Apoptosis programmed cell death a story about 7th october 2002
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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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Apoptosis programmed cell death 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

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

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


Robert horvitz

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


Apoptosis programmed cell death a story about 7th october 2002

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


Apoptosis programmed cell death a story about 7th october 2002

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


Apoptosis programmed cell death a story about 7th october 2002

分布

  • 淡水,海水,沙漠和土壤等自然環境


Apoptosis vs pcd

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


Apoptosis vs necrosis

Apoptosis vs. Necrosis

  • Apoptosis – programmed cell death

  • Necrosis – un-programmed cell death


Necrosis

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


Apoptosis

Apoptosis

  • 1972 Kerr 鼠肝實驗提出


Apoptosis vs necrosis1

Apoptosis vs. Necrosis


Back to apoptosis

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)


Please refer to page 428 of your textbook

Please refer to page 428 of your textbook…


2 main integration pathways

2 main integration pathways

  • Death receptor pathway

  • Mitochondrial pathway

  • Both pathways converge to a common execution phase


Execution phase

Execution phase


Multiples of 180 200 bp fragments

Multiples of 180~200 bp fragments

Ladder


Apoptosis in detail

Apoptosis in detail

  • Signal

  • Cell shrinkage/ Loss of cell-cell contact

  • Condensation of nuclear chromatin

  • Nuclear fragmentation

  • Membrane ruffling/ blebbing

  • Phagocytosis of apoptotic bodies


Apoptosis programmed cell death a story about 7th october 2002

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]


Apoptosis programmed cell death a story about 7th october 2002

粒線體與細胞凋亡

電位耗散

細胞進入不可逆的凋亡過程


Apoptosis programmed cell death a story about 7th october 2002

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


Apoptosis programmed cell death a story about 7th october 2002

PT pore


Apoptosis programmed cell death a story about 7th october 2002

  • 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 …)


Apoptosis programmed cell death a story about 7th october 2002

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」


Apoptosis programmed cell death a story about 7th october 2002

  • 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。


Apoptosis programmed cell death a story about 7th october 2002

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)


Apoptosis programmed cell death a story about 7th october 2002

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。


Apoptosis programmed cell death a story about 7th october 2002

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。


Bc l 2

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


Apoptosis is all around us

Apoptosis is all around us


Where can we see apop

Where can we see apop.?

  • Surprisingly…..

    all multi-cellular organisms!

  • And even some single.. @@

    Team strategy.


Let s see

Let’s see…

  • Animals!


Apoptosis inducer

Apoptosis Inducer

  • infected with a virus

  • undergoing stress conditions (such as starvation)

  • ionizing radiation

  • toxic chemicals


Apoptosis function

Apoptosis Function

  • Reduce energy lost

  • Prevent cancer development

  • PCD

  • Homeostasis


In plants as well

In plants as well

  • 防止自花授粉


In plants as well 2

In plants as well (2)

  • Transduction ducts (木質 韌皮部)


In plants 3

In plants (3)

  • 藏卵器

    (頸管 到 腹)


Afterthoughts

Afterthoughts

  • Death is so useful…

  • What is life??


Paradox life is dependent on cell death

Paradox:Life is dependent on cell death

Demonstration of single HT-29/B6 apoptotic cells.


Inhibition of apoptosis cancer

Inhibition of apoptosis: Cancer

  • Deletion/mutation of p53

  • express high levels of Bcl-2

  • FAS signaling


Apoptosis programmed cell death a story about 7th october 2002

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


Excessive apoptosis alzheimer

Excessive apoptosis: Alzheimer

  • Loss of neural cells

  • Induced by beta-amyloid peptides

    (Abeta)


Apoptosis programmed cell death a story about 7th october 2002

  • 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


Inappropriate apoptosis hiv

Inappropriate apoptosis: HIV

  • Death of CD4+ T cells most by apoptosis

  • Expression of Nef gene in effected CD4+ T cells


Apoptosis programmed cell death a story about 7th october 2002

謝謝大家!

Death is only the beginning


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