請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96668完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 顏伯勳 | zh_TW |
| dc.contributor.advisor | Bo-Shiun Yan | en |
| dc.contributor.author | 簡瑋成 | zh_TW |
| dc.contributor.author | Wei-Cheng Jian | en |
| dc.date.accessioned | 2025-02-20T16:27:14Z | - |
| dc.date.available | 2025-02-21 | - |
| dc.date.copyright | 2025-02-20 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-11-29 | - |
| dc.identifier.citation | 1. O'Sullivan, J.M., et al., The nucleolus: a raft adrift in the nuclear sea or the keystone in nuclear structure? Biomol Concepts, 2013. 4(3): p. 277-86.
2. Andersen, J.S., et al., Nucleolar proteome dynamics. Nature, 2005. 433(7021): p. 77-83. 3. Ahmad, Y., et al., NOPdb: Nucleolar Proteome Database—2008 update. Nucleic Acids Research, 2008. 37(suppl_1): p. D181-D184. 4. Leung, A.K. and A.I. Lamond, The dynamics of the nucleolus. Crit Rev Eukaryot Gene Expr, 2003. 13(1): p. 39-54. 5. Pecoraro, A., et al., Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress. International Journal of Molecular Sciences, 2020. 21(19): p. 7334. 6. Pelletier, J., G. Thomas, and S. Volarević, Ribosome biogenesis in cancer: new players and therapeutic avenues. Nature Reviews Cancer, 2018. 18(1): p. 51-63. 7. Jiao, L., et al., Ribosome biogenesis in disease: new players and therapeutic targets. Signal Transduction and Targeted Therapy, 2023. 8(1): p. 15. 8. Chen, D. and S. Huang, Nucleolar components involved in ribosome biogenesis cycle between the nucleolus and nucleoplasm in interphase cells. J Cell Biol, 2001. 153(1): p. 169-76. 9. Lindström, M.S., et al., Nucleolus as an emerging hub in maintenance of genome stability and cancer pathogenesis. Oncogene, 2018. 37(18): p. 2351-2366. 10. Boisvert, F.-M., et al., The multifunctional nucleolus. Nature Reviews Molecular Cell Biology, 2007. 8(7): p. 574-585. 11. Marciniak, R.A., et al., Nucleolar localization of the Werner syndrome protein in human cells. Proc Natl Acad Sci U S A, 1998. 95(12): p. 6887-92. 12. Heiss, N.S., et al., Dyskerin localizes to the nucleolus and its mislocalization is unlikely to play a role in the pathogenesis of dyskeratosis congenita. Hum Mol Genet, 1999. 8(13): p. 2515-24. 13. Brosh, R.M., Jr., et al., p53 Modulates the Exonuclease Activity of Werner Syndrome Protein *. Journal of Biological Chemistry, 2001. 276(37): p. 35093-35102. 14. Woo, L.L., et al., The Rothmund-Thomson gene product RECQL4 localizes to the nucleolus in response to oxidative stress. Experimental Cell Research, 2006. 312(17): p. 3443-3457. 15. Zink, D., A.H. Fischer, and J.A. Nickerson, Nuclear structure in cancer cells. Nat Rev Cancer, 2004. 4(9): p. 677-87. 16. Hetman, M. and M. Pietrzak, Emerging roles of the neuronal nucleolus. Trends Neurosci, 2012. 35(5): p. 305-14. 17. Corman, A., et al., Targeting the nucleolus as a therapeutic strategy in human disease. Trends in Biochemical Sciences, 2023. 48(3): p. 274-287. 18. Mizielinska, S., et al., Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathol Commun, 2017. 5(1): p. 29. 19. Maehama, T., et al., Nucleolar stress: Molecular mechanisms and related human diseases. Cancer Sci, 2023. 114(5): p. 2078-2086. 20. Zisi, A., J. Bartek, and M.S. Lindström, Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward. Cancers, 2022. 14(9): p. 2126. 21. Calabresi, P., et al., Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death & Disease, 2023. 14(3): p. 176. 22. Liu, L.