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系統識別號 U0026-0812200910205224
論文名稱(中文) Caspase-8及Erk-1/-2在dome細胞上的活化在調控因MDCK細胞長過滿所引發的細胞凋亡過程中所扮演的角色
論文名稱(英文) Activation of caspase-8 and Erk-1/-2 in domes regulates cell death induced by confluence in MDCK cells
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 90
學期 2
出版年 91
研究生(中文) 張永恆
研究生(英文) Yung-Heng Chang
電子信箱 bioforever@ms6.url.com.tw
學號 s3689101
學位類別 碩士
語文別 英文
論文頁數 39頁
口試委員 口試委員-楊倍昌
口試委員-莊季瑛
指導教授-湯銘哲
口試委員-楊性芳
中文關鍵字 confluent cell death  caspase-8  細胞凋亡  細胞長滿  Erk-1/-2 
英文關鍵字 confluent cell death  confluence  Erk-1/-2  apoptosis  caspase-8 
學科別分類
中文摘要 在正常細胞培養環境下,細胞會貼附到培養皿的表面,伸展出去,進行複製,最後會在培養皿達到長滿的狀態。在長滿的過程中,細胞複製會被抑制而細胞分化則會開始進行。同時,在細胞長滿的過程中會發現細胞的凋亡。為了去釐清長滿過程引發細胞死亡的機制,我們使用狗的腎臟上皮細胞株Madin-Darby canine kidney (MDCK)來做為實驗的材料。我們發現在接近細胞長滿時MDCK cells會表現出高量的caspase-2 而且會增加caspase-8的活性。利用各種不同的caspases抑制劑去抑制因細胞長滿引發的死亡,我們發現只有caspase-8抑制劑z-IETD-fmk有效。這一些結果顯示因細胞長滿引發的凋亡是藉由活化caspase-8來達成。為了更進一步的去釐清活化的caspase-8促進細胞長滿引發的死亡是否透過粒線體路徑來達成,我們利用Bcl-2轉染之MDCK來探討此一過程。我們發現細胞長滿會促進 cytochrome c 從粒線體中釋放到細胞質中。而大量表現的Bcl-2能夠抑制因細胞長滿而引發cytochrome c 從粒線體中釋放到細胞質中。從這些結果看來因細胞長滿引發的死亡有粒線體路徑參與其中。此外,我們同時還發現phospho-Erk (p-Erk) 的活化在細胞增殖過程中是先下降,但是等到細胞長滿後又再度的上升。免疫螢光染色的結果顯示p-Erk主要是表現在形成dome的細胞上,而這一群細胞是主要進行細胞凋亡的部分。當給予長滿的細胞MEK的抑制劑PD98059時會增強細胞凋亡的程度而且會輕微的增加caspase-8的活化以及活性。這些證據顯示細胞長滿後上升的p-Erk活性可以減低因細胞長滿引發的死亡。由以上的結果顯示,caspase-8的活化參與了因細胞長滿引發的死亡,然而p-Erk使MDCK細胞免於因長滿造成之凋亡過程藉由調節caspase-8的活化以及活性來達到。
英文摘要 Under normal culture conditions, cells adhere to the culture dish surface, spread out, proliferate and finally cover all areas and reach confluence. During the confluent stage, cell proliferation ceases and differentiation is enhanced. In the meanwhile, cell death occurs during confluent process. To delineate the mechanism of cell death induced by confluent process, we employed Madin-Darby canine kidney (MDCK) cells. We found that approaching confluence, MDCK cells exhibited elevated levels of caspase-2 and enhanced activity of caspase-8. Using various caspase inhibitors to inhibit confluent cell death, we found that only caspase-8 inhibitor, z-IETD-fmk was effective. These results suggest that confluent cell death is mediated by activation of caspase-8. To further delineate whether activated caspase-8 triggered confluent cell death through mitochondria-dependent or -independent pathway, we employed MDCK cell overexpressing Bcl-2. We found that confluence triggered cytochrome c release from mitochondria. Overexpression of Bcl-2 could inhibit cytochrome c release as well as confluent cell death, suggesting the involvement of mitochondria-dependent pathway in confluent cell death. Interestingly, we also found that activity of phospho-Erk (p-Erk) was initially decreased during confluence, but was markedly increased after confluence. Immunofluorescent staining studies showed that p-Erk activity was expressed exclusively on dome-forming cells that underwent apoptosis. Treatment of confluent MDCK cells with PD98059, inhibitor of MEK, enhanced apoptosis and slightly increased activation and activity of caspase-8. These data suggest that elevation of p-Erk activity during confluence may serve to suppress confluent cell death. In summary, activation of caspase-8 is involved in confluent cell death whereas p-Erk prevents MDCK cells from this death process by regulating activation and activity of caspase-8.
論文目次 Abstract 1
中文摘要 2
誌謝 3
Content 4
Figure content5
Introduction 6
Materials and methods 11
Results 17
Discussion 25
References30
Figures
作者簡歷
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