层次与其它微/宏观层次相结合； 3. 细胞的结构与其功能相结合； 4. 与普通生物学、生理学、分子生物学相结合、与生理和病理过程相结合； 5本专业知识与其它学科相结合：,教 学 要 点,整体及生理、病理过程中的细胞结构与功能,将基础理论知识与学科前沿发展相结合 将分子细胞层次与病理生理过程相结合 将夯实基本概念与培养创新意识相结合 将国内教师主讲与外聘教师授课相结合,教 学 理 念,寓学科前沿于基本理论之中 寓实验原理于基本概念之中 寓科学思维于基本概念之中,中英文教学英文教学 国内教师主讲外聘教师短期授课,循序渐进、国际化和多元化的双语教学,Molecular Biology of the
3、 CellBruce Alberts 细胞生物学王金发 Molecular Cell BiologyHarvey Lodish 外籍教师教学录像：共84盘,教材及参考资料,第1章： 细胞概述（2学时）； 第3章： 细胞质膜与跨膜运输（3学时）； 第4章： 细胞环境与互作（3学时）； 第5章： 细胞通讯（6学时）； 第6章： 核糖体与核酶（2学时）； 第7章： 线粒体与过氧化物酶体（4学时）； 第9章： 内膜系统与蛋白质分选和膜运输（6学时）； 第10章：细胞骨架与细胞运动（4学时）； 第11章：细胞核与染色体（2学时）； 第12章：细胞周期与细胞分裂（4学时）； 第13和: 细胞死亡（2学时）
4、。,课 时 安 排,第十三章 细胞死亡 基础概念与实际应用,Apoptosis vs necrosis,Apoptosis,Necrosis,Death by apoptosis is a neat, orderly process,Cell death,Cells die by one of two mechanisms: necrosis or apoptosis Two physiologically different processes - Necrosis: death by injury - Apoptosis: death by suicide Apoptosis and ne
5、crosis have different characteristics,Necrosis, Death by accident Associated with nonphysiological circumstances that disrupt cellular homeostasis (eg., ischemia, hypoxia and poisoning) Necrosis is caused by membrane dissolution (osmotic lysis, shear stress, pore-forming proteins, loss of ATP) Necro
6、sis is bad because cellular material (including degradative enzymes) is released into surrounding tissue Affects contiguous groups of cell Necrosis usually causes inflammatory reaction Cytological characteristics of necrosis Initial swelling of the cell Rupture of the plasma membrane Cytoplasm is sp
7、illed to the extracellular environment,Apoptosis, Death by design genetically programmed cell death Induced by new gene synthesis, primarily in response to developmental cues Requires new RNA and protein synthesis Inhibitors of transcription or translation prevent apoptosis Important for development
8、, homeostasis and elimination of pathogens and tumor cells Causes deletion of individual cells in the midst of others But it can be involved in deletion of entire structures Apoptosis is followed by fast phagocytosis Anti-inflammatory (housekeeping),Morphologic changes during apoptosis, Membranes be
9、come irregular Chromatin becomes condensed and segregated Condensation of cytoplasm DNA is fragmented Cell is fragmented and phagocytosed,Morphological and biochemical characteristics of apoptosis, Morphological changes: Early : Chromosome condensation, cell body shrink Later : Blebbing and Nucleus
10、and cytoplasm fragment Apoptotic bodies At last: Phagocytosed,A、Normal cell,B、Apoptosis: Apoptotic bodies, Biochemical characteristics of apoptosis:,Apoptosis induced by Cyto C Lane 10 h 21 h 32 h 43 h 54 h 6Control 7Marker,180200bp DNA ladder, Accumulation of tTG, PS flip-flop,体内细胞凋亡检测紫杉醇治疗小鼠肺癌肿瘤,肺
11、癌肿瘤组织的免疫组织化学分析,Apoptosis Does Not Damage Neighboring Cells,Morphological features of apoptosis: Cytoskeleton collapses Nuclear envelope disassembles Nuclear DNA breaks up into fragments Cell surface changes so that the cell can be rapidly phagocytosed The consequence is neat death -no damage to the
12、neighboring cells,Death by cell necrosis; cell contents spilled all over the neighbors,Cell apoptosis, in culture dish,Cell apoptosis, in tissue. Showing phagocytosis,Forms of cell death,Necrosis Apoptosis Passive Active Pathological Physiological or pathological Swelling, lysis Condensation, cross-
13、linking Dissipates Phagocytosed Inflammation No inflammation Externally induced Internally or externally induced,APOPTOSIS,Programmed cell death Orderly cellular self destruction Process: as crucial for survival of multi-cellular organisms as cell division MULTIPLE FORMS?,Apoptosis Is Important to t
14、he Development and Survival of the Organism,In human, billions of cells die in bone marrow and intestine every day Why such a “waste”? Normal development Balancing cell division Removing abnormal cells,The paw in mouse embryo showing apoptosis,One day later,As tadpole changes into frog, the tail is
