臺灣博碩士論文加值系統

非整倍體主要是因為染色體分離機制產生問題所導致的，它也為人類腫瘤常見的特徵。但相反的，非整倍體會產生一些有害細胞生長的改變，包括干擾細胞訊息的傳遞、改變細胞代謝、影響蛋白質平衡、以及增加蛋白毒性壓力，甚至造成細胞的死亡。因此我們要探討轉型的細胞是如何應對異常有絲分裂所帶來的生存逆境，使細胞得以持續存活、增生。本研究以過度表現aurora kinase B (AURKB) 的細胞作為異常有絲分裂的細胞模式，觀察熱休克逆境反應是否幫助異常有絲分裂細胞的存活，而在這之中扮演什麼角色。實驗結果顯示過度表現AURKB會導致微管動態異常，誘導偽雙極紡錘體、偽雙極細胞分裂、及多核細胞的形成。若以GF-15抑制中心體叢集，則會減少偽雙極紡錘體，增加多極紡錘體，顯示過度表現AURKB可能會促進中心體叢集，而導致偽雙極紡錘體的產生。此外，發現過度表現AURKB會增加γ-tubulin、NEDD1、NuMA這三個參與中心體功能的蛋白質於紡錘極的累積，因此推論過度表現AURKB可能透過增加中心體蛋白質，促進中心體叢集，誘導偽雙極紡錘體形成。過度表現AURKB也會誘導HSF1轉錄活性和HSP70表現增加，從免疫螢光染色也可以看到HSP70在過度表現AURKB的細胞中於紡錘極的累積增加。降低HSP70表現則會使偽雙極紡錘體減少，增加多極紡錘體，並且也會導致NEDD1和γ-tubulin於紡錘極的累積降低。由以上結果說明，過度表現AURKB 可能會透過HSP70調控NEDD1和γ-tubulin於紡錘體的累積，促進中心體叢集，使細胞形成偽雙極紡錘體，進行偽雙極細胞分裂，來克服異常有絲分裂，幫助細胞能夠持續存活。

Aneuploidy, mainly resulting from defects in chromosome segregation machineries, is a common feature of human tumors. Conversely, aneuploidy deleteriously alters cell growth by impairing cellular signaling, metabolism, and protein homeostasis, inducing proteotoxic stresses, and leading to cell death. In the present study, we explore how the transformed cells respond to aberrant mitosis to maintain cell survival and proliferation. Overexpression of aurora kinase B (AURKB) resulted in altered microtubule dynamics and induced the formation of pseudo-bipolar spindle, pseudo-bipolar cell division, and multi-nucleated cell. In addition, treatment of cells overexpressing AURKB (AURKB-T1) with GF-15, an inhibitor of centrosome clustering, significantly reduced the percentage of cells undergone pseudo-bipolar cytokinesis and increased that with multipolar mitotic spindles, indicating that overexpression of AURKB may promote centrosome clustering to facilitate pseudo-bipolar spindle formation. In addition, the spindle pole accumulation of γ-tubulin, NEDD1, and NuMA was also significantly increased in AURKB-T1 cells. Overexpression of AURKB significantly increased HSF1 transactivation activity and HSP70 expression. The spindle pole accumulation of HSP70 was also increased in AURKB-T1 cells. Depletion of HSP70 not only decreased γ-tubulin and NEDD1 expression at spindle pole but decreased the percentage of mitotic cells with pseudo-bipolar spindle and increased that with multipolar spindles in AURKB-T1 cells. These results indicated that HSP70 may mediate NEDD1 and γ-tubulin accumulation at the spindle pole and promote centrosome clustering in AURKB-T1 cells, leading to the assembly of pseudo-bipolar spindles and pseudo-bipolar cell division to facilitate the survival of cells experiencing aberrant mitosis.

目錄
致謝 I
中文摘要 II
英文摘要 IV
目錄 V
圖目錄 VII
第一章 前言 1
第一節 研究背景 1
1. 不正常的有絲分裂 1
2. Aurora B激酶 2
3. 熱休克逆境反應 4
4. 細胞自噬 6
第二節 研究目的 9
第二章 研究方法 10
第一節 研究設計 10
第二節 研究材料 11
第三節 實驗方法 17
第三章 研究結果 28
第一節 熱休克逆境反應和細胞自噬對於基因完整性的影響 28
第二節 過度表現AURKB會促進中心體分離，抑制紡錘體重新組裝 29
第三節 過度表現AURKB可能透過抑制微管聚合及促進微管解聚，導致微管成核受抑制 30
第四節 過度表現AURKB會誘導偽雙極紡錘體分裂及多核細胞的形成 31
第五節 過度表現AURKB可能透過促進中心體叢集，導致偽雙極紡錘體的形成 32
第六節 過度表現AURKB不會增加細胞自噬，但會增加HSF1的轉錄活性及HSP70的mRNA及蛋白質的表現量 33
第七節 降低AURKB-T1細胞內的HSP70或HSF1會抑制偽雙極紡錘體的形成 34
第八節 降低AURKB-T1細胞內HSP70會增加有絲分裂干擾藥物對細胞的毒性 35
第四章 討論 37
第五章 結論與建議 44
第一節 結論 44
第二節 建議 44
圖表 45
參考文獻 67
 

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