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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17254完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭靜穎(Ching-Ying Kuo) | |
| dc.contributor.author | Yu-Shu Liu | en |
| dc.contributor.author | 劉育書 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:03:16Z | - |
| dc.date.copyright | 2020-08-27 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-08 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17254 | - |
| dc.description.abstract | 在實質固態瘤 (solid tumor) 中心區域之癌細胞會因缺乏氧氣與養分而面臨代謝壓力，粒線體的動態平衡對於癌細胞在此等不利環境下之生長具有重要影響。 KRAB-associated protein-1 (KAP1)是個多方參與細胞生理功能調控的共轉錄調節因子。本實驗室先前研究發現在乳癌細胞缺乏養分時，活性氧物質(reactive oxygen species, ROS) 與p38 MAPK會促進KAP1 S473位點磷酸化，進而抑制粒線體融合蛋白 mitofusin 2 (MFN2) 之表現量，避免在缺乏養分時粒線體過度融合、引發不利細胞生存的氧化壓力 (oxidative stress)。然而，KAP1 S473位點磷酸化調控MFN2之相關機制尚未被探討。本論文分別就轉錄調控、轉錄後調控與蛋白質降解等不同機制進行探討。 根據實驗室先前研究，首先挑選出了會被KAP1 S473位點磷酸化調控的微小核醣核酸(microRNA, miRNA) miR-20b-5p作為探討目標。miR-20b-5p可結合至MFN2 3’UTR且可抑制MFN2，但其抑制效果有限，因此初步認為miR-20b-5p可能非主要調控MFN2表現量之因子。另外，轉錄因子EGR1之表現量雖然在缺乏養分時明顯增加，且其被誘發之機制與KAP1 S473位點磷酸化修飾機制相同，但是抑制EGR1後並未影響MFN2表現量，因此EGR1參與調控MFN2之可能性也較低。最終，在抑制蛋白酶體活性後發現MFN2蛋白量明顯增加，顯示在缺乏養分時MFN2下降是與蛋白質降解相關，未來須更進一步探討KAP1 S473位點磷酸化與MFN2蛋白質降解之間的關係。 | zh_TW |
| dc.description.abstract | Cancer cells in the core region of a solid tumor encounter metabolic stress induced by hypoxia and insufficient nutrition. Mitochondrial dynamics has a profound effect on the survival of cancer cells under this unfavorable condition. KRAB-associated protein-1 (KAP1) is a transcriptional co-regulator participating in multiple cellular physiological processes. Previously, our study has revealed that KAP1 is phosphorylated at serine 473 (S473) under nutrient deprivation by reactive oxygen species (ROS)-p38 MAPK signaling in breast cancer cells. pS473KAP1 reduces mitochondrial fusion protein mitofusin 2 (MFN2) expression and thus prevents mitochondrial hyperfusion. Mitochondrial hyperfusion leads to ROS overproduction causing detrimental effects to cancer cells under metabolic stress. Therefore, it has been demonstrated that phosphorylation at KAP1 S473 site benefits breast cancer cell survival under nutrient insufficiency-induced metabolic stress. However, pS473KAP1 mediated regulation of MFN2 remains unclear. In this thesis, the regulatory mechanisms of MFN2 including transcriptional regulation, post-transcriptional regulation and protein degradation will be discussed. Based on previous study, microRNA (miRNA) miR-20b-5p, which can be upregulated by pS473KAP1, was chosen. Although miR-20b-5p bound to MFN2 3’UTR to repress MFN2 expression, miR-20b-5p had only limited effect on MFN2 reduction. Current results suggested that miR-20b-5p might not be the main regulator of MFN2. Besides, even though the stress response transcription factor EGR1 seemed to share the same regulatory route of KAP1 S473 phosphorylation under nutrient deprivation, knockdown of EGR1 did not affect MFN2 expression. Hence, EGR1 was not likely to involve in the MFN2 regulation. At last, inhibition of proteasomal degradation accumulated MFN2 protein under nutrient deprivation, which suggested the downregulation of MFN2 under nutrient deprivation was associated with protein degradation. In the future, the detailed regulatory mechanism of pS473-KAP1 and MFN2 degradation will be further investigated. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:03:16Z (GMT). No. of bitstreams: 1 U0001-0608202016154200.pdf: 5745595 bytes, checksum: 79e097c51a1d12452139ebbe0a7e1df4 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 口試委員審定書 i 中文摘要 ii Abstract iii List of Abbreviations v Table of Contents vi List of Tables xi List of Figures xii Chapter 1 Introduction 1 1.1 Introduction of breast cancer 1 1.2 Intratumoral metabolic stress. 