15、lost due to apoptosis,Apoptosis pathways,APOPTOSIS: important in embryogenesis,APOPTOSIS,Evolutionarily conserved Occurs in all multicellular animals studies (plants too!) Stages and genes conserved from nematodes (worms) and flies to mice and humans,Apoptosis pathways, Intrinsic/ Mitochondrial Apop
16、tosis Regulated by Mitochondria Cytochrome c release Extrinsic/ Death Receptor Apoptosis Activated by ligation of Death Receptors Fas, TNF alpha These pathways intersect at the effector caspases,Two Pathways that Initiate Apoptosis,APOPTOSIS: control,Receptor pathway (physiological):,Death receptors
17、: (FAS, TNF-R, etc),FAS ligand,TNF,Death domains,Adaptor proteins,Pro-caspase 8 (inactive),Caspase 8 (active),Pro-execution caspase (inactive),Execution caspase (active),Death,MITOCHONDRIA,APOPTOSIS: control,Physiological Intrinsic receptor pathway damage pathway,MITOCHONDRIAL SIGNALS,Caspase cleava
18、ge cascade,Orderly cleavage of proteins and DNA,CROSSLINKING OF CELL CORPSES; ENGULFMENT (no inflammation),Apoptosis Is Mediated by a Caspases,Apoptosis depends on a group of proteases - Caspases (胱冬蛋白酶) Have a cysteine (半胱氨酸) in the active site Cleave the target proteins at specific aspartic acid (
19、天冬氨酸) residues Caspases are synthesized as inactive procursor, “procaspase”. Other caspases activate it by cleaving it:,A apoptotic proteolytic system caspase,Why called caspase?,Active site: Cysteine Cleavage site: Asparatic acid,Cysteine Asparatic acid specific protease,Aps-Xxx,天冬氨酸特异性的半胱氨酸蛋白水解酶,C
20、aspases Trigger a Proteolysis Cascade,Cleaves inhibitors of DNase,DNA fragmentation,APOPTOSIS: Role in Disease Cancer,Apoptosis eliminates damaged cells (damage = mutations = cancer ) Tumor suppressor p53 controls senescence and apoptosis responses to damage Most cancer cells are defective in apopto
21、tic response (damaged, mutant cells survive) High levels of anti-apoptotic proteins or Low levels of pro-apoptotic proteins = CANCER,TRAIL: 一种细胞凋亡诱导蛋白质,TRAIL: 肿瘤坏死因子相关的凋亡诱导配体,TRAIL肿瘤选择性: 不同TRAIL受体表达的结果,死亡受体(DR4，DR5): 介导细胞凋亡信号,诱骗受体 (DcR1，DcR2) : 不传导细胞凋亡信号,DcRs 与 DRs 竞争结合TRAIL，赋予正常组织TRAIL抗性,TRAIL变体具有更
22、好的细胞凋亡活性,Adaptor proteins bring many copies of initiator procaspase together Initiator caspase has low activity, but when they form aggregates, they can cross-activate each other. Aggregation causes conformational changes,Apoptosis Is Activated by Binding to Adaptor Proteins to Form Aggregates,Activ
23、ation of Apoptosis from Outside the Cell,Death receptors Killer lymphocytes produce Fas ligand to bind to Fas protein (death receptor) on target cells Adaptor proteins aggregate caspase 8, which cross-activate,Some damaged cells produce both Fas ligand and Fas protein for self-destruction,Extrinsic
24、pathway,APOPTOSIS: control,Intrinsic pathway (damage):,Mitochondria,Cytochrome c release,Pro-caspase 9 cleavage,Pro-execution caspase (3) cleavage,Caspase (3) cleavage of cellular proteins, nuclease activation, etc.,Death,BAX BAK BOK BCL-Xs BAD BID B IK BIM NIP3 BNIP3,BCL-2 BCL-XL BCL-W MCL1 BFL1 DI
25、VA NR-13 Several viral proteins,Activation of Apoptosis from Inside the Cell,Intrinsic pathway,When cells are damaged: Mitochondria release cytochrome c In cytosol, cytochrome c binds to Apaf-1 (adaptor protein) Apaf-1 aggregates of procaspase 9 p53 activates transcription of Bcl-2 family,Bcl-2 Fami
26、ly Proteins and IAP proteins Regulates Apoptosis,Members of the Bcl-2 family have different roles: Bcl-2, Bcl-X, etc:Inhibit apoptosis by blocking cytochrome c release Bad:Promotes apoptosis by binding to and inactivating Bcl-2, Bcl-X, etc, Bax, Bak, etc:Stimulate the release of cytochrome c,The IAP (inhibitor of apoptosis) family inhibit apoptosis: Bind to procaspases to prevent their activations Bind to caspases to prevent their activity Mitochrondria release cytochrome c AND inhibitors of IAP to fully start the apoptosis,Cell proliferation,谢 谢 ！ Thanks for your kind attention,