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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐尚德(Shang-Te Danny Hsu) | |
| dc.contributor.author | Tzu-Jing Yang | en |
| dc.contributor.author | 楊子靖 | zh_TW |
| dc.date.accessioned | 2022-11-25T07:49:01Z | - |
| dc.date.available | 2024-02-09 | |
| dc.date.copyright | 2022-02-21 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-02-11 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82668 | - |
| dc.description.abstract | "BRCA1-associated protein 1 (BAP1) 是一重要的腫瘤抑制因子 (tumor suppressor)，屬於泛素碳端水解酶 (ubiquitin C-terminal hydrolase, UCH) 家族。BAP1 藉由其去泛素化活性(deubiquitination activity) 參與多種細胞內調控路徑，包括轉錄調控、染色質重塑、細胞週期進程、細胞分化和凋亡、 DNA 損傷反應和 DNA 修復。據報導，多種人類惡性腫瘤中帶有突變型 BAP1基因，其中包括惡性間皮瘤、葡萄膜黑色素瘤、腎透明細胞癌。許多研究中均顯示多種癌症相關的突變位點可導致 BAP1 的去泛素化活性受損，以及異常的細胞質分佈，從而促進腫瘤生長。相反之，重新導入具有功能性的 BAP1 則可抑制癌細胞的生長。因此， BAP1 的腫瘤抑制活性 (tumor suppressor activity) 取決於其酵素活性和正確的細胞內定位。此外，利用觀察 BAP1 的細胞內定位染色結果，將可作為上述惡性癌症的預後標記。 由於 BAP1 的進核機制尚未明確，我們在本研究中確認 Tranportin-1 (TNPO1) 透過辨識 BAP1 的碳端脯氨酸-酪氨酸核定位訊號 (PY-NLS) 作為主要調控者控制 BAP1 的進核機轉。此外，我們發現碳端功能區塊 (CTD) 具有調控 BAP1 的自我聚集能力。TNPO1 則可藉由與 CTD 結合來調控 BAP1 聚集的程度，並以 1:1 的方式形成 TNPO1: BAP1CTD 異二聚體。 我們進一步解析 TNPO1 與 BAP1PY-NLS 複合體的晶體結構以提供 TNPO1 與 BAP1PY-NLS 交互作用的分子決定機制。UBE2O 為一種非典型的 E2/E3 泛素結合酶，可針對 BAP1 的核定位訊號進行單泛素化修飾 (NLS monoubiquitination) 調控其細胞內定位。然而，我們發現 TNPO1 結合 BAP1PY-NLS 後，可利用立體障礙掩蓋 PY-NLS 序列中的四個單泛素化 (mUb) 位點，從而阻礙UBE2O進行隨後的核定位訊號單泛素化修飾。 我們接著證明 BAP1 是一種容易自我聚集 (aggregation) 的蛋白質。當 BAP1 分別攜帶與癌症相關的 UCH 功能區塊突變位： N78S 或G128R 時， 可以觀察到此二種BAP1突變型重組蛋白容易形成蛋白聚集物 (protein aggregates) 或是在細胞內大量聚集在細胞質中。儘管這些突變型保留了與 TNPO1 相互作用的能力，但研究結果表明這些突變增強了 BAP1 的聚集特性，進而導致 BAP1 無法順利轉運至細胞核內。 雖然 BAP1 主要分布在細胞核內，仍有一小部分 BAP1 被發現位於粒腺體-內質網接觸位點 (Mitochondria-ER contact sites)。 BAP1 在細胞質中的生物學相關性被描述為它通過去泛素化調節 IP3R3 受體的蛋白質穩定性。由於 IP3R3 受體可作為鈣離子控制裝置(IP3R3-VDAC1-GRP75 複合體)的組成部分。因此，該機制穩定了此控制裝置的穩定性進而促進了鈣離子從內質網流入粒腺體和隨後由鈣離子調節的細胞凋亡機轉。在這項工作的最後一章中，我們著力於從人類細胞中分離出粒腺體-內質網接觸位點並建立系統，此系統將有助於未來進一步了解 BAP1 如何與 IP3R3 交互作用的分子機制。 " | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T07:49:01Z (GMT). No. of bitstreams: 1 U0001-0702202211563200.pdf: 17598910 bytes, checksum: a1d1ab710c826da3f694bb0936132712 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | "口試委員會審定書 # 誌謝 i 中文摘要 ii ABSTRACT iv CONTENTS vi LIST OF FIGURES x LIST OF TABLES xiii Abbreviations xiv Chapter 1 General Introduction 1 1.1 Ubiquitination 2 1.2 The erasers of ubiquitin-code work: Deubiquitinating enzymes (DUBs) 6 1.3 BRCA1-associated protein 1 (BAP1) 7 1.4 Mechanism of nuclear import cycle 11 Chapter 2 Transportin-1 (TNPO1) governs the nuclear import of the tumor suppressor BAP1 14 2.1 Abstract 15 2.2 Introduction 15 2.3 Materials and Methods 17 2.3.1 Molecular cloning, protein expression and purification. 17 2.3.2 Subcellular localization and phenotypic profiling of BAP1 variants 18 2.3.3 Cas9 Ribonucleoprotein (RNP) Nucleofection 19 2.3.4 Genomic PCR amplification and editing analysis 20 2.3.5 Establish homozygous gene knock-out HEK293T single cell clone 20 2.3.6 Size-exclusion chromatography-coupled with multiangle static light scattering (SEC-MALS) analysis 21 2.3.7 In vitro monoubiquitination assay 21 2.3.8 Protein in-solution digestion 22 2.3.9 Shotgun proteomic identifications 22 2.3.10 Fluorescence polarization 23 2.3.11 Crystallization, data collection and structure determination. 