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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4578完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 阮雪芬(Hsueh-Fen Juan) | |
| dc.contributor.author | Siao-Ting Chong | en |
| dc.contributor.author | 張曉婷 | zh_TW |
| dc.date.accessioned | 2021-05-14T17:43:38Z | - |
| dc.date.available | 2020-08-16 | |
| dc.date.available | 2021-05-14T17:43:38Z | - |
| dc.date.copyright | 2015-08-16 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-06 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4578 | - |
| dc.description.abstract | 微小染色體維持蛋白2（MCM2）是DNA複製的主要調控因子。 MCM2與其它MCM蛋白結合形成六聚體複合物（MCM2-7），並發揮具有解旋酶活性的功能。其功能除了用於DNA解旋，還會限制DNA在每個細胞週期僅複製一次。 MCM2在增殖細胞中表現量高，因此在許多種癌症被廣泛用作生物標誌物。然而，MCM2的分子調控機制在肺癌細胞中研究甚少。在這項研究中，我們用A549 (wild-type p53）和H1299（p53-null）細胞株探討MCM2在肺腺癌扮演的角色。研究結果顯示，在A549細胞中過表達MCM2會促進細胞增殖,而在H1299細胞中抑制MCM2表達則會減少細胞增殖。接著，我們進行定量磷酸化蛋白質體學來揭示在肺癌細胞中受MCM2調控的重要下游基因的網絡。我們在過度表達MCM2的A549細胞中共鑑定出594個磷酸化蛋白及1494個磷酸化位點。這些磷酸化位點中，有164磷酸化蛋白具有顯著差異。此外，在低表達MCM2的H1299細胞中，我們鑑定588個磷酸化蛋白及1599個磷酸化位點。這些磷酸化位點中，有82個磷酸化蛋白有顯著差異。這些有顯著差異的磷酸化蛋白參與了RNA剪接，細胞週期和細胞骨架等功能。在表達MCM2的A549細胞過和低表達MCM2的H1299細胞中，我們發現一個共同被調控的磷酸化位點，即是絲氨酸-99（Ser99），它位在高遷移率族蛋白HMG-Ⅰ/ HMG -Y（HMGA1）上。這表明HMGA1-Ser99對肺癌細胞有著重要的調節作用。我們的結果提供肺癌細胞受MCM2調控的磷酸化蛋白質體，並發現其調控磷酸化網絡。這些研究為肺癌治療提供了新的目標。 | zh_TW |
| dc.description.abstract | Minichromosome maintenance protein 2 (MCM2) is a licensing factor for DNA replication. It interacts with other MCM proteins to comprise MCM2-7 complex, which acts as a helicase for DNA unwinding and limits DNA replication to one round per cell cycle. MCM2 has been widely used as a biomarker for proliferation in many types of cancer. However, the molecular regulation underlying MCM2 in lung cancer cells is poorly understood. In this study, we investigated the role of MCM2 in lung adenocarcinoma A549 (wild-type p53) and H1299 (null p53) cells. MCM2 overexpression increased cell proliferation in A549 cells while silencing MCM2 decreased cell proliferation in H1299 cells. We performed global quantitative phosphoproteomic analysis to uncover the important downstream networks regulated by MCM2 in lung cancer cells. We identified 1484 phosphorylation sites in 593 phosphoproteins of MCM2-overexpressed A549 cells. Of these phosphosites, 110 phosphoproteins were significantly changed in response to MCM2 overexpression. In addition, we identified 1599 phosphorylation sites in 592 phosphoproteins of MCM2-silenced H1299 cells. Of these phosphosites, 57 phosphoproteins were significantly changed in response to MCM2 silencing. The differentially regulated phosphoproteins are involved in biological functions such as RNA splicing, cell cycle and cytoskeleton regulation. Functional study demonstrated that MCM2 overexpression promoted cell migration in A549 cells. Moreover, silencing MCM2 inhibits cell migration and induces cell cycle arrest in H1299 cells. Furthermore, we observed a common phosphorylation change at Ser-99 of high mobility group protein HMG-I/HMG-Y (HMGA1) in both MCM2 overexpression and silencing, indicating an important regulatory effect of Ser-99 HMGA1 on lung cancer cells. The phosphoproteomic profiling of MCM2 in lung cancer cells provides new insight about phosphorylation networks regulated by MCM2 and reveals novel targets for lung cancer therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-14T17:43:38Z (GMT). No. of bitstreams: 1 ntu-104-R02b43032-1.pdf: 2364345 bytes, checksum: e57ceaecc7e5d08a85d709833a899c5b (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | Contents
