細胞穿透性p53蛋白促進血癌細胞凋亡但具有血漿不穩定性

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姓名	盧宗祺(Tsung-Chi Lu) 查詢紙本館藏	畢業系所	生命科學系
論文名稱	細胞穿透性p53蛋白促進血癌細胞凋亡但具有血漿不穩定性 (Cell-penetrating p53 protein promotes leukemia cell apoptosis but is unstable in plasma)
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摘要(中)	在人類的腫瘤細胞，特別是高級別癌症或轉移性腫瘤中，TP53基因的突變或缺陷尤為常見。p53是一個重要的轉錄因子，能調控細胞中許多基因的表現，其中其扮演抑癌基因的角色更是眾所矚目。p53蛋白可藉由參與控制細胞週期及促進細胞凋亡以預防細胞癌化的發生。因此，讓具突變型或缺陷型TP53基因的癌細胞重新獲得並恢復正常的 p53功能成為對抗癌症的一種積極性治療策略。在本研究中，我們開發一種重組的嵌合型p53蛋白，在其N端融合能促進轉錄活性的MyoD轉錄活化域，在其C端則鏈接具有細胞穿透能力的聚精氨酸多肽，並將其命名為M3-p53-R12 蛋白。該嵌合型p53蛋白以大腸桿菌作為表現宿主，並透過固定化金屬離子親和性層析法及透析取得重新折疊的蛋白質。研究證明，嵌合型p53蛋白具有穿過細胞膜並擁有遷移至細胞核的能力。此外該蛋白亦保留著p53蛋白的DNA結合及寡聚化等重要的轉錄因子特性。在細胞試驗中，嵌合型 p53 蛋白能抑制包含HL-60、Jurkat和K-562這三種血癌在內的多種TP53基因突變型腫瘤細胞的生長。在軟瓊脂細胞群落形成能力試驗表明嵌合型p53蛋白不僅能誘導血癌細胞的凋亡，還能抑制血癌細胞的生長。在Annexin V/PI 染色實驗中，更顯示嵌合型p53蛋白能選擇性誘導血癌細胞死亡，且不對間質幹細胞造成影響。這突顯出嵌合型p53蛋白具有選擇性對癌細胞造成傷害的能力。與此同時，我們成功建立了可用於研究嵌合型p53蛋白治療功效的異種血癌移植小鼠模型。然而，在嵌合型p53蛋白的血漿內代謝動力學研究中顯示，該蛋白對血漿中的蛋白酶非常敏感以致於其半衰期極短。這使得若想將嵌合型p53蛋白開發展成靜脈注射藥物，開發具有抗蛋白酶特性的次世代p53蛋白應為當務之急。
摘要(英)	TP53 mutants or defectives are commonly occurred in tumor cells, especially metastatic tumors. p53 protein is the most famous transcription factor, which plays a tumor suppressor role in regulating the cell cycle and promoting apoptosis of cancer cells. Therefore, restoring normal p53 activity in TP53-mutant cancer cells may be an aggressive strategy against cancer. In this study, we designed a chimeric p53 protein which N-and C-terminal fused with MyoD transcriptional activation domain and poly-arginine cell-penetrating peptide respectively. The chimeric p53 protein used E. coli as the expression host and was obtained by immobilized metal ion chromatography purification followed by a serial refolding process. The purified chimeric p53 protein gain-of-function of cell-penetration and preserves abilities of DNA binding and oligomerization. In addition, the chimeric p53 protein, named M3-p53-R12 protein, suppressed the growth of human TP53-mutated tumor cell lines, including three hematopoietic malignancy cell lines, HL-60, Jurkat, and K-562. The soft-agar assay demonstrated that the chimeric p53 protein does not only induce apoptosis but also arrests the cell cycle of leukemia cell lines. The Annexin V/PI staining revealed that the chimeric p53 protein induces the death of leukemia cell lines but has no apoptotic effect on mesenchymal stem cells, highlighting its selective impact on normal and tumor cells. A leukemia xenograft murine model has also been successfully developed for investigated the in vivo efficacy of the chimeric p53 protein. However, the metabolism kinetics in plasma showed the rapid biodegradation of the chimeric p53 protein, suggesting prevent hydrolysis from serine protease of chimeric p53 in the future is imperative.
