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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張瀞仁(Ching-Jin Chang) | |
| dc.contributor.author | Jia-Yuan Bei | en |
| dc.contributor.author | 貝佳媛 | zh_TW |
| dc.date.accessioned | 2022-11-23T09:15:32Z | - |
| dc.date.available | 2021-11-19 | |
| dc.date.available | 2022-11-23T09:15:32Z | - |
| dc.date.copyright | 2021-11-19 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-07-14 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79891 | - |
| dc.description.abstract | TRIM28，也稱為KAP1或TIF1-β，它會參與癌細胞的發展。Trim28通過 N 端的RBCC域與KRAB-ZNF鋅指蛋白的KRAB域相互作用，RING finger含有 E3 連接酶活性。 為了研究TRIM28在白血病細胞系K562中的功能作用，我們通過 CRISP/Cas9 基因組編輯生成了TRIM28剔除(KO)突變體。我們發現胚胎ε- (HBE) 和胎兒γ- (HBG) 珠蛋白在TRIM28 KO 細胞中增加。通過 RNA-seq 分析，我們知道 SOX6 作為 β 蛋白抑制物在TRIM28 KO突變體中被減少。此外，TRIM28 KO K562細胞中SOX6的過表達將恢復對HBE和HBG的抑制。我們證明剔除TRIM28通過增加microRNA而減少SOX6。我們還試圖解釋TRIM28在細胞增殖、細胞週期轉變和細胞凋亡中起著關鍵的調節作用。用藥物處理細胞會使細胞進入分化階段，這與TRIM28 KO細胞相似。 同時，我們還通過免疫沉澱和 LC-MS/MS分析鑒定了TRIM28相互作用蛋白。我們發現TRIM28與GID/CTLH E3連接酶複合物（包括 YPEL5、RanBP9、RMND5A、MAEA、WDR26、RBP10、ARMC8、TWA1 和 GID4）相關。我們已經證明TRIM28直接與 YPEL5相互作用，並發現了TRIM28的相關相互作用域。此外，我們已經檢查了 TRIM28可能調節RMND5A和MAEA的蛋白質穩定性。我們對GID/CTLH複合物和 TRIM28的E3連接酶活性的相互調節如何控制它們的底物穩定性感興趣。綜上所述，我們將從基因表達和蛋白質穩定性調控方面闡明TRIM28如何影響血癌細胞的生長和分化。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-23T09:15:32Z (GMT). No. of bitstreams: 1 U0001-1207202121250300.pdf: 2551369 bytes, checksum: 15190e75ee29236077785803a3d9f81b (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "口試委員審定書…………………………………………………………………………i 中文摘要………………………………………………………………………………...ii Abstract………………………………………………………………………………...iii 1. Introduction…………………………………………………………………………..1 1.1 Tripartite motif-containing protein 28 (TRIM28)…………………………….......1 1.2 Glucose-induced degradation-deficient/multi-subunit C-terminal to LisH (GID/ CTLH) complex……………………………………………………………………….1 1.3 Sry type HMG box（SOX6）………………………………………………........2 1.4 Hemoglobin (HBE/ HBG/ HBB) and K562 cells…………………………………3 1.5 MicroRNAs……………………………………………………………………….3 2. Experimental Methods Materials………………………………………………..6 2.1 Cell lines and cell culture…………………………………………………………6 2.2 Plasmid constructs…………………………………………………………….......6 2.3 Transformation and plasmid preparation……………………………………….....7 2.4 Lentivirus-carrying short-hairpin RNA (shRNA) knockdown………………........7 2.5 Restriction enzyme digestion and agarose gel separation………………………...8 2.6 DNA transfection……………………………………………………………….....8 2.7 Whole cell extract preparation, western blotting, and immunoprecipitation……..9 2.8 RNA isolation, reverse transcription, real time PCR…………………………….11 2.9 Antibodies………………………………………………………………………..12 2.10 Dual Luciferase reporter assay……………………………………………........12 2.11 Chromatin immunoprecipitation（ChIP）…………………………………….12 2.12 Recombinant protein expression and purification………………………….......15 2.13 GST pull-down assay…………………………………………………………...16 3. Results……………………………………………………………………………….17 Part Ⅰ.TRIM28-miRNA axis regulates cell cycle-related and