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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
| dc.contributor.author | Fei-Yun Chen | en |
| dc.contributor.author | 陳飛澐 | zh_TW |
| dc.date.accessioned | 2021-07-10T22:09:58Z | - |
| dc.date.available | 2021-07-10T22:09:58Z | - |
| dc.date.copyright | 2018-08-23 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-02 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77582 | - |
| dc.description.abstract | 屬於BH3-only的促進細胞凋亡蛋白BIK會受到泛素-蛋白酶體系統調控。然而，這種調控的根本機制及其生理功能仍然不清楚。在此，我們發現了一個泛素連接酶CRL5ASB11介導BIK泛素化/降解的機制。在內質網壓力下，ASB11被XBP1轉錄激活，從而促進BIK的泛素化，與p97的相互作用以及蛋白降解。相反地，基因損害藥物通過上調p53來下調IRE1/XBP1，導致BIK穩定。這樣相反的ASB11介導BIK泛素化調控，部分參與了內質網壓力下的適應性反應以及DNA損傷下的凋亡反應。透過IRE1抑制劑阻斷泛素化途徑可穩定活性突變體的BIK並增加它對三陰性乳腺癌的抗腫瘤功效。我們的研究發現一個BIK的泛素連接酶，通過內質網壓力和DNA損傷揭示了正反向BIK泛素化的調控機制，並且涉及一個抗癌策略，透過共同施用標靶BIK的泛素化途徑以及活性BIK。 | zh_TW |
| dc.description.abstract | The BH3-only pro-apoptotic protein BIK is regulated by ubiquitin-proteasome system. However, the underlying mechanism of this regulation and its physiological functions remain elusive. Here, we identify a BIK ubiquitination/degradation mechanism mediated by ubiquitin ligase CRL5ASB11. Under ER stress, ASB11 is transcriptionally activated by XBP1, thereby stimulating BIK ubiquitination, interaction with p97, and proteolysis. Conversely, genotoxic agents act through p53 to downregulate IRE1/XBP1 axis, leading to BIK stabilization. These opposite regulations of ASB11-medaited BIK ubiquitination participate in part to the adaptive response to ER stress and apoptotic response to DNA damage. Blockage of this ubiquitination pathway by IRE1 inhibitors stabilizes BIK active mutant and increases its anti-tumor efficacy in triple negative breast cancers. Our study identifies a BIK ubiquitin ligase, uncovers the opposite regulations of this BIK ubiquitination by ER stress and DNA damage, and implicate an anti-cancer strategy by targeting BIK ubiquitination pathway in combined with administration of active BIK. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T22:09:58Z (GMT). No. of bitstreams: 1 ntu-107-D01b46002-1.pdf: 7017517 bytes, checksum: a968ee3faed498c6dfcfdf797f665d31 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 論文口試委員審定書
誌謝 II 摘要 IV Abstract V Contents VI Literature Review 1 1. The ubiquitin-proteasome system 1 1.1 The ubiquitin E3 ligases 2 1.2 The Cullin-RING E3 ligases 3 1.3 Ankyrin repeat and SOCS box 11 4 2. BCL-2 family 5 2.1 BCL-2 interacting killer 6 3. Endoplasmic reticulum stress 7 3.1 The activation and stress sensors of UPR 9 3.2 The mechanism of UPR in controlling the cell fate 11 3.3 The IRE1 signaling in cancer diseases and therapy 14 4. DNA damage-induced apoptosis 18 Introduction 22 Materials and Methods 26 Antibodies and reagents 26 Cell Culture and Transfection 26 Plasmids 27 RNA interference 27 Immunoprecipitation and Western blot 28 Ubiquitination assays 28 Apoptosis assay 30 mRNA extraction and RT-qPCR 30 Luciferase reporter assay 30 ChIP assay 31 MTT assay 31 Animal experiments 32 Statistical analysis 32 Results 33 Identification of CRL5ASB11 as a BIK ubiquitin ligase 33 ASB11 promotes BIK proteasomal degradation 34 ASB11 is a transcriptional target of XBP1s 35 ER stress promotes BIK degradation through the actions of ASB11 and p97 37 DNA damage induces p53-dependent BIK stabilization by suppressing XBP1/ASB11 axis 38 Opposite regulations of ASB11-dependent BIK ubiquitination by ER stress and DNA damage govern the life-death cell fate 40 Targeting ASB11-dependent BIK degradation pathway enhances the anti-tumor effect of BIKDD 42 Discussion 45 Reference 51 Figures 75 Figure 1. Both Cul2 and Cul5 dominant negative (DN) mutants increase the protein level but not mRNA level of BIK. 75 Figure 2. Exogenous ANKRD9, ASB11 and ASB17 interact with endogenous BIK. 77 Figure 3. ASB11, but not ASB17 and ANKRD9 can promote BIK ubiquitination. 78 Figure 4. ASB11 recruits BIK to Cul5 for ubiquitination. 79 Figure 5. Cul5ASB11 complex is responsible for BIK ubiquitination in vitro. 81 Figure 6. ASB11 promotes BIK degradation. 82 Figure 7. Overexpression and knockdown of ASB11 increases and decreases BIK protein turnover, respectively. 83 Figure 8. ER stress inducers upregulate the mRNA level of ASB11. 