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Apoptosis: Programmed Cell Death 細胞凋亡 A story about 7th October 2002

Apoptosis: Programmed Cell Death 細胞凋亡 A story about 7th October 2002. 第 3 組 組員：大老邱， 喇塞 King ， 小萱，朱哥， 翔格葛，徐客 ，小吳. Sydney Brenner. 1927 年生 (80 歲 ) 英國人 美國分子科學研究室 established C. elegans as a novel experimental model organism. John Sulston. 1947 年生 (60 歲 ) 美國人 麻省理工學院

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Apoptosis: Programmed Cell Death 細胞凋亡 A story about 7th October 2002

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  1. Apoptosis:Programmed Cell Death細胞凋亡A story about 7th October 2002 第3組 組員：大老邱，喇塞King，小萱，朱哥，翔格葛，徐客，小吳

  2. Sydney Brenner • 1927年生(80歲) • 英國人 • 美國分子科學研究室 • established C. elegans as a novel experimental model organism

  3. John Sulston • 1947年生(60歲) • 美國人 • 麻省理工學院 • mapped a cell lineage where every cell division and differentiation could be followed in the development of a tissue in C. elegans

  4. Robert Horvitz • 1942年生(65歲) • 英國人 • The Wellcome Trust Sanger Institute • has discovered and characterized key genes controlling cell death in C. elegans

  5. 線蟲 • 線形動物門的線蟲綱 • 種類多，而且數目也極大 • Ex:蛔蟲、鉤蟲、絲蟲、旋毛蟲

  6. 生活史 • 分為蟲卵、幼蟲和成蟲三個階段 • 依有無中間宿主分成兩類:直接發育;間接發育

  7. 分布 • 淡水,海水,沙漠和土壤等自然環境

  8. Apoptosis vs. PCD • 近年來PCD和細胞凋亡常被做為同義詞使用 • 兩者實質上有異 • 功能性概念 vs.形態學概念

  9. Apoptosis vs. Necrosis • Apoptosis – programmed cell death • Necrosis – un-programmed cell death

  10. Necrosis • 成因 氰化物、氮芥、CCl4、內外毒素等 • 步驟 • 缺氧 • 酸化、電解質紊亂胞器壞死 • 胞器壞死、膜破裂

  11. Apoptosis • 1972 Kerr 鼠肝實驗提出

  12. Apoptosis vs. Necrosis

  13. Back to apoptosis… 左上，正常胸腺細胞；右上，凋亡胸腺細胞（注意凋亡小體） 左下，正常胸腺細胞；右下，凋亡胸腺細胞（注意凋亡小體）

  14. Please refer to page 428 of your textbook…

  15. 2 main integration pathways • Death receptor pathway • Mitochondrial pathway • Both pathways converge to a common execution phase

  16. Execution phase

  17. Multiples of 180~200 bp fragments Ladder

  18. Apoptosis in detail • Signal • Cell shrinkage/ Loss of cell-cell contact • Condensation of nuclear chromatin • Nuclear fragmentation • Membrane ruffling/ blebbing • Phagocytosis of apoptotic bodies

  19. E.g.: FasL/TNF Death factors… Bind to death receptors…[cluster and trimerise] E.g.: Fas/TNFR Recruits FADD… DED Recruits pro-caspase 8 [induced proximity]

  20. 粒線體與細胞凋亡 電位耗散 細胞進入不可逆的凋亡過程

  21. 電位耗散 粒線體內膜的通透性改變 粒線體生成PT pore ( PT 孔道） PT pore：由多個蛋白質組成、位於粒線體內膜及 外膜接觸點的通透性轉變通道

  22. PT pore

  23. PT pore 的性質： • 1. PT pore 在不同細胞中的調節可能稍有不同。 • （ANT是由一個基因家族所編碼，其表達有嚴格的組織專一性） • PT pore 的作用有自動放大的效應。 • （PT的結果例如ΔΨm耗散、自由基的生成會導致PT） • PT pore 作為許多生理效應的感受器 • （二價陽離子、ATP、ADP、NAD、ΔΨm …）

  24. PT pore 的開放與關閉 當PT pore 與cyclosporin A 、SH 或bongkrekacid結合時，PT pore 被關閉。 當PT pore開放時 粒線體是放細胞凋亡誘導因子AIF 粒線體釋放「細胞色素C」

  25. 證據 • 誘導生成PT通道的粒線體＋純化的細胞核 • 細胞開始凋亡變化。 • 細胞死亡調節蛋白（抑制死亡的bcl-2家族or促進死亡的Bax家族）均以粒線體作為靶胞器。 • 高表達bcl-2能防止ΔΨm的耗散; 反之，高表達Bax則導致ΔΨm的耗散。

  26. 細胞凋亡的調控 • 在線蟲—ced9 • 在人類—凋亡抑制分子bcl-2(即ced9之同源基因)

  27. 凋亡抑制分子 • P35:被靶Caspases特異切割，切割後的P35與 Caspase的結合更強，形成穩定的具有空間位阻效應的複合體並且抑制Caspases活性 • CrmA：血清蛋白酶抑制劑，能夠直接抑制多種蛋白酶的活性，但目前還未發現在哺乳動物中發現P35和CrmA的同源分子。

  28. 凋亡抑制分子 • FLIPs:能抑制Fas/TNFR1介導的細胞凋亡。通過DED功能區，與FADD和Caspase-8，10結合，拮抗它們之間的相互作用，從而抑制Caspase8，10募集到死亡受體複合體和它們的起始化。

  29. bcl-2家族 • 既有抗凋亡作用，也有促凋亡的作用。 • 功能相當於線蟲中的ced-9。 • 它們在線粒體參與的凋亡途徑中起調控作用，能控制線粒體中細胞色素c等凋亡因素的釋放。 • 都含有1-4個Bcl-2同源結構域

  30. Apoptosis is all around us

  31. Where can we see apop.? • Surprisingly….. all multi-cellular organisms! • And even some single.. @@ Team strategy.

  32. Let’s see… • Animals!

  33. Apoptosis Inducer • infected with a virus • undergoing stress conditions (such as starvation) • ionizing radiation • toxic chemicals

  34. Apoptosis Function • Reduce energy lost • Prevent cancer development • PCD • Homeostasis

  35. In plants as well • 防止自花授粉

  36. In plants as well (2) • Transduction ducts (木質 韌皮部)

  37. In plants (3) • 藏卵器 (頸管 到 腹)

  38. Afterthoughts • Death is so useful… • What is life??

  39. Paradox:Life is dependent on cell death Demonstration of single HT-29/B6 apoptotic cells.

  40. Inhibition of apoptosis: Cancer • Deletion/mutation of p53 • express high levels of Bcl-2 • FAS signaling

  41. Cancers associated with viruses ex: HPV (cervical cancer ) EBV (lymphomas) Other cancer cells ex: B-cell leukemias Melanoma FasL ex: lung and colon cancer cells

  42. Excessive apoptosis: Alzheimer • Loss of neural cells • Induced by beta-amyloid peptides (Abeta)

  43. Abeta trigger toxicity via activation of caspases • The activation of caspase-8 and –9 by Abeta and C31 • APP： (1)a source of cytotoxic Abeta (2)represent a source of C31 contributing cytotoxic activity of Abeta

  44. Inappropriate apoptosis: HIV • Death of CD4+ T cells most by apoptosis • Expression of Nef gene in effected CD4+ T cells

  45. 謝謝大家! Death is only the beginning

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