hemoglobin beta subunits gene expression in K562 cell line…………………………………………...17 3.1 The molecular mechanisms underlying TRIM28-controlled cell proliferation…...17 3.2 TRIM28 regulates ε and γ globin gene expression via SOX6 in K562 cells……18 3.3 Overexpression of TRIM28 or SOX6 restores ε and γ globin gene expression....19 3.4 Knockout of TRIM28 downregulates SOX6 through increasing of microRNAs…19 3.5 Drug treatments induce hemoglobin beta subunits gene expression in wild-type K562 cells …………………………………………………………..………………..20 Part Ⅱ. TRIM28 associates with GID/CTLH E3 ligase complex………………........21 3.6 GID/CTLH complex component YPEL5 interacts TRIM28 directly……………..21 3.7 Mapping the interacting domain of TRIM28 with YPEL5 in 293T cells………….22 3.8 Knockdown of GID/CTLH complex members in K562 cells…………………….22 3.9 RMND5A is stabilized when human TRIM28 presence………………………….23 3.10 HBP1 is stabilized by proteasome inhibitor MG132…………………………….23 3.11 MAEA, RMND5A, and HBP1 protein stability in wild-type and TRIM28 K304Q knock-in K562 cells…………………………………………………………………..24 4. Discussion…………………………………………………………………………...25 5. Figures……………………………………………………………………………….28 Figure 1………………………………………………………………………………28 Figure 2………………………………………………………………………………30 Figure 3…………………………………………………………………………........34 Figure 4………………………………………………………………………………36 Figure 5. ……………………………………………………………………………..38 Figure 6…………………………………………………………………………........40 Figure 7………………………………………………………………………………42 Figure 8………………………………………………………………………………44 Figure 9………………………………………………………………………...…….46 Figure 10………………………………………………………………………..……47 Figure 11. ……………………………………………………………………………48 6. Tables………………………………………………………………………..……….50 Table 1………………………………………………………………………………..50 Table 2………………………………………………………………………………..51 Table 3……………………………………………………………………….……….52 Table 4……………………………………………………………………….….........53 Table 5……………………………………………………………………………….54 References ………………………………………………………………….….………55 Appendix……………………………………………………………………..………...63" | |
| dc.language.iso | en | |
| dc.subject | GID/ CTLH 複合物 | zh_TW |
| dc.subject | TRIM28 | zh_TW |
| dc.subject | SOX6 | zh_TW |
| dc.subject | 小分子核糖核酸 | zh_TW |
| dc.subject | 血紅蛋白 | zh_TW |
| dc.subject | hemoglobin | en |
| dc.subject | microRNAs | en |
| dc.subject | GID/ CTLH complex | en |
| dc.subject | TRIM28 | en |
| dc.subject | SOX6 | en |
| dc.title | 探討在人類慢性骨髓性白血病細胞K562中由TRIM28介導的基因調控的分子機制 | zh_TW |
| dc.title | The molecular mechanism of TRIM28-mediated gene regulation in leukemia K562 cells | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 余榮熾(Hsin-Tsai Liu),朱善德(Chih-Yang Tseng) | |
| dc.subject.keyword | TRIM28,SOX6,小分子核糖核酸,血紅蛋白,GID/ CTLH 複合物, | zh_TW |
| dc.subject.keyword | TRIM28,SOX6,microRNAs,hemoglobin,GID/ CTLH complex, | en |
| dc.relation.page | 63 | |
| dc.identifier.doi | 10.6342/NTU202101418 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2021-07-15 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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