84 Figure 9. ER stress increases ASB11 mRNA expression through XBP1. 85 Figure 10. XBP1s increases ASB11 mRNA. 87 Figure 11. ASB11 is a transcriptional target of XBP1s. 89 Figure 12. NFY-A/B/C complex binds XBP1s. 90 Figure 13. ER stress increases BIK protein turnover. 91 Figure 14. ASB11 knockdown blocks tunicamycin-induced BIK downregulation. 92 Figure 15. Tunicamycin elevates the ubiquitination levels of exogenous and endogenous BIK and promotes BIK proteasomal degradation. 93 Figure 16. XBP1 knockdown blocks tunicamycin-induced BIK downregulation and BIK ubiquitination. 95 Figure 17. p97 and its adaptors UFD1L/NPL4 participate in the ER stress-induced BIK degradation. 97 Figure 18. p97-NPL4-UFD1L complex interacts with ubiquitinated BIK under ER stress. 99 Figure 19. Genotoxic agents reduce mRNA and protein levels of ASB11 and increase BIK in a p53-dependent manner. 100 Figure 20. Doxorubicin downregulates ASB11 mRNA in p53-transfected H1299 cells but not in p53-deficient H1299 cells. 101 Figure 21. 5-FU stabilizes BIK in control cells and cannot further stabilize BIK in ASB11 knockdown cells. 102 Figure 22. Overexpression of p53 in H1299 cells decreases ASB11 promoter activity. 103 Figure 23. Doxorubicin and 5-FU reduce IRE1 level and XBP1 splicing through a p53-dependent manner. 104 Figure 24. Overexpression of XBP1s restores ASB11 mRNA and BIK ubiquitination in doxorubicin-treated cells. 105 Figure 25. Overexpression of ASB11 but not its mutant decreases DNA damage-induced apoptosis. 106 Figure 26. Overexpression of ASB11 reduces DNA damage-induced apoptosis, which is reversed by BIK overexpression. 108 Figure 27. ASB11 knockdown increases apoptosis under ER stress, which is reversed by BIK knockdown. 110 Figure 28. ER stress induces a higher level of apoptosis in BIK2KR expressing cells than BIK WT cells. 112 Figure 29. ASB11 and tunicamycin promote BIKDD ubiquitination. 114 Figure 30. IRE1 inhibitors enhance the killing effect of CMV-BIKDD in three TNBC cells. 116 Figure 31. IRE1 inhibitor enhances the killing effect of VISA-BIKDD in Hs578T cells. 117 Figure 32. Combined treatment of IRE1 inhibitor and BIKDD enhances the killing effect of BIKDD in TNBC bearing nude mice. 118 Figure 33. Combined treatment of IRE1 inhibitor and VISA-BIKDD enhances the killing effect of VISA-BIKDD in TNBC bearing nude mice. 120 Appendixes 121 Appendix 1. Knockdown of Cul5 but not Cul2 increases the protein level of BIK. 121 Appendix 2. ASB11 directly interacts with BIK. 122 Appendix 3. Overexpression of ASB11 but not ASB11 mutant promotes BIK ubiquitination. 123 Appendix 4. ASB11 promotes BIK proteasomal degradation. 124 Appendix 5. Knockdown of ASB11 increases the protein level of BIK in H1299 cells. 125 Appendix 6. ER stress inducers upregulate the mRNA level of ASB11 in two TNBC cells. 126 Appendix 7. ER stress inducers elevate ASB11 protein expression and reduce BIK protein level in multiple cell lines. 127 Appendix 8. ER stress downregulates BIK through ASB11. 128 Appendix 9. ER stress promotes BIK proteasomal degradation. 129 Appendix 10. p53 represses ASB11 mRNA expression. 130 Appendix 11. BIK(2KR) mutant is resistant to ASB11-medaited ubiquitination and degradation. 131 Appendix 12. ASB11 and tunicamycin promote BIKDD degradation. 133 Appendix 13. IRE1 inhibitor stabilizes BIKDD in three TNBC cell lines. 134 Appendix 14. IRE1 inhibitor increases the cleavage PARP in three TNBC cell lines. 135 Table 1: Information for antibodies used in this study 136 Table 2: Primers for (quantitative) PCR and cloning 137 Table 3: Targeting sequences for shRNAs 141 | |
| dc.language.iso | en | |
| dc.title | BIK泛素化的調控決定細胞壓力反應下生與死的命運以及抗腫瘤的活性 | zh_TW |
| dc.title | Regulation of BIK ubiquitination determines life-death fate of cellular stress responses and anti-tumor activity | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 施修明,謝小燕,陳光超,顏雪琪 | |
| dc.subject.keyword | BIK,ASB11,泛素化,內質網壓力,IRE1α,XBP1s,DNA損傷,p53, | zh_TW |
| dc.subject.keyword | BIK,ASB11,ubiquitination,ER stress,IRE1,XBP1s,DNA damage,p53, | en |
| dc.relation.page | 141 | |
| dc.identifier.doi | 10.6342/NTU201701408 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2018-08-02 | |
| 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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