Apoptosis: Programmed Cell Death 細胞凋亡 A story about 7th October 2002
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Apoptosis:Apoptosis:Programmed Cell DeathProgrammed Cell Death
細胞凋亡細胞凋亡A story about 7th October 2002A story about 7th October 2002
第第 33組組組員:大老邱,組員:大老邱,喇塞喇塞 KingKing ,小萱,朱哥,,小萱,朱哥,
翔格葛,徐客翔格葛,徐客,小吳,小吳
Sydney Brenner Sydney Brenner
19271927 年生年生 (80(80 歲歲 )) 英國人英國人 美國分子科學研究室美國分子科學研究室 established C. elegans as a established C. elegans as a
novel experimental model novel experimental model organismorganism
John Sulston John Sulston
19471947 年生年生 (60(60 歲歲 )) 美國人美國人 麻省理工學院麻省理工學院 mapped a cell lineage where mapped a cell lineage where
every cell division and every cell division and differentiation could be followed differentiation could be followed in the development of a tissue in in the development of a tissue in C. elegansC. elegans
Robert Horvitz Robert Horvitz
19421942 年生年生 (65(65 歲歲 )) 英國人英國人 The Wellcome Trust Sanger The Wellcome Trust Sanger
Institute Institute has discovered and has discovered and
characterized key genes characterized key genes controlling cell death in C. controlling cell death in C. eleganselegans
線蟲線蟲
線形動物門的線蟲綱線形動物門的線蟲綱 種類多,而且數目也極大種類多,而且數目也極大 Ex:Ex: 蛔蟲、鉤蟲、絲蟲、旋毛蟲蛔蟲、鉤蟲、絲蟲、旋毛蟲
生活史生活史
分為蟲卵、幼蟲和成蟲三個階段分為蟲卵、幼蟲和成蟲三個階段 依有無中間宿主分成兩類依有無中間宿主分成兩類 :: 直接發直接發
育育 ;; 間接發育間接發育
分布分布
淡水淡水 ,, 海水海水 ,, 沙漠和土壤等自然環沙漠和土壤等自然環境境
Apoptosis vs. PCDApoptosis vs. PCD
近年來近年來 PCDPCD 和細胞凋亡常被做和細胞凋亡常被做為同義詞使用 為同義詞使用
兩者實質上有異 兩者實質上有異 功能性概念 功能性概念 vs.vs. 形態學概念 形態學概念
Apoptosis vs. NecrosisApoptosis vs. Necrosis
Apoptosis – programmed cell deathApoptosis – programmed cell death Necrosis – un-programmed cell deathNecrosis – un-programmed cell death
Necrosis Necrosis
成因成因氰化物、氮芥、氰化物、氮芥、 CCl4CCl4 、內外毒素、內外毒素
等等 步驟步驟1.1. 缺氧缺氧2.2. 酸化、電解質紊亂胞器壞死酸化、電解質紊亂胞器壞死3.3. 胞器壞死、膜破裂胞器壞死、膜破裂
ApoptosisApoptosis
1972 Kerr 1972 Kerr 鼠肝實驗提出鼠肝實驗提出
Apoptosis vs. NecrosisApoptosis vs. Necrosis區別點 細胞凋亡( apoptosis) 細胞壞死 (necrosis)
起因 生理或病理性 病理性變化或劇烈損傷
範圍 單個散在細胞 大片組織或成群細胞
調節過程 受基因調控 被動進行
炎症反應 無,不釋放細胞內容物 有,釋放內容物。
Back to apoptosis…Back to apoptosis…
左左上上,正常胸腺細胞;右,正常胸腺細胞;右上上,凋亡胸腺細胞(注意凋亡小體),凋亡胸腺細胞(注意凋亡小體)左左下下,正常胸腺細胞;右,正常胸腺細胞;右下下,凋亡胸腺細胞(注意凋亡小體) ,凋亡胸腺細胞(注意凋亡小體)
Please refer to page 428 of Please refer to page 428 of your textbook…your textbook…
2 main integration pathways2 main integration pathways
Death receptor pathwayDeath receptor pathway Mitochondrial pathwayMitochondrial pathway
Both pathways Both pathways converge to a converge to a common execution common execution phasephase
Execution phaseExecution phase
Multiples of 180~200 bp fragmentsMultiples of 180~200 bp fragments
Ladder
Apoptosis in detailApoptosis in detail
1.1. SignalSignal
2.2. Cell shrinkage/ Loss of cell-cell Cell shrinkage/ Loss of cell-cell contactcontact
3.3. Condensation of nuclear Condensation of nuclear chromatinchromatin
4.4. Nuclear fragmentationNuclear fragmentation
5.5. Membrane ruffling/ blebbingMembrane ruffling/ blebbing
6.6. Phagocytosis of apoptotic Phagocytosis of apoptotic bodiesbodies
Death factors…
Bind to death receptors…[cluster and trimerise]
Recruits FADD…
DED
Recruits pro-caspase 8 [induced proximity]
E.g.: FasL/TNF
E.g.: Fas/TNFR
粒線體與細胞凋亡
電位耗散 細胞進入不可逆的凋亡過程
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
PT pore
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)
2. 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 )
3. PT pore 作為許多生理效應的感受器 (二價陽離子、 ATP 、 ADP 、 NAD 、 ΔΨm … )
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 」