3 1.3 Mitochondrial dynamics is a key regulatory mechanism to sustain cell survival under metabolic stress. 6 1.3.1 Introduction of mitochondrial dynamics 6 1.3.2 Role of mitochondrial dynamics in cancer 8 1.3.3 Mitochondrial dynamics and metabolic stress response 9 1.4 Phosphorylation of KAP1 S473 site has been demonstrated to regulate mitochondrial dynamics under metabolic stress in breast cancer. 9 1.4.1 Introduction of KAP1 10 1.4.2 pS473KAP1 regulates mitochondrial dynamics under metabolic stress in breast cancer. 11 1.5 Introduction of MFN2 protein regulatory pathways: production and degradation of MFN2. 12 1.5.1 Transcription of MFN2 12 1.5.2 Post transcriptional regulation of MFN2: miRNA silences mRNA translation 13 1.5.3 Degradation of MFN2 15 Chapter 2 Specific aim 17 Chapter 3 Materials and Methods 18 3.1 Cell culture and reagents 18 3.2 Plasmid preparation 19 3.3 Virus production and transduction 20 3.4 miRNA transfection 21 3.5 miRNA target prediction 22 3.6 Dual luciferase assay 22 3.7 RNA isolation, cDNA synthesis and real-time quantitative PCR (qPCR) and RNA-sequencing data acquisition 23 3.8 Western blotting analysis 24 3.9 Co-immunoprecipitation assay 25 3.10 Subcellular fractionation 25 3.11 Immunofluorescence staining 26 3.12 Statistical analysis 27 Chapter 4 Results 28 4.1 MFN2 protein decreased under nutrient deprivation in MDA-MB-231 cells. 28 4.2 Knockdown of KAP1 upregulated MFN2 expression. 28 4.3 Putative mechanisms of pS473KAP1 regulating MFN2 under nutrient deprivation. 29 4.4 pS473KAP1-miR-20b-5p-MFN2 regulatory pathway 30 4.4.1 miR-20b-5p was upregulated in KAP1 S473D expressing MDA-MB-231 cells. 31 4.4.2 miR-20b-5p repressed MFN2 expression by targeting the 3’-UTR of MFN2. 31 4.4.3 miR-20b-5p expression under glucose deprivation. 33 4.5 KAP1-EGR1-MFN2 regulatory pathway 34 4.5.1 EGR1 was induced by ROS-p38 pathway under nutrient deprivation. 34 4.5.2 KAP1 repressed EGR1 under glucose deprivation in MDA-MB-231 cells. 35 4.5.3 KAP1-EGR1 interaction under glucose deprivation remained elusive. 36 4.5.4 Knockdown of EGR1 did not affect MFN2 expression under nutrient deprivation in MDA-MB-231 cells. 36 4.6 pS473KAP1-MFN2 degradation pathway 38 4.6.1 KAP1 might promote MFN2 degradation under nutrient deprivation. 38 4.6.2 KAP1 might not promote MFN2 degradation through mitophagy under nutrient deprivation. 38 4.6.3 MFN2 reduction under nutrient deprivation was associated with proteasomal degradation. 39 4.6.4 Subcellular localization of endogenous KAP1 and pS473KAP1 under nutrient deprivation. 40 4.6.5 Subcellular localization of KAP1 S473 mutants under nutrient deprivation. 41 4.6.6 Interaction of KAP1 and MFN2 under nutrient deprivation. 43 4.7 Conclusion 43 Chapter 5 Discussion 45 Part I: General discussion 45 Part II: Experimental discussion 46 (I) miR-20b-5p in pS473KAP1-MFN2 pathway 46 (II) EGR1 in pS473KAP1-MFN2 pathway 48 (III) E2F1 is a transcription factor candidate for MFN2 under nutrient deprivation. 49 (IV) pS473KAP1-MFN2 degradation pathway 50 Tables 52 Figures 55 References 79 | |
| dc.language.iso | en | |
| dc.title | 探討乳癌代謝壓力下粒線體融合蛋白MFN2表現量之調控機制 | zh_TW |
| dc.title | Investigating the regulatory mechanisms of mitofusin 2 (MFN2) expression under metabolic stress in breast cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊雅倩(Ya-Chien Yang),蘇剛毅(Kang-Yi Su),林亮音(Liang-In Lin) | |
| dc.subject.keyword | 乳癌,代謝壓力,養份缺乏,粒線體動態平衡,KAP1,MFN2,miR-20b-5p,EGR1,蛋白酶體降解, | zh_TW |
| dc.subject.keyword | breast cancer,metabolic stress,nutrient deprivation,mitochondrial dynamics,KAP1,MFN2,miR-20b-5p,EGR1,proteasomal degradation, | en |
| dc.relation.page | 91 | |
| dc.identifier.doi | 10.6342/NTU202002554 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-08-10 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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