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研究生:劉君儀
研究生(外文):Chun-Yi Liu
論文名稱:PKCδ及ERK1/2訊息傳遞在帶有4977bp斷損突變粒線體DNA的人類細胞易受UV誘發細胞凋亡之調控角色
論文名稱(外文):Involvement of PKCd and ERK1/2 Signaling in the Susceptibility to UV-Induced Apoptosis of Human Cells Harboring 4977 bp-Deleted Mitochondrial DNA
指導教授:魏耀揮魏耀揮引用關係
指導教授(外文):Yau-Huei Wei
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:106
中文關鍵詞:細胞凋亡細胞外訊號調控激酶1/2粒線體DNA氧化壓力蛋白激酶C delta
外文關鍵詞:ApoptosisERK1/2Mitochondrial DNAOxidative stressPKCd
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MELAS、MERRF及CPEO症候群等粒線體疾病已經證實與多種特定的粒線體DNA點突變和大片段斷損突變有關,且突變的粒線體DNA會造成粒線體功能失調、ATP生成不足及活性氧分子過量累積在病變組織中。近十餘年來的研究顯示,粒線體在調控及執行細胞凋亡的過程扮演一關鍵性的角色。我利用本研究室先前以細胞質融合技術建構之帶有不同種類粒線體DNA突變的融合細胞株,包含A3243G和A8344G點突變以及4977 bp和4366 bp 斷損突變,探討與致病相關的粒線體DNA突變是否會影響人類細胞中細胞凋亡的行為。結果顯示,細胞存活率降低、caspase 3活性增加、DNA崩解和細胞色素c自粒線體釋放,在帶有粒線體DNA突變的細胞株中都較野生株顯著,這表示突變的粒線體DNA會增加細胞對外來的刺激引發細胞凋亡的敏感性。我透過帶有不同百分比之粒線體DNA斷損突變的融合細胞株,來釐清致病相關的粒線體DNA突變對細胞凋亡行為的量化效應。實驗結果顯示,UV射線造成的caspase 3活化程度會隨著細胞中粒線體DNA斷損突變百分比增加而愈加顯著,且這一caspase 3活化是經由caspase 8與caspase 9活化所導致的;此外,UV射線所引發的細胞色素c釋放與Bak聚合反應,均在帶有高度粒線體DNA斷損突變的細胞株中較為明顯。因此,粒線體DNA 4977 bp斷損突變透過細胞色素c釋放及caspase 3活化,使細胞易於進入UV射線所引發的細胞凋亡,且與粒線體DNA突變含量成高度正相關。另外,我評估coenzyme Q10對於UV射線誘發細胞凋亡的保護效應,發現UV射線所引起的活性氧分子增生及caspase 3活化,均可透過100 mM coenzyme Q10的預處理得到顯著的減緩效用,這表示粒線體DNA突變所引起的氧化壓力,對於細胞易受刺激誘發進入細胞凋亡有相關性。同時,我探究帶有粒線體DNA突變的細胞較易受刺激誘發進入細胞凋亡所涉及的訊號傳遞,發現H2O2的生成與PKCδ和ERK1/2之磷酸化程度,均在易受刺激誘發進入細胞凋亡的突變細胞株中顯著增加;若以N-acetyl L-cysteine(NAC)處理細胞,透過rottlerin和PKCδ-siRNA阻斷PKCδ的訊號,或是藉由PD98059和ERK1/2-siRNA擾亂ERK1/2的作用,均可有效緩解突變細胞對細胞凋亡的高敏感性。再者,在突變細胞株中因氧化壓力而累積表現的PKC�唌A透過caspase 3酶解切割大量活化後,可放大訊號來強化突變細胞株易受UV射線引發進入細胞凋亡的訊息。此外,我發現由CPEO病患組織培養之皮膚纖維母細胞,其PKCδ與ERK1/2也呈高度磷酸化。上述的研究顯示,粒線體DNA斷損突變造成氧化壓力累積,並引發PKCδ與ERK1/2訊號傳遞之活化,這在帶有粒線體DNA斷損突變的融合細胞株對UV射線的高敏感性反應上扮演重要的角色。本研究的發現,對於帶有CPEO等腦肌病變的病患腦部及肌肉組織上常出現的退化病徵,提供進一步的解釋;並有利新藥及新療法的開發,以緩解或治療與粒線體DNA突變相關的疾病。
Mitochondrial diseases, such as MELAS, MERRF and CPEO syndromes, are associated with specific point mutations or large-scale deletions of mitochondrial DNA (mtDNA), which cause mitochondrial dysfunction, decreased ATP production and over-production of reactive oxygen species (ROS) in affected tissues. In the past decade, mitochondria have been established to play a critical role in the regulation of apoptosis. To investigate whether a pathogenic mutation of mtDNA affects the apoptosis of human cells, we used human cybrids harboring different types of mtDNA mutation including A3243G or A8344G point mutation or 4977 bp or 4366 bp deletion, which had been constructed in this laboratory by cytoplasmic fusion of patients’ skin fibroblasts with mtDNA-depleted ρo cells. We observed that decrease in cell viability, increase in caspase 3 activation, enhanced DNA fragmentation and cytochrome c release after UV irradiation were more pronounced in the cybrids harboring mutated mtDNA. This indicates that mtDNA mutation increases the susceptibility of human cells to apoptosis triggered by exogenous stimuli. Furthermore, we used a series of