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標題: | 類固醇轉錄因子SF-1對中心體複製調控機制之研究 The Role of Steroidogenic Factor 1 in Regulating Centrosome Homeostasis |
作者: | Chia-Yih Wang 王家義 |
指導教授: | 張文章(Wen-Chang Chang) |
關鍵字: | 中心體,類固醇,轉錄因子,細胞週期,基因組損傷, centrosome,SF-1,DNA-PK,Akt,DNA damage, |
出版年 : | 2011 |
學位: | 博士 |
摘要: | DNA損傷監控蛋白 (DNA damage checkpoint protein) 表現在細胞核以及中心體。這些損傷監控蛋白在細胞核中負責維持基因組的完整性;但是他們在中心體的功能卻仍不清楚。在本篇研究中發現,有一種稱之為DNA-PK的損傷監控蛋白不僅存在於中心體,而且還負責調控中心體的複製。在腎上腺皮質癌細胞中,DNA-PK的活性是受到SF-1 (NR5A1)所抑制。SF-1透過與DNA-PK的次單元Ku70/80結合,使得Ku70/80無法與DNA-PK的催化單元(DNA-PKcs)結合,進而抑制DNA-PK的活化。
當SF-1的表現被shRNA所抑制時,會導致中心體內的DNA-PK異常活化,進而活化其下游的Akt訊息傳導路徑。被活化的Akt訊息傳導路徑會導致 DNA damage checkpoint proteins reside in the nucleus and the centrosome. In the nucleus, they maintain genomic integrity; however, their function in the centrosome remains unclear. Here I show that one such checkpoint protein, DNA-PK, controls centrosome duplication. In adrenocortical Y1 cells, DNA-PK activity is inhibited by SF-1 (NR5A1), which interacts with and sequesters Ku70/Ku80 from DNA-PK catalytic subunit in the centrosome. Following SF-1 depletion by shRNA, centrosomal DNA-PK was aberrantly activated, triggering centrosomal Akt (PKB) signaling, leading to accumulation of β-catenin and Cyclin A/CDK2 in the centrosome, causing centriole splitting and over-duplication. SF-1 depletion did not, however, induce DNA damage response and Akt signaling in other cellular compartments. Inhibition of DNA-PK/Akt in HeLa, U2OS, and H1299 cells also blocked centrosome over-duplication upon replication stress. I have, thus, uncovered a novel function of DNA-PK/Akt signaling in controlling centrosome duplication. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48102 |
全文授權: | 有償授權 |
顯示於系所單位: | 生化科學研究所 |
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