證據1. 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。2. 細胞死亡調節蛋白(抑制死亡的 bcl-2 家族 or 促進死亡的 B
ax 家族)均以粒線體作為靶胞器。3. 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。
細胞凋亡的調控細胞凋亡的調控
在線蟲—在線蟲— ced9ced9 在人類—凋亡抑制分子在人類—凋亡抑制分子
bcl-2(bcl-2( 即即 ced9ced9 之同源之同源基因基因 ))
凋亡抑制分子凋亡抑制分子
P35:P35: 被靶被靶 CaspasesCaspases 特異切割,切割特異切割,切割後的後的 P35P35 與 與 CaspaseCaspase 的結合更強,的結合更強,形成穩定的具有空間位阻效應的複合形成穩定的具有空間位阻效應的複合體並且抑制體並且抑制 CaspasesCaspases 活性 活性
CrmACrmA :血清蛋白酶抑制劑,能夠直: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未發現在哺乳動物中發現 P35P35 和和 CrCrmAmA 的同源分子。的同源分子。
凋亡抑制分子凋亡抑制分子
FLIPs:FLIPs: 能抑制能抑制 Fas/TNFR1Fas/TNFR1 介導介導的細胞凋亡。的細胞凋亡。通過通過 DEDDED功能區,與功能區,與 FADDFADD和和 CCaspase-8aspase-8,, 1010結合,拮抗它們結合,拮抗它們之間的相互作用,從而抑制之間的相互作用,從而抑制 CasCaspase8pase8,, 1010 募集到死亡受體複募集到死亡受體複合體和它們的起始化。 合體和它們的起始化。
bcl-2bcl-2 家族家族
既有抗凋亡作用,也有促凋亡的既有抗凋亡作用,也有促凋亡的作用。 作用。
功能相當於線蟲中的功能相當於線蟲中的 ced-9ced-9 。。 它們在線粒體參與的凋亡途徑中它們在線粒體參與的凋亡途徑中
起調控作用,能控制線粒體中細起調控作用,能控制線粒體中細胞色素胞色素 cc 等凋亡因素的釋放。 等凋亡因素的釋放。
都含有都含有 1-41-4個個 Bcl-2Bcl-2 同源結構域同源結構域
Apoptosis is all around usApoptosis is all around us
Where can we see apop.?Where can we see apop.?
Surprisingly….. Surprisingly…..
all multi-cellular organisms!all multi-cellular organisms!
And even some single.. @@And even some single.. @@
Team strategy. Team strategy.
Let’s see…Let’s see…
Animals!Animals!
Apoptosis InducerApoptosis Inducer
infected with a infected with a virusvirus undergoing stress conditions undergoing stress conditions
(such as starvation)(such as starvation) ionizing radiationionizing radiation toxic chemicals toxic chemicals
Apoptosis FunctionApoptosis Function
Reduce energy lostReduce energy lost Prevent cancer developmentPrevent cancer development PCDPCD Homeostasis Homeostasis
In plants as wellIn plants as well
防止自花授粉 防止自花授粉
In plants as well (2)In plants as well (2)
Transduction ducts (Transduction ducts ( 木質 韌皮部木質 韌皮部 ) )
In plants (3)In plants (3)
藏卵器藏卵器(( 頸管 到 腹頸管 到 腹 ))
AfterthoughtsAfterthoughts
Death is so useful…Death is so useful… What is life??What is life??
Paradox:Paradox:Life is dependent on cell deathLife is dependent on cell death
Demonstration of single HT-29/B6 apoptotic cells.
Inhibition of apoptosis: CancerInhibition of apoptosis: Cancer
Deletion/Deletion/mutation of mutation of p53p53
express higexpress high levels of Bh levels of Bcl-2cl-2
FAS signalinFAS signalingg
Cancers associated with virusesCancers associated with viruses ex: HPV (cervical cancer )ex: HPV (cervical cancer ) EBV (lymphomas)EBV (lymphomas)
Other cancer cells Other cancer cells ex: B-cell leukemiasex: B-cell leukemias MelanomaMelanoma FasLFasL ex: lung and colon cancer cells ex: lung and colon cancer cells
Excessive apoptosis: Excessive apoptosis: AlzheimerAlzheimer Loss of neural cellsLoss of neural cells Induced by beta-amyloid peptidesInduced by beta-amyloid peptides
(Abeta)(Abeta)
Abeta trigger toxicity via activatiAbeta trigger toxicity via activation of caspaseson of caspases
The activation of caspase-8 and The activation of caspase-8 and –9 by Abeta and C31 –9 by Abeta and C31
APPAPP :: (1)a source of cytotoxic Abeta (1)a source of cytotoxic Abeta
(2)represent a source of C31 co(2)represent a source of C31 contributing cytotoxic activity of Abntributing cytotoxic activity of Abeta eta
Inappropriate apoptosis: HIVInappropriate apoptosis: HIV
Death of CD4+ T cells most by Death of CD4+ T cells most by apoptosisapoptosis
Expression of Nef gene in effected Expression of Nef gene in effected CD4+ T cells CD4+ T cells
謝謝大家謝謝大家 !!
Death is only the beginningDeath is only the beginning