23 2.4 Associated content 24 2.5 Results 25 2.5.1 Identification of nuclear import factor of BAP1 25 2.5.2 The nuclear import of BAP1 is primarily mediated by TNPO1. 31 2.5.3 TNPO1 regulates CTD-mediated self-association of BAP1. 37 2.5.4 TNPO1 regulates the UBE2O-dependent monoubiquitination of BAP1. 39 2.6 Discussion 46 Chapter 3 Establishment of in vitro monoubiquitination of BAP1 48 3.1 Introduction 49 3.2 Materials and Methods 51 3.2.1 Construction, protein expression and purification 51 3.2.2 Fluorescein-labeling of Cys-UbWT and Cys-UbK0 52 3.2.3 In vitro monoubiquitination assay 52 3.3 Results and Discussion 53 3.3.1 Purification of an E2/E3 hybrid ubiquitin ligase, UBE2O 53 3.3.2 Purification of BAP1CTD as the substrate 53 3.3.3 Purification of engineered ubiquitin with an additionally N-terminal cysteine for fluorescein labelling. 54 3.3.4 Establishment of in vitro UBE2O-mediated monoubiquitination 60 3.3.5 Site-specific identification identified by mass spectrometry 61 Chapter 4 Aggregation tendency of the tumor suppressor BAP1 67 4.1 Introduction 68 4.2 Materials and Methods 69 4.2.1 Molecular cloning, protein expression and purification. 69 4.2.2 Subcellular localization and phenotypic profiling of BAP1 variants 69 4.3 Results and Discussion 71 4.3.1 Cancer-associated mutations enhances the aggregation tendency of BAP1 in cells 71 4.3.2 BAP1 is an aggregation-prone protein in vitro 74 Chapter 5 Isolation of Mitochondria-Associated Endoplasmic reticulum (ER) membranes (MAMs) 78 5.1 Introduction 79 5.2 Procedure 83 5.2.1 Cell preparation (step 1-2) 83 5.2.2 Homogenization (step 3-6) 84 5.2.3 Fractionation of cytosolic organelle (step 7) 85 5.2.4 Fractionation of crude mitochondria. (step 8-12) 85 5.2.5 MAM isolation from crude mitochondria (step 13-17) 86 5.2.6 Further isolation of pure MAM from the crude MAM fraction (step 18-23) 87 5.2.7 Further isolation of pure mitochondria from the crude mitochondria (step 24-27) 87 5.2.8 Confirmation of MAM preparation by western blotting 89 5.3 Materials 91 5.4 Equipment 91 5.5 Buffer recipes 92 Chapter 6 Conclusion and Perspectives 93 References 97 Curriculum Vitae 112" | |
| dc.language.iso | en | |
| dc.subject | 去泛素化酶 | zh_TW |
| dc.subject | 核輸入 | zh_TW |
| dc.subject | 腫瘤抑制蛋白 | zh_TW |
| dc.subject | 泛素化 | zh_TW |
| dc.subject | ubiquitination | en |
| dc.subject | Deubiquitinating enzyme | en |
| dc.subject | BRCA1-associated protein 1 | en |
| dc.subject | Transportin-1 | en |
| dc.subject | Nuclear import | en |
| dc.subject | Tumor suppressor | en |
| dc.title | 解析腫瘤抑制蛋白BAP1特性及其進核之調控機制 | zh_TW |
| dc.title | Dissecting the nuclear import mechanism and characterization of the tumor suppressor BRCA1-assocated protein 1 (BAP1) | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳瑞華(Sheng-Jean Huang),吳昆峯(Jau-Yih Tsauo),凌嘉鴻(Shih-Liang Shih),王慧菁 | |
| dc.subject.keyword | 去泛素化酶,泛素化,腫瘤抑制蛋白,核輸入, | zh_TW |
| dc.subject.keyword | BRCA1-associated protein 1,Deubiquitinating enzyme,ubiquitination,Tumor suppressor,Nuclear import,Transportin-1, | en |
| dc.relation.page | 115 | |
| dc.identifier.doi | 10.6342/NTU202200321 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-02-12 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-02-09 | - |
| 顯示於系所單位： | 生化科學研究所 | |
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