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系統識別號 U0026-0302202113101100
論文名稱(中文) 探討調控中心體功能以及初級纖毛生長的機制
論文名稱(英文) To investigate the regulatory mechanism of centrosome function and primary cilia formation
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 109
學期 1
出版年 110
研究生(中文) 陳亭羽
研究生(英文) Ting-Yu Chen
學號 S58041030
學位類別 博士
語文別 英文
論文頁數 137頁
口試委員 指導教授-王家義
口試委員-唐堂
召集委員-盧福翊
口試委員-劉校生
口試委員-黃柏憲
中文關鍵字 Septin7  微管  細胞遷移  DNA依賴性蛋白  p53  初級纖毛  自噬作用  基因毒性  基因損傷反應 
英文關鍵字 Septin7  microtubule nucleation  migration  DNA-PK  p53  primary cilium  autophagy  genotoxic stress  DNA damage response 
學科別分類
中文摘要 中心體由一對中心粒組成包含一個母中心粒以及子中心粒,並且被中心粒周圍的物質所包圍,中心體對於細胞生長、微管的架構以及初級纖毛的生長都扮演非常重要的角色,因此我們的研究想要探討可能機制以及環境條件下調控中心體的功能。
在第一個部分,我們檢視Septin 蛋白如何調控中心體的功能。Septin是一個具GTP結合位的蛋白質,已經知道對於許多生理以及病理機制上扮演重要的角色,Septin家族由十三種Septin蛋白所構成,並分成四個分組,藉此調控Septin骨架的形成,在這些蛋白中只有Septin7是獨一無二且無法被取代的,先前研究提到當小鼠產生Septin7基因受損時會導致小鼠胚胎早期的死亡,另外文獻中也提到Septin7 對於初級纖毛的生長是重要的,並且會位在初級纖毛的底部,因此我們證明Septin7是一個中心體蛋白並且可以調控細胞週期的進程以及維持有絲分裂產生的紡錘體,當Septin7缺損的情況下,會導致微管架構的失敗以及細胞移動的能力受損,而Septin7會與P150蛋白結合,並且幫助維持細胞週期的進程以及微管的架構,因此Septin7對於調控中心體的功能扮演重要的角色。另外,我們也探討了基因損傷下對於不正常的中心體形成以及初級纖毛的生長機制。當細胞遭受基因損傷的威脅,會誘發一連串的訊息調控藉此幫助受損的基因進行修補,這些基因的損傷會導致不正常的中心體發生,研究中我們探討長期低濃度的基因損傷藥物會如何影響中心體的功能,在這樣的刺激下,cyclin A/CDK2 and ERK1/2 會不正常的活化導致導致中心體過度的複製,此外也發現細胞的自噬作用會被活化,當我們抑制了細胞的自噬作用,可以抑制由長期損傷所導致的中心體過度複製的現象,我們證明抑制自噬作用的活化可以有效抑制由藥物所誘發的中心體過度複製現象,繼而可以避免基因組的不穩定以及癌症的發生。
此外在我們的研究中發現基因毒性產生會活化DNA-PK-p53的訊號,並促使初級纖毛的生長,我們利用會產生基因毒性的不同藥物刺激細胞,發現不論在人類視網膜上皮細胞、滋養層細胞、肺癌細胞以及老鼠萊式前驅細胞都會誘發初級纖毛生成,當細胞遭受藥物誘發基因毒性攻擊,會活化許多下游的訊息傳遞,但只有DNA-PK-p53的訊號會參與在初級纖毛的生長中,抑制或去除DNA-PK-p53的訊號會減少由基因毒性所誘發的初級纖毛。此外誘發基因毒性的藥物也會刺激細胞的自噬作用,抑制自噬作用的初始作用以及溶酶體的降解作用會減少由基因毒性所誘發的初級纖毛。此外透過去除初級纖毛基因IFT88或CEP164抑制初級纖毛的生長會減少由基因毒性所活化的DNA損傷反應的訊號。在本研究中呈現了由基因毒性活化的DNA-PK-p53的訊號以及細胞的自噬作用會刺激初級纖毛的生長,並且這些初級纖毛可維持DNA損傷反應的訊息傳遞。
英文摘要 The centrosome consists a pair of centriole, a mother centriole and a daughter centriole, and surrounding by pericentriolar material. It plays important roles in cell division, microtubule nucleation, and ciliogenesis. Thus, we examined the possibility of the mechanism or conditions can regulate centrosomal functions such as cell division, microtubule nucleation, centrosome homeostasis, and ciliogenesis.
In part I, we investigated the role of Septin7-regulated centrosomal functions. Septins are GTP-binding proteins play numerous roles in physiological and pathological development. Septins are composed of 13 genes and divided to the four sub groups for cytoskeleton assembly. Only Septin7 is unique and irreplaceable. Recent studies show that the defect of Septin7 cause the embryo lethal in mice model. Septin7 is also required for primary cilium formation and localizes to the mother centriole. Here, we showed that Septin7 is a centrosome protein to maintain the S phase entry and mitotic spindle poles. In addition, depletion of Septin7 leads to disorganized microtubule arrays and defective directional migration. Furthermore, Septin7 interacts with the subunit of dynactin complex p150glued. Taken together, our findings indicated that Septin7 regulated the abundance of p150glued for proper cell cycle progression and microtubule array nucleation, Septin7 seems to link these two biological events at the centrosome.
