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研究生:陳旻君
研究生(外文):Min-Chun Chen
論文名稱:異位表達ATP合成酶經由粒線體碎裂運輸的途徑探討
論文名稱(外文):Trafficking of Ectopic ATP Synthase via Mitochondrial Fission
指導教授:阮雪芬阮雪芬引用關係
口試日期:2017-06-15
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:分子與細胞生物學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:128
中文關鍵詞:異位表達ATP合成酶蛋白質體蛋白運輸途徑粒線體分裂影像分析
外文關鍵詞:Ectopic ATP synthasesproteomeprotein traffickingmitochondrial fissionimage analysis
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異位表達ATP合成酶,指的是被運送至細胞膜表現的ATP合成酶,它具有功能性且能夠促進細胞增生。先前,我們針對內質網和粒線體蛋白運輸途徑上的基因分別抑制,結果發現當抑制Drp1, Mfn1, Parkin的基因表現,會影響異位表達ATP合成酶在膜上的表現量。然而,其更細節的運輸途徑仍然未知。我們將A549肺癌細胞株的粒線體以及細胞膜分離,並進行的蛋白質體分析,發現粒線體和細胞膜上同時具有來自核編碼的ATP合成酶次單元以及粒線體編碼的ATP6次單元,顯示出ATP合成酶是在粒線體中組合後,再送上細胞膜。另外,我們發現缺乏血清的培養液,會促進ATP合成酶在膜上的表現;然而,當加入Drp1的抑制劑Mdivi1,則反轉該現象。粒線體影像分析顯示出,粒線體分裂導向的細胞株,容易表現較多的ATP合成酶在細胞膜表面。因此,我們認為異位表達ATP合成酶的運輸和粒線體動態有所關連。在高風險神經母細胞瘤中,我們利用免疫螢光染色和流式細胞儀實驗,發現關鍵轉錄因子MYCN會影響了ATP合成酶的運送。欲了解MYCN和粒線體動態以及ATP合成酶運送途徑的相關性,我們分析了MYCN染色質免疫沉澱定序(ChIP-seq)資料,發現Drp1, Mfn1, Parkin等基因會被MYCN調控。高解析影像分析中,顯示出高表現MYCN的神經母細胞瘤中,粒線體分裂頻率增加,且ATP合成酶的的表現亦上升。反之,當抑制MYCN基因表現時,會降低細胞粒線體的分裂,以及Drp1的表現。總結,我們認為異位表達ATP合成酶可能是透過粒線體動態來進行運輸。
Ectopic ATP synthase is a functional onco-protein increases cell proliferation when transported to plasma membrane of cancer cells. Our previous study performed large scale gene silencing screening indicated ER and mitochondrial transport pathways may lead to ectopic ATP synthase expression. Silencing dynamin-related protein 1 (Drp1), mitofusin-1 (Mfn1) and Parkin affected ectopic ATP synthases expression. However, the underlying trafficking mechanism is poorly understood. Here, we analyzed our membrane and mitochondrial proteome of lung cancer A549 cells and found that both nuclear-encoded ATP synthase subunits and mitochondrial-encoded components-ATP6 translocated to cell surface, indicating that ATP synthase subunits assembled in mitochondria. Furthermore, serum starvation enhanced ATP synthase translocation to plasma membrane, Mdivi-1, a chemical inhibitor of the mitochondrial fission protein Drp1, rescued the phenomena. Additionally, image quantification of mitochondria, showing that mitochondrial fission preference cells expressed more ectopic ATP synthase. Therefore, we proposed that ectopic ATP synthase trafficking may be related to mitochondrial dynamics. Additionally, ICC and flow cytometry revealed the expression of a critical transcription factor associated with high-risk neuroblastoma, MYCN, correlated with ectopic ATP synthase expression. To better understand whether MYCN mediated mitochondrial fission and affected ATP synthase trafficking, we first analyzed MYCN ChIP-sequencing data and found Drp1, Mfns and Parkin possessed the consensus DNA-binding motif of MYCN. Further high-resolution image analysis showed higher mitochondrial fission and ectopic ATP synthase expression in MYCN-amplified neuroblastoma. Last, silencing MYCN reduced the fission level by detecting DRP1. In summary, we suggest that trafficking of ectopic ATP synthase may via mitochondrial dynamics.
論文口試委員審定書 i
誌謝 ii
中文摘要 iii
Abstract iv
Abbreviation vi
Contents viii
List of Figures xi
List of Tables xi
Chapter 1. Introduction 1
1.1 ATP synthase 1
1.2 Ectopic ATP synthase 2
1.3 Protein sorting pathway 4
1.4 Mitochondrial dynamics 6
1.5 Motivation 9
Chapter 2. Materials and Methods 11
Chapter 3. Results 23
3.1 Ectopic ATP synthase expressed on pan cancer cell lines. 23
3.2 Mitochondrial proteins expressed on the surface of lung cancer cell line-A549. 23
3.3 Mitochondrial fission induced the expression of ectopic ATP synthase. 25
3.4 Quantification of the mitochondrial fission and fusion through image processing. 26
3.5 Induction of the mitochondrial fission through long term serum-deprived starvation increased the expression of ectopic ATP synthase. 27
3.6 Reduction of the mitochondrial fission through Mdivi-1 treatment decreased the expression of the ectopic ATP synthase. 28
3.7 MYCN silencing in neuroblastoma reduced the expression of ectopic ATP synthase as well as mitochondrial fission level 29
Chapter 4. Discussion 31
4.1 Malignancies affect the expression of ectopic ATP synthase. 31
4.2 Mitochondrial dynamics and transportation in tumor. 32
4.3 Mitochondrial dynamics and endoplasmic reticulum. 34
4.4 Stress and MYCN 35
Chapter 5. Conclusion 38
Chapter 6. Future work 39
References 41
Tables 55
Figures 104
Appendix 126
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