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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Mei-Yi Hsieh | en |
| dc.contributor.author | 謝美儀 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:10:28Z | - |
| dc.date.available | 2016-10-09 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-03-25 | |
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DNA looping facilitates targeting of a chromatin remodeling enzyme. Mol Cell 50, 93-103. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58291 | - |
| dc.description.abstract | 人類的DNA拓撲異構酶III alpha（hTOP3a）同功酶藉由與腫瘤抑制因子形成複合物的方式參與DNA修復的監視和細胞週期檢查點之調控。然而，hTOP3a在腫瘤發生過程中所扮演的角色仍尚未被探討。在本篇論文中，我們的研究指出hTOP3a和轉錄因子p53蛋白質之間的交互作用對於腫瘤發生的進程是一個重要的染色質表觀遺傳調控點。我們研究中顯示，(i) 在非致癌性RHEK -1細胞中降低hTOP3a的表現 (sh- hTOP3a) 會引起較高的anchorage-independent growth，(ii) 在不同的細胞株中分別降低hTOP3a的表現會促進形成腫瘤的能力，反之，當於不同的細胞株中異位表達hTOP3 | zh_TW |
| dc.description.abstract | The human DNA topoisomerase III alpha (hTOP3a) isozyme is involved in DNA-repair surveillance and cell cycle checkpoints through the formation of a complex with tumor suppressors. However, the role of hTOP3a in tumorigenesis remains unexplored. Here, we report novel interactions between the epigenetic chromatin modulator hTOP3a and the transcription factor p53 that are important for tumorigenesis. We have determined that (i) hTOP3a knockdown (sh-hTOP3a) in non-tumorigenic RHEK-1 cells caused a higher anchorage-independent growth; (ii) modulation of hTOP3a levels by shRNA knockdown or ectopic expression approaches in different cancer cell lines also cause an increase or a reduction in tumorigenic abilities, respectively; (iii) hTOP3a binds to p53 and interacts with p53 functionally to suppress tumor growth; and (iv) the tumor-suppressive activity of hTOP3a requires functional hTOP3a, p53 and p21. To study the underlying mechanisms of hTOP3a in cancer, chromatin immunoprecipitation data revealed that hTOP3a binds to both the p53 and p21 promoters, and hTOP3a and p53 affect the recruitments of each other to corresponding promoters. Moreover, hTOP3a not only positively regulates p53 expression but also cooperates with p53 to promote p21 transcription. We defined the molecular basis of this collaboration with p21 expression and identified that hTOP3a is recruited to the p21 promoter via p53. Functionally, sh-hTOP3a and sh-p53 in AGS cells caused a similar amount of reduced senescence. Above interactions require functional hTOP3a and p53, as the active-site mutant of hTOP3a and the DNA-binding mutant of p53 were unable to promote p21 expression and to suppress anchorage-independent growth. Therefore, we suggest that hTOP3a contributes significantly to tumorigenesis in part through interactions with p53. In support of this hypothesis, hTOP3a mRNA levels were lower in gastric and renal tumor samples. Together, our results suggest that hTOP3a regulates p53 and p21 expression and might contributes to the p53-mediated senescence and tumor suppression. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T08:10:28Z (GMT). No. of bitstreams: 1 ntu-103-D95445005-1.pdf: 3092736 bytes, checksum: 976d24e021bf826964a5b7a21933cd24 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 論文口試委員審定書 ………………………………………………………………… i
中文摘要 ………………………………………………………………………………… ii Abstract ………………………………..……………………………………………… iii Contents …………………………………….………………………………………… v 1. Introduction 1.1 Tumorigenesis ……………………………………….………………………… 1 1.2 DNA topoisomerases ……………………………………….………………… 2 1.3 DNA topoisomerases and their biological functions …………….……… 4 2. Materials and Methods 2.1 Chemicals, plasmids and antibodies …………….…………………………… 7 2.2 Cell culture and cell proliferation assay……………………………………… 7 2.3 Lentivirus-based RNA interference (RNAi) ………………………….……… 8 2.4 Co-immunoprecipitation (co-IP), immunoblotting (IB) and RT-PCR analyse …………………………………………………….…….………….……… 8 2.5 Chromatin immunoprecipitation (ChIP) assay .……….…………….……… 9 2.6 Tumorigenesis assays: anchorage-independent growth on soft agar and tumor formation in NOD-SCID mice .……….…………….………….……… 9 2.7 Cellular senescence assay.……….………….……………….………….……… 10 2.8 Cancer profiling Array.……….….………….……………….………….……… 11 2.9 Cell Invasion Assay .….……….….………….……………….………….……… 12 2.10 Flow cytometry.….………….….………….……………….………….……… 12 2.11 Clonogenic assays .….………….….………….……………….…….……… 13 2.12 mRNA decay analysis.….………….….……………………….…….……… 13 2.13 Statistical analyses .….………….….………….……………….…….……… 13 3. Results 3.1 The physical interaction between hTOP3 | |
| dc.language.iso | en | |
| dc.title | 人類DNA拓樸異構酶IIIa在腫瘤發生之功能探討 | zh_TW |
| dc.title | Study on the Roles of Human Topoisomerases IIIa in tumorigenesis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),賴逸儒(I-Rue Lai),李明學(Ming-Shyue Lee),董馨蓮(Shin-Lian Doong) | |
| dc.subject.keyword | 拓樸異構?,轉錄,腫瘤新生,衰老, | zh_TW |
| dc.subject.keyword | Topoisomerase,p53,Transcription,Tumorigenesis,Senescence, | en |
| dc.relation.page | 77 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-03-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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