-l., et al., Loss of DJ-1 function contributes to Parkinson’s disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation. Acta Pharmacologica Sinica, 2023. 44(10): p. 1948-1961. 23. Caudle, W.M., et al., A role for a novel protein, nucleolin, in Parkinson's disease. Neurosci Lett, 2009. 459(1): p. 11-5. 24. Vilotti, S., et al., Parkinson's disease DJ-1 L166P alters rRNA biogenesis by exclusion of TTRAP from the nucleolus and sequestration into cytoplasmic aggregates via TRAF6. PLoS One, 2012. 7(4): p. e35051. 25. Engbrecht, M. and A. Mangerich, The Nucleolus and PARP1 in Cancer Biology. Cancers (Basel), 2020. 12(7): p. 1813. 26. Ma, T.S., et al., Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops. Nucleic Acids Res, 2023. 51(21): p. 11584-11599. 27. Yang, K., J. Yang, and J. Yi, Nucleolar Stress: hallmarks, sensing mechanism and diseases. Cell Stress, 2018. 2(6): p. 125-140. 28. Hua, L., et al., Nucleolus and Nucleolar Stress: From Cell Fate Decision to Disease Development. Cells, 2022. 11(19): p. 3017. 29. Pecoraro, A., et al., Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress. Int J Mol Sci, 2020. 21(19). 30. Latonen, L., Phase-to-Phase With Nucleoli - Stress Responses, Protein Aggregation and Novel Roles of RNA. Front Cell Neurosci, 2019. 13: p. 151. 31. Ianni, A., et al., SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress. Proceedings of the National Academy of Sciences, 2021. 118(5): p. e2015339118. 32. Woods, S.J., et al., The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2015. 1849(7): p. 821-829. 33. Zhang, Y. and H. Lu, Signaling to p53: ribosomal proteins find their way. Cancer Cell, 2009. 16(5): p. 369-77. 34. Wang, M., et al., Nucleolar Sequestration: Remodeling Nucleoli Into Amyloid Bodies. Front Genet, 2019. 10: p. 1179. 35. Visintin, R., E.S. Hwang, and A. Amon, Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. Nature, 1999. 398(6730): p. 818-823. 36. Weber, J.D., et al., Nucleolar Arf sequesters Mdm2 and activates p53. Nature Cell Biology, 1999. 1(1): p. 20-26. 37. Brooks, C.L. and W. Gu, p53 Ubiquitination: Mdm2 and Beyond. Molecular Cell, 2006. 21(3): p. 307-315. 38. Haupt, Y., et al., Mdm2 promotes the rapid degradation of p53. Nature, 1997. 387(6630): p. 296-299. 39. Frottin, F., et al., The nucleolus functions as a phase-separated protein quality control compartment. Science, 2019. 365(6451): p. 342-347. 40. Morotomi-Yano, K. and K.-i. Yano, Nucleolar translocation of human DNA topoisomerase II by ATP depletion and its disruption by the RNA polymerase I inhibitor BMH-21. Scientific Reports, 2021. 11(1): p. 21533. 41. Rubbi, C.P. and J. Milner, Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. Embo j, 2003. 22(22): p. 6068-77. 42. Eischen, C.M., Genome Stability Requires p53. Cold Spring Harb Perspect Med, 2016. 6(6). 43. Hernández Borrero, L.J. and W.S. El-Deiry, Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer, 2021. 1876(1): p. 188556. 44. Ozaki, T. and A. Nakagawara, Role of p53 in Cell Death and Human Cancers. Cancers (Basel), 2011. 3(1): p. 994-1013. 45. Bang, S., S. Kaur, and M. Kurokawa, Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway. Int J Mol Sci, 2019. 21(1): p. 261. 46. Karni-Schmidt, O., M. Lokshin, and C. Prives, The Roles of MDM2 and MDMX in Cancer. Annu Rev Pathol, 2016. 11: p. 617-44. 47. Linares, L.K., et al., HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci U S A, 2003. 100(21): p. 12009-14. 48. Dai, C. and W. Gu, p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med, 2010. 