In part II, we investigated the mechanism of DDR-regulated centrosome amplification and ciliogenesis. When cells suffer from the genotoxic stress, it causes the damaged DNA to trigger the DNA damage response then several signaling pathways are activated to repair the damaged DNA. The defect of nuclear events cause the centrosome homeostasis. Here we showed that we checked the effect of sublethal dose of ETO in adrenal cortical tumor cells. Under this stress condition, cyclin A/CDK2 and ERK1/2 were aberrantly activated for centrosome amplification. In addition, autophagy was still activated. Inhibition by autophagy inhibitor, chloroquine, inhibited ETO-induced centrosome amplification. It demonstrated that chloroquine inhibited DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrent cancer.
In addition, DNA-PK-p53 cascade induced primary cilia formation (ciliogenesis) under genotoxic stress. Treatment with genotoxic drugs led to ciliogenesis in human retina (RPE1), trophoblast (HTR8), and lung (A459) and mouse Leydig progenitor (TM3) cell lines. Upon genotoxic stress, several DNA damage signaling pathways were activated, but only the DNA-PK-p53 cascade contributed to ciliogenesis. In addition, genotoxic stress induced autophagy. Inhibition of autophagy initiation or lysosomal degradation or depletion of ATG7 decreased genotoxic stress-induced ciliogenesis. Furthermore, inhibition of ciliogenesis by depletion of IFT88 or CEP164 attenuated the genotoxic stress-induced DNA damage response. Our study showed that genotoxic stress-activated DNA-PK-p53 cascade and autophagy induced ciliogenesis and which maintained the DNA damage response under genotoxic stress.
論文目次 學位考試合格證明………………………………………………………I
摘要…………………………………………………… II
Abstract…………………………………………...IV
Acknowledgement………………………...VI
Table of Contents………………………………………VII
List of Figures…………………………........X
Abbreviations…………………………………………XIV
Chapter 1: Introduction………………………………..1
1.1 Centrosome structure and function………………………………..1
1.2 Septin structure and function……………………………...5
1.3 Primary cilia structure and function……………….…………....7
1.4 DNA damage responses regulates centrosome homeostasis…13
Chapter 2: Objective and Specific Aims……………………….19
Chapter 3: Materials and Methods…………………………………………..25
3.1 Cell culture…………………….………..25
3.2 Drug treatments………………………………....25
3.3 Immunostaining…………………………………….26
3.4 Immunoblotting………………………………………….26
3.5 MTT assay…………………………………………….27
3.6 EdU incorporation assay…………………….……...27
3.7 Microtubule nucleation assay……………………………………27
3.8 RNA interference (RNAi)……………………………….....27
3.9 Lentivirus………………………………………………….....28
3.10 Antibodies………………………………………………………....29
3.11 Statistical analysis……………………………………………....30
Chapter 4: Results……………………………………………………....31
Part I
Aim 1: To investigate the mechanism of Sentin7-regulated centrosomal functions during the embryo development.
4.1 Septin7 is required for S phase entry………………………..31
4.2 Septin7 is the centrosome targeting protein………………32
4.3 Septin7 maintains mitotic spindle and cell migration……33
4.4 Septin7 is required for the microtubule nucleation……….35
4.5 Septin7 is required for the microtubule nucleation via maintaining the expression of the p150glued protein…………….35
Aim 2: To examine the effects of the sub lethal dose of genotoxic stress-induced centrosome amplification to promote the recurrent cancer in adrenal cortical tumor cells.
4.6 Etoposide inhibits adrenal cortical growth………………………….38
4.7 ETO induces centrosome amplification by activating cyclin A/CDK2, Chk2 and ERK1/2……………………………………………………………………39
4.8 Chloroquine alleviates DNA damage-induced centrosome amplification in ACT and osteosarcoma cells…………………………...41
Part II
Aim 3: To investigate the effects of genotoxic stress on ciliogenesis in cells.
4.9 Genotoxic drug ETO induced ciliogenesis in all the tested cell lines…………………43
4.10 ETO-triggered DNA-PK activation contributed to ciliogenesis………………………45
4.11 Genotoxic drugs-triggered DNA-PK activation contributed to ciliogenesis…………47
4.12 ETO-induced AKT or P53 activation contributed to ciliogenesis……………………48
4.13 ETO-induced autophagy promoted ciliogenesis……………………….49
4.14 ETO-induced ciliogenesis maintained DNA damage response…51
4.15 ETO induced two independent pathways contributed to ciliogenesis………………..52
Chapter 5: Discussion………………………………..55
Chapter 6: Conclusion…………………………….58
Chapter 7: References……………………....62
Chapter 8: Figures…………………………………68
Chapter 9: Publication……………………...136
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