口試委員會審定書 I 誌謝 II 中文摘要 III ABSTRACT IV LIST OF FIGURES IX LIST OF TABLES XI Chapter 1 INTRODUCTION 1 1.1 Lung cancer 1 1.2 Minichromosome maintenance protein 2 (MCM2) 1 1.3 The MCM2 and cancer 2 1.4 Phosphoproteomics 2 1.4 Aim of the study 4 1.5 Experimental Design 4 Chapter 2 EXPERIMENTAL PROCESSES 6 2.1 Cell Culture human lung epithelial cells 6 2.2 Protein extraction 6 2.3 Reduction, Alkylation and Protein Digestion 7 2.4 Dimethyl labelling 7 2.5 Phosphopeptide Enrichment 8 2.6 NanoLC−MS/MS Analysis 8 2.7 Data Processing and Analyses 9 2.8 Plasmid construction and transfection 10 2.9 siRNA transfection 10 2.10 Site-directed mutagenesis 11 2.11 MTT and MTS cell viability assay 11 2.12 Colony formation assay 12 2.13 Cell migration assay 12 2.14 Cell cycle analysis using flow cytometry 12 2.15 Western blot 13 2.16 Statistics analysis 14 Chapter3 RESULTS 15 3.1 Overexpression of MCM2 in A549 increased cell proliferation and silencing MCM2 in H1299 cells decreased cell proliferation 15 3.2 P53 might be the up-regulator of MCM2 16 3.3 Phosphoproteome of MCM2 overexpression in A549 cells and silencing MCM2 in H1299 cells 16 3.4 Identification of differentially regulated phosphoproteins in response to MCM2 18 3.5 Overlap between phosphoproteome of MCM2 overxepression and silencing MCM2 18 3.6 Functional annotation of MCM2-regulated phosphoproteins 19 3.7 Overexpression of MCM2 in A549 increased cell migration while silencing MCM2 in H1299 cells decreased cell migration 20 3.8 Silencing MCM2 in H1299 cells induced cell cycle arrest 20 3.9 Phosphorylation of HMGA1 at Ser99 is essential for viability 21 Chapter 4 DISCUSSION 23 Chapter 5 CONCLUSION 28 Chapter 6 FUTURE WORK 29 ABBREVIATION 30 REFERENCES 32 FIGURES.. 41 TABLES 61 | |
| dc.language.iso | en | |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | 定量磷酸化蛋白質體學 | zh_TW |
| dc.subject | 微小染色體維持蛋白2 | zh_TW |
| dc.subject | 調控網絡 | zh_TW |
| dc.subject | regulatory networks | en |
| dc.subject | lung cancer cells | en |
| dc.subject | Quantitative phosphoproteome | en |
| dc.subject | minichromosome maintenance protein-2 | en |
| dc.title | 藉由定量磷酸化蛋白質體學分析探討MCM2在肺癌細胞中的調控網絡 | zh_TW |
| dc.title | Quantitative phosphoproteomic analysis uncovers the regulatory networks of minichromosome maintenance protein 2 in lung cancer cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃宣誠(Hsuan-Cheng Huang),王憶卿(Wang, Yi-Ching),李岳倫(Yueh-Luen Lee),陳頌方(Sung-Fang Chen) | |
| dc.subject.keyword | 定量磷酸化蛋白質體學,微小染色體維持蛋白2,調控網絡,肺癌, | zh_TW |
| dc.subject.keyword | Quantitative phosphoproteome,minichromosome maintenance protein-2,regulatory networks,lung cancer cells, | en |
| dc.relation.page | 81 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2015-08-06 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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