16(11): p. 528-36. 49. Sakaguchi, K., et al., Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem, 2000. 275(13): p. 9278-83. 50. Meek, D.W. and C.W. Anderson, Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol, 2009. 1(6): p. a000950. 51. Stommel, J.M., et al., A leucine‐rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. The EMBO Journal, 1999. 18(6): p. 1660-1672. 52. Shaulsky, G., et al., Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol, 1990. 10(12): p. 6565-77. 53. Ho, T., B.X. Tan, and D. Lane, How the Other Half Lives: What p53 Does When It Is Not Being a Transcription Factor. Int J Mol Sci, 2019. 21(1): p. 13. 54. Marei, H.E., et al., p53 signaling in cancer progression and therapy. Cancer Cell International, 2021. 21(1): p. 703. 55. Chen, J., The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. Cold Spring Harb Perspect Med, 2016. 6(3): p. a026104. 56. Wang, Y.-C., et al., Severe cellular stress drives apoptosis through a dual control mechanism independently of p53. Cell Death Discovery, 2022. 8(1): p. 282. 57. Klibanov, S.A., H.M. O’Hagan, and M. Ljungman, Accumulation of soluble and nucleolar-associated p53 proteins following cellular stress. Journal of Cell Science, 2001. 114(10): p. 1867-1873. 58. Levine, A.J. and M. Oren, The first 30 years of p53: growing ever more complex. Nat Rev Cancer, 2009. 9(10): p. 749-58. 59. Miyachi, M., et al., Restoration of p53 pathway by nutlin-3 induces cell cycle arrest and apoptosis in human rhabdomyosarcoma cells. Clin Cancer Res, 2009. 15(12): p. 4077-84. 60. Nguyen, D., et al., Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent. Cell Cycle, 2011. 10(23): p. 4074-82. 61. Holmberg Olausson, K., M. Nistér, and M.S. Lindström, p53 -Dependent and -Independent Nucleolar Stress Responses. Cells, 2012. 1(4): p. 774-98. 62. Boulon, S., et al., The Nucleolus under Stress. Molecular Cell, 2010. 40(2): p. 216-227. 63. Zatsepina, O.V., et al., Ultrastructural changes in nucleoli and fibrillar centers under the effect of local ultraviolet microbeam irradiation of interphase culture cells. Experimental Cell Research, 1989. 181(1): p. 94-104. 64. David-Pfeuty, T.s., et al., Common and reversible regulation of wild-type p53 function and of ribosomal biogenesis by protein kinases in human cells. Oncogene, 2001. 20(42): p. 5951-5963. 65. Fátyol, K. and I. Grummt, Proteasomal ATPases are associated with rDNA: the ubiquitin proteasome system plays a direct role in RNA polymerase I transcription. Biochim Biophys Acta, 2008. 1779(12): p. 850-9. 66. Kim, H.J., et al., Systemic analysis of heat shock response induced by heat shock and a proteasome inhibitor MG132. PLoS One, 2011. 6(6): p. e20252. 67. Zhang, D., et al., Transferrin receptor targeting chimeras for membrane protein degradation. Nature, 2024. DOI: 10.1038/s41586-024-07947-3 68. Hsia, O., et al., Targeted protein degradation via intramolecular bivalent glues. Nature, 2024. 627(8002): p. 204-211. 69. Ly, J., et al., Nuclear release of eIF1 restricts start-codon selection during mitosis. Nature, 2024. 635(8038): p. 490-498. 70. Lee, D.H. and A.L. Goldberg, Proteasome inhibitors: valuable new tools for cell biologists. Trends in Cell Biology, 1998. 8(10): p. 397-403. 71. Khamis, I. and J.J. Heikkila, Effect of isothiocyanates, BITC and PEITC, on stress protein accumulation, protein aggregation and aggresome-like structure formation in Xenopus A6 kidney epithelial cells. Comp Biochem Physiol C Toxicol Pharmacol, 2018. 