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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37286完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳義雄(Yee-Hsiung Chen) | |
| dc.contributor.author | Nai-Jia Huang | en |
| dc.contributor.author | 黃乃家 | zh_TW |
| dc.date.accessioned | 2021-06-13T15:23:25Z | - |
| dc.date.available | 2013-07-23 | |
| dc.date.copyright | 2008-07-23 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-07-22 | |
| dc.identifier.citation | Reference
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(2000). - 82 - Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. The Journal of experimental medicine 191, 631-640. Zhu, J., Zhou, J., Peres, L., Riaucoux, F., Honore, N., Kogan, S., and de The, H. (2005). A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer cell 7, 143-153. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37286 | - |
| dc.description.abstract | 骨髓性淋巴癌(PML)和類色素酸接受體α(RARα)的融合造成了急性前骨髓性
白血病（acute promyelocytic leukemia, APL）。類色素酸活性調控下游基因表現影響 了血球的發育，在APL 細胞中，許多corepressor，像NcoR, SMRT, HDACs 與PML、 RARα相互作用而更加抑制了RARα下游基因。此外，最近的研究報導Daxx 與 PML 作用會促使更多的co-repressor 結合到PML-RARα上，此作用是藉著PML 上 的Lys160 site 的小類泛素修飾蛋白（small ubiquitin-like modifier, SUMO）與Daxx 上的特定胺基酸的SUMO interacting motif (SIM)結合，但Daxx 如何和sumoylated 的PML 專一性結合的機制尚未清楚。 在這篇論文中， 我們藉由不同的方法， 得知PML/PML-RARα 上三個 SUMO-acceptor Lys（Lys65, Lys160, Lys490）都會與Daxx 相互作用。並探討了PML 及PML-RARα上三個Lys residue 受SUMO 修飾的不同，訂出了每一個Lys 所代表 的修飾位置，並發現這些Lys 受SUMO 修飾是相互影響的，將Lys 突變成Arg， 會影響其他site 的SUMO 修飾，顯示了PML 上每個Lys 的sumoylation 不是獨立 的。 我們還發現了外加與Daxx SUMO interacting motif (SIM)序列一樣的peptide， 可以有效的回復Daxx 所造成的轉錄抑制，促使RAR 下游基因的表現。將此peptide 加至來自APL 的細胞：NB4 中，可以有效的降低NB4 不正常的生長速度。綜合言 之，本篇論文詳加瞭解了PML 及PML-RARα上的sumoylation 和Daxx 的專一性 結合，更證明了Daxx-SIM 可以當作一個有效抑制APL transformarion 的治療方法。 | zh_TW |
| dc.description.abstract | PML (promyelocytic leukemia gene) fused to retinoic acid receptor α (RARα),
derived from the t(15;17) translocation, causes acute promyelocytic leukemia (APL). Several transcriptional corepressors such as NcoR, SMRT and HDACs were shown to associate with PML-RARα, leading to transcriptional repression. Besides, recent reports indicated that Daxx could contribute to transcriptional repression of PML/RARα-targeted genes via interacting with SUMO modification at Lys160 of PML portion. The specificity of how Daxx binds to sumoylated PML has not been well characterized. In this study, we used different approaches to show that all three SUMO-acceptor Lys sites of PML and PML-RARα are important for Daxx interaction. In addition, we found that sumoylation level of PML at each Lys acceptor site is affected by each other when individual sumoylation site was mutated, indicating that PML sumoylation at each Lys acceptor is not independent. In addition, we found exogenous Daxx SUMO-interacting motif (SIM) peptide could reverse Daxx-elicited repression on PML-RARα-mediated reporter activity and could affect APL cell line-NB4 cells proliferation rate. Together, our studies elucidate the sumoylation-mediated interaction between PML or PML-RARα and Daxx and provide the evidence that Daxx-SIM peptide may be considered a potential agent for blocking APL-mediated transformation phenotype. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T15:23:25Z (GMT). No. of bitstreams: 1 ntu-97-R95b46013-1.pdf: 3189277 bytes, checksum: 4f99bec1c1301b80a36ce7bea20f2c75 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | Table of Contents
中文摘要......................................................................................................................- 1 - Abstract .......................................................................................................................- 2 - I. Introduction.............................................................................................................- 4 - 1. The mysterious Daxx ......................................................................................- 5 - 1.1 The role of Daxx in apoptosis.................................................................- 5 - 1.2 Daxx involves in transcription regulation..............................................- 8 - 2. SUMO protein modification ..........................................................................- 9 - 2.1 The mechanism of reversible sumoylation............................................- 10 - 2.2 SUMO-acceptor sites............................................................................- 11 - 2.3 Non-covalent interaction with SUMO..................................................- 11 - 2.4 The functions of sumoylation modification...........................................- 13 - 3. PML ...............................................................................................................- 14 - 3.1 PML nuclear body ................................................................................- 15 - 4. PML-RARα and APL...................................................................................- 17 - 4.1 The repressive activity of PML-RAR α..................................................- 17 - 4.2 APL Therapy.........................................................................................- 18 - 5. Specific Aims .................................................................................................- 20 - II.Material and Methods..........................................................................................- 22 - III. Result...................................................................................................................