cybrids harboring different proportions of 4977 bp-deleted mtDNA to investigate the quantitative effect of a pathogenic mutation of mtDNA on apoptosis. We found that UV-induced activation of caspase 3 of human cells increased with the proportion of 4977 bp-deleted mtDNA, and was preceded by the activation of caspase 8 and caspase 9. Most importantly, we observed that UV-induced cytochrome c release from mitochondria and Bak oligomerization were much more pronounced in the cybrids harboring higher proportions of 4977 bp-deleted mtDNA. We suggest that 4977 bp-deleted mtDNA increases the susceptibility of human cells to UV-induced apoptosis in a quantitative manner through cytochrome c release from mitochondria and caspase 3 activation. Subsequently, we evaluated the protection effect of coenzyme Q10 on the UV-triggered apoptosis, and found that the UV-induced cell damage (i.e., ROS production and activation of caspase 3) was significantly reduced upon pre-treatment of the cybrids with 100 mM coenzyme Q10, which indicates that mtDNA mutation-elicited oxidative stress is involved in the susceptibility to apoptosis of human cells. Finally, we investigated the signaling mechanism underlying the apoptotic susceptibility of the mutant cybrids harboring deleted mtDNA. The production of hydrogen peroxide (H2O2) and phosphorylation of PKCδ and ERK1/2 were increased in the mutant cybrids, which was more susceptible to UV-induced apoptosis. Moreover, treatment with NAC or blocking of activation of PKCδ by rottlerin or PKCδ-siRNA, and inhibition of ERK1/2 by PD98059 or ERK1/2-siRNA significantly attenuated the susceptibility of the mutant cybrids to apoptosis. Furthermore, the increase of PKC�� expression in the mutant cybrids also amplified the apoptotic signal through caspase 3-mediated proteolytic activation of PKCδ In addition, PKCδ and ERK1/2 were hyperphosphorylated in skin fibroblasts of CPEO patients harboring 4977 bp-deleted mtDNA. We suggest that the activation of PKCδ and ERK1/2 elicited by 4977 bp-deleted mtDNA-induced oxidative stress plays a role in the susceptibility of the mutant cells to apoptosis. This may explain, at least in part, the degenerative manifestation of brain and muscle in patients with mitochondrial encephalomyopathies such as CPEO syndrome, and provide useful information for the development of new drugs or therapy for these overt diseases caused by mtDNA mutations.
目 錄

中文摘要…………………………………………………………… 1
英文摘要…………………………………………………………… 3
縮寫表……………………………………………………………… 5
緒論…………………………………………………………………
1. 粒線體是細胞中能量代謝中心亦是活性氧分子產生的主要場所 7
2. 粒線體與細胞凋亡 8
3. 粒線體DNA之特性 10
4. 粒線體DNA突變與粒線體疾病之關係 11
5. 粒線體DNA 4977 bp斷損突變 12
6. 粒線體疾病與細胞凋亡 14
7. 蛋白激酶C delta(PKCδ) 15
8. 細胞外訊號調控激酶1/2(ERK1/2) 17
研究目的及實驗設計……………………………………………… 20
材料與方法………………………………………………………… 22
實驗結果…………………………………………………………… 34
討論………………………………………………………………… 45
圖與表……………………………………………………………… 61
參考文獻…………………………………………………………… 87
個人著作目錄……………………………………………………… 105
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