204: p. 1-13. 72. Tajima, K., et al., The proteasome inhibitor MG132 promotes accumulation of the steroidogenic acute regulatory protein (StAR) and steroidogenesis. FEBS Lett, 2001. 490(1-2): p. 59-64. 73. Fraschilla, I. and K.L. Jeffrey, The Speckled Protein (SP) Family: Immunity's Chromatin Readers. Trends Immunol, 2020. 41(7): p. 572-585. 74. Bloch, D.B., et al., Sp110 localizes to the PML-Sp100 nuclear body and may function as a nuclear hormone receptor transcriptional coactivator. Mol Cell Biol, 2000. 20(16): p. 6138-46. 75. Dundr, M. and T. Misteli, Biogenesis of nuclear bodies. Cold Spring Harb Perspect Biol, 2010. 2(12): p. a000711. 76. Shan, L., et al., Emerging roles of nuclear bodies in genome spatial organization. Trends in Cell Biology, 2024. 34(7): p. 595-605. 77. Chang, S.Y., et al., SP110 Polymorphisms Are Genetic Markers for Vulnerability to Latent and Active Tuberculosis Infection in Taiwan. Dis Markers, 2018. 2018: p. 4687380. 78. Leu, J.-S., et al., Functional domains of SP110 that modulate its transcriptional regulatory function and cellular translocation. Journal of Biomedical Science, 2018. 25(1): p. 34. 79. Dittmer, D., et al., Gain of function mutations in p53. Nat Genet, 1993. 4(1): p. 42-6. 80. Tan, B.S., et al., Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF). Cell Death & Disease, 2015. 6(7): p. e1826-e1826. 81. Chiang, Y.T., et al., The Function of the Mutant p53-R175H in Cancer. Cancers (Basel), 2021. 13(16): p. 4008. 82. Zhang, C., et al., Gain-of-function mutant p53 in cancer progression and therapy. J Mol Cell Biol, 2020. 12(9): p. 674-687. 83. Sosa-Carrillo, S., et al., Maximizing protein production by keeping cells at optimal secretory stress levels using real-time control approaches. Nature Communications, 2023. 14(1): p. 3028. 84. Fulda, S., et al., Cellular stress responses: cell survival and cell death. Int J Cell Biol, 2010. 2010: p. 214074. 85. Jorgovanovic, D., et al., Roles of IFN-γ in tumor progression and regression: a review. Biomarker Research, 2020. 8(1): p. 49. 86. Han, Y., et al., The Interaction of the IFNγ/JAK/STAT1 and JAK/STAT3 Signalling Pathways in EGFR-Mutated Lung Adenocarcinoma Cells. J Oncol, 2022. 2022: p. 9016296. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96668 | - |
| dc.description.abstract | 核仁是細胞核中的一個區域，不僅在核醣體生物合成中非常的重要，而且在壓力反應中發揮著至關重要的作用，使細胞能夠在惡劣的條件下生存。當核醣體生物合成因發生刺激而中斷時，核仁壓力反應被激活，導致核仁完整性被破壞。 p53 是一種維持基因組穩定性的轉錄因子，通常因多種方式的壓力反應而被活化。蛋白酶體抑制劑 MG132 誘導的核仁壓力會導致 p53 在細胞核中積聚、核仁易位以及p53 轉錄活性減弱。然而，MG132誘導p53核仁轉移的機制仍不清楚。我們先前的研究顯示，SP110 蛋白的主要亞型 SP110b 與 p53 蛋白能相互作用，減弱 p53誘導的細胞死亡，並影響 p53 細胞分佈。因此，本研究的目的是確定在 MG132處理下 SP110b 是否會改變 p53 轉移到核仁中。為了了解SP110b介導的p53核仁轉移效應，研究使用了SP110b突變體SP110b M1+3，其中核仁定位訊號（NoLS）為突變型，並被證明比野生型SP110b核仁定位訊號具有更明顯的核仁定位能力。由於SP110b M1+3 和p53蛋白之間較微弱的交互作用，SP110b M1+3在MG132處理下對 p53 核仁轉移幾乎沒有影響。此外，MG132 誘導的 p53 核仁轉移在缺乏SP110 的細胞中也不受影響。基於上述結果，MG132誘導的p53核仁轉移似乎不依賴SP110b。未來的研究可以利用在類似壓力條件下與p53共轉移到核仁中的蛋白質，或是使用將SP110b轉移到核仁中的缺氧條件來觀察p53核仁轉移的變化。 | zh_TW |