- 28 - 1. Three sumoylation sites of PML mediate Daxx interaction .....................- 29 - 1.1 Analysis the sumoylation modification of PML....................................- 29 - 1.2 SUMO modification of PML is critical for Daxx interaction...............- 30 - 2. Sumoylation of PML in modulating Daxx activity ....................................- 32 - 2.1 The effect of SUMO-modified PML on Daxx transcriptional repression activity ........................................................................................................- 32 - 2.2 Sumoylation mutants of PML form abnormal PML NBs......................- 33 - 2.3 The effect of SUMO-modified PML on Daxx recruitment into PML-NBs... - 34 - 2.4 The effect of SUMO-modified PML on Daxx interaction in mammalian cells.............................................................................................................- 35 - 3. Sumoylation of PML-RARα mediates Daxx interaction ..........................- 36 - 3.1 Analysis the sumoylation modification of PML-RAR α.........................- 36 - 3.2 Daxx represses RARE promoter activity through interaction with sumoylation on K65 and K490 of PML-RAR α...........................................- 37 - 3.3 Each sumoylation site of PML-RAR α is critical sumoylation sites for the interaction with Daxx .................................................................................- 37 - 4. The effect of Daxx SIM peptide on cellular events....................................- 39 - 4.1 Daxx SIM peptide can be targeted into PML NBs................................- 39 - 4.2 Daxx-SIM peptide transduction relieves the RARE promoter activity.- 40 - 4.3 The effect of FITC-peptide on cell growth arrest.................................- 40 - IV. Discussion............................................................................................................- 42 - 1. PML sumoylation and Daxx interaction.....................................................- 43 - 2. PML-RARα and Daxx interaction..............................................................- 46 - 3. Daxx-SIM peptide attenuate APL cells proliferation................................- 48 - Reference...................................................................................................................- 70 - Figures Fig.1 Analysis of PML sumoylation in COS-1 cells..................................................- 51 - Fig.2 Analysis of PML sumoylation in vitro..............................................................- 52 - Fig.3 Each sumoylation site contributes to PML and Daxx interaction.....................- 53 - Fig.4 The inhibition of Daxx-mediated repression by PML is attenuated when sumoylation site is mutated........................................................................................- 54 - Fig.5 Sumoylation mutants of PML affect PML NBs number and structure.............- 57 - Fig.6 Sumoylation mutants of PML alter the co-locolization of PML and Daxx......- 61 - Fig.7 Analysis of PML sumoylation and Daxx interaction with arsenic trioxide treatment.....................................................................................................................- 63 - Fig.8 Analysis of PML-RARα (L) sumoylation in COS-1 cells................................- 64 - Fig.9 Daxx mediates PML-RARα-elicited repression on RARE reporter activity....- 65 - Fig.10 Each sumoylation site is critical for PML-RARα and Daxx interaction........- 66 - Fig.11 Investigate the localization of FITC-TAT-Daxx-SIM and FITC-TAT-scramble peptides in COS-1 cells..............................................................................................- 67 - Fig.12 FITC-TAT-Daxx-SIM peptide transduction relieves the RARE promoter activity.- 68 - Fig.13 FITC-TAT-Daxx-SIM peptide attenuates the cell growth of NB4 cells..........- 69 - Tables Table 1. Difference in numbers of PML NBs between sumoylated mutants in Hela cells....................................................................................................................................- 58 - Table 2. Comparison of the Daxx and PML co-localization rate between different sumoylation mutants in PML -/- cells........................................................................- 62 - | |
| dc.language.iso | en | |
| dc.subject | 骨髓性淋巴癌 | zh_TW |
| dc.subject | 小類泛素修飾蛋白 | zh_TW |
| dc.subject | 死亡結構域相關蛋白 | zh_TW |
| dc.subject | 類色素酸接受體α | zh_TW |
| dc.subject | Fas death domain associated protein (Daxx) | en |
| dc.subject | promyelocytic leukemia (PML) | en |
| dc.subject | acute promyelocytic leukemia (APL) | en |
| dc.subject | small ubiquitin-related | en |
| dc.subject | retinoic acid receptor α (RARα) | en |
| dc.title | 探討PML及PML-RARα的小類泛素修飾對Daxx結合之專一性 | zh_TW |
| dc.title | Specificity of PML and PML-RARα SUMO modification in recruiting Daxx | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 施修明(Hsiu-Ming Shih) | |
| dc.contributor.oralexamcommittee | 陳瑞華(Ruey-Hwa Chen),阮麗蓉(Li-Jung Juan) | |
| dc.subject.keyword | 骨髓性淋巴癌,類色素酸接受體α,死亡結構域相關蛋白,小類泛素修飾蛋白, | zh_TW |
| dc.subject.keyword | promyelocytic leukemia (PML),retinoic acid receptor α (RARα),Fas death domain associated protein (Daxx),acute promyelocytic leukemia (APL),small ubiquitin-related, | en |
| dc.relation.page | 82 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-07-23 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-97-1.pdf 未授權公開取用 | 3.11 MB | Adobe PDF |
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