關鍵字(中)	★ p53 ★ 血癌細胞 ★ 細胞穿透	關鍵字(英)	★ p53 ★ leukemia ★ Cell-penetrating
論文目次	中文摘要 I Abstract II Declaration III Acknowledgement IV Publications arising from this thesis V Table of Contents VI List of Figures IX List of Tables X Abbreviations XI Chapter I. General Introduction 1 1.1 General introduction to TP53 gene 1 1.1.1 The brief history of p53 1 1.1.2 The functional domain of p53 2 1.1.3 p53 maintains genomic integrity 3 1.1.4 Mutant TP53 4 1.1.5 p53 and zinc ions 5 1.1.6 Epithelial-mesenchymal transition and p53 6 1.1.7 p53 and hematologic malignancies 6 1.1.8 p53-related gene therapy 7 1.1.8.1 Gendicine 7 1.1.8.2 Oncorine (H101) 9 1.2 General introduction to traditional cancer therapy for hematologic malignancies 10 1.2.1 Radiotherapy 10 1.2.2 Chemotherapy 11 1.2.3 Targeted therapy 11 1.3 General introduction to modern cancer therapy for hematologic malignancies 12 1.3.1 Hematopoietic stem cell transplantation 12 1.3.2 Cellular therapy 12 1.3.3 Cell-based gene therapy 13 1.3.3.1 Zalmoxis 14 1.3.3.2 Kymriah (tisagenlecleucel) 15 1.3.3.3 Yescarta (Axicabtagene Ciloleucel; axi-cel) 17 1.3.3.4 Tecartus (brexucabtagene autoleucel) 18 1.3.3.5 Breyanzi (lisocabtagene maraleucel) 19 1.3.3.6 Abecma (Idecabtagene vicleucel) 19 1.4 Introduction to current in vitro cancer gene therapy products 20 1.4.1 Rexin-G 21 1.4.2 Imlygic (T-VEC) 22 1.4.3 Rigvir (ECHO-7) 24 1.5 Introduction to protein transduction platform 25 1.6 Aim of this thesis 26 Chapter II. Materials and methods 29 Plasmids 29 Cell Lines and cell culture 29 Protein expression and purification 30 Protein oligomerization assay 31 Electrophoretic mobility shift assay (EMSA) 31 M3-p53-R12 transduction ability and translocation analysis 32 MTT assay 32 Annexin V /PI apoptosis detection 33 Soft agar assay 33 Mesenchymal stem cell (MSC) isolation and culture 33 Pick up reporter stable clones from soft agar 34 Busulfex® conditioning in NOD-SCID mice 34 Statistical analysis 34 Chapter III. Results 36 3.1 Small scale expression and solubility test of chimeric p53 proteins 36 3.2 Purification strategy of chimeric proteins in this study 37 3.3 Characterization of the refolded M3-p53-R12 protein 37 3.3.1 No interchain disulfide bond was formed during the M3-p53-R12 protein purification 37 3.3.2 Purified M3-p53-R12 protein has oligomerization potency 38 3.3.3 Purified M3-p53-R12 protein retains its DNA binding ability 38 3.3.4 Purified M3-p53-R12 protein could penetrate through the cell membrane and import to the nucleus 39 3.3.5 Durable stability analysis of purified M3-p53-R12 protein 39 3.4 M3-p53-R12 protein is cytotoxicity to p53 mutant cancer cell line 40 3.5 M3-p53-R12 has cytotoxic effect on leukemia cell lines 41 3.6 M3-p53-R12 has an apoptotic effect on leukemia cell lines 42 3.7 M3-p53-R12 protein suppresses leukemia cell proliferation 42 3.8 M3-p53-R12 protein has no apoptotic effect on normal cells 43 3.9 Jurkat-GFP and K-562-GFP stable cell lines can be used for tracking 43 3.10 In vitro analysis of fluorescence leukemia cell lines for preliminary study 44 3.11 The hematopoietic malignancy xenograft mouse model had developed 45 3.12 M3-p53-R12 protein is highly sensitive to enzymes in the plasma 47 3.13 Proline-endopeptidase and thrombin may be involved in the degradation of M3-p53-R12 protein in plasma 47 Chapter IV. Discussion and Conclusion 49 References 58 Figures 75 Tables 113 Appendices 116 Appendix A. The brief timeline and main findings of the p53 research. 116 Appendix B. Schematic diagram for the location and functional domain of p53. 117 Appendix C. Schematic diagram for the functional domain and PTM sites of the p53 protein 118 Appendix D. Schematic diagram for the p53-MDM2 negative feedback loop 119 Appendix E. TP53 mutations prevalence in sporadic cancers 120 Appendix F. Global cancer statistical analysis in 2020 121 Appendix G. Protein identification report of the N-terminal peptide sequencing of purified protein fragments. 123
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指導教授	陳盛良劉俊揚(Shen-Liang Chen Jun-Yang Liou)	審核日期	2021-10-4
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