| dc.description.abstract | The nucleolus, a compartment in the nucleus, plays a crucial role not only in ribosome biogenesis, but also in stress responses, which enable cells to survive harsh conditions. The nucleolus stress response is activated when the ribosome biogenesis is interrupted by the stimuli, resulting in the destruction of nucleolus integrity. p53, a transcription factor that maintains genome stability, is often activated as a consequence of stress responses in many ways. Nucleolar stress induced by MG132, a proteasome inhibitor, results in p53 accumulation in the nucleus, nucleolar translocation, and dulled transcriptional activity of p53. However, the mechanism of MG132-induced nucleolar translocation of p53 is still unclear. Our previous studies demonstrated that SP110b, the major isoform of speckle protein 110 (SP110), interacts with p53 protein, attenuates the p53-induced cell death, and affects p53 cellular distribution. Therefore, the purpose of this study is to determine whether SP110b alters the localization of p53 into the nucleolus under MG132 treatment. In order to examine the SP110b-mediated effect on p53 nucleolar translocation, an SP110b mutant, SP110b M1+3, in which the nucleolar localization signal (NoLS) has been mutated and demonstrated to be more obvious nucleolar localization capabilities than that of the wild-type SP110b protein was used. Due to the weak interaction between SP110b M1+3 and p53 protein, SP110b M1+3 has little to no impact on p53 nucleolus localization under MG132 treatment. Furthermore, MG132-induced nucleolar translocation of p53 remained unaffected in cells lacking SP110. Based on the results above, it appears that MG132-induced p53 nucleolar translocation is independent of SP110. Future studies could use proteins that are co-translocated with p53 into the nucleolus under similar stress conditions or use a hypoxic condition for SP110b translocation into the nucleolus to observe changes in p53 nucleolar translocation. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-02-20T16:27:14Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-02-20T16:27:14Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 摘要 i
Abstract ii 目次 iv 圖次 vi Chapter 1 緒論 1 1.1 核仁 (Nucleolus) 1 1.1.1 核仁與疾病 1 1.1.2 核仁壓力反應 (Nucleolus Stress Response) 2 1.2 p53 3 1.2.1 p53 與核仁壓力反應的關係 4 1.3 MG132 5 1.4 SP110 5 1.5研究目標 7 Chapter 2 實驗材料與方法 8 2.1 細胞株及培養方法 8 2.2 慢病毒的生產 8 2.3 慢病毒的轉染(Transduction) 8 2.4 螢光照片 (Fluorescence image) 拍攝 9 2.5核質分離與免疫共沉澱法 9 2.6 西方墨點法 (Western blot) 10 2.7 蛋白質定量及標準化 10 2.8 核仁定位比例統計分析 11 Chapter 3 結果 12 3.1 MG132 沒有造成DsRed-p53 and eGFP-SP110b蛋白的累積 12 3.2 DsRed-p53 and eGFP-SP110b蛋白在細胞中的降解及DsRed-p53穩定eGFP-SP110b-WT的表現 13 3.3 MG132誘導的DsRed-p53核仁轉移可能不需要eGFP-SP110b 13 3.4 DsRed-p53與eGFP-SP110b-WT之間的交互作用強於與eGFP-SP110b-M1+3的交互作用 14 3.5 MG132誘導的DsRed-p53核仁轉移與SP110b無關 15 Chapter 4 討論 16 Chapter 5 附圖 19 Chapter 6 參考文獻 36 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | SP110b | zh_TW |
| dc.subject | 核仁 | zh_TW |
| dc.subject | p53核仁轉移 | zh_TW |
| dc.subject | MG132 | zh_TW |
| dc.subject | 核仁壓力反應 | zh_TW |
| dc.subject | Nucleolus | en |
| dc.subject | Nucleolar stress response | en |
| dc.subject | MG132 | en |
| dc.subject | p53 nucleolar translocation | en |
| dc.subject | SP110b | en |
| dc.title | SP110b核蛋白在p53核仁轉移上的角色 | zh_TW |
| dc.title | The role of SP110b nuclear protein in p53 nucleolar translocation | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 蘇剛毅;詹世鵬;歐展言 | zh_TW |
| dc.contributor.oralexamcommittee | Kang-Yi Su;Shih-Peng Chan;Chan-Yen Ou | en |
| dc.subject.keyword | 核仁壓力反應,MG132,p53核仁轉移,SP110b,核仁, | zh_TW |
| dc.subject.keyword | Nucleolar stress response,MG132,p53 nucleolar translocation,SP110b,Nucleolus, | en |
| dc.relation.page | 47 | - |
| dc.identifier.doi | 10.6342/NTU202404629 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-11-29 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-113-1.pdf 未授權公開取用 | 2.42 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。