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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張文章(Wen-Chang Chang) | |
dc.contributor.author | Chia-Yih Wang | en |
dc.contributor.author | 王家義 | zh_TW |
dc.date.accessioned | 2021-06-15T06:46:16Z | - |
dc.date.available | 2011-07-06 | |
dc.date.copyright | 2011-07-06 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-06-20 | |
dc.identifier.citation | References
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48102 | - |
dc.description.abstract | 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 | zh_TW |
dc.description.abstract | 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. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T06:46:16Z (GMT). No. of bitstreams: 1 ntu-100-F92b46029-1.pdf: 2625445 bytes, checksum: b3e98359ada6e915eefcea2dc2c59b21 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | Contents
論文口試委員審定書 …...…………………………………………………………. I Acknowledgement ………………………………………………………………...... II Chinese abstract ……………………………………………………………………. III English abstract …………………………………………………………………….. IV Abbreviations ……………………………………………………………………….. V Introduction A. The function of centrosome. …………………………………………… 1 B. Regulation of centrosome duplication. ………………………………... 1 C. Coordination of DNA damage with centrosome homeostasis. ………. 3 D. The function of SF-1. ………………………………………………….... 4 Results Part A, SF-1 controls centrosome duplication and configuration. A1, SF-1 resides in the centriole. …………………………………………... 6 A2, Overexpression of SF-1 prevents centrosome amplification but does not affect normal centrosome duplication. ……………………………….. 6 A3, SF-1 depletion induces centrosome over-duplication in a CyclinA/CDK2 dependent manner. ……………………………………………………... 7 A4, SF-1 depletion induces centriole splitting and increases centrosomal B-catenin level. …………………………………………………………. 10 Part B, SF-1 interacts with Ku in the centrosome and regulats centrosomal DNA-PK/Akt signaling. B1, SF-1 interacts with Ku70/80 in the centrosome but not in the nucleus. ..11 B2, Centrosome over-duplication and splitting following SF-1 depletion depends on DNA-PK. ………………………………………………….. 12 B3, SF-1 depletion activates centrosomal DNA-PK/Akt signaling. ……… 13 B4, SF-1 depletion does not activate DNA damage response. ……………. 14 Part C, Activation of DNA-PK/Akt signaling induces centrosome over-duplication upon replication stress in SF-1 negative cells. C1, Aberrant activation of DNA-PK/Akt signaling induces centrosome over-duplication upon replication stress in SF-1-negative cells. ……. 15 C2, DNA-PK facilitates centrosome amplification, while ATM/ATR maintain nuclear integrity during replication stress. …………………………... 16 Discussion A. Activation of DNA-PK induces centrosome amplification upon replication stress. …………………………………………………………………….. 17 B. Coordination between the nuclear and centrosomal DNA damage response proteins. ………………………………………………………………….. 18 C. DNA-PK/Akt signaling controls centrosomal CDK2. ………………… 19 D. DNA-PK/Akt/GSK3β signaling maintains centriole configuration by controlling centrosomal β-catenin in Y1 cells. ………………………… 19 E. DNA-PK is inhibited by SF-1 in steroidogenic cells. ………………….. 20 F. Cell type-specific centrosome regulation and composition. …………... 21 MATERIAL AND METHODS …………………………………………………... 23 References ………………………………………………………………………… 28 Figures …………………………………………………………………………….. 35 Tables ……………………………………………………………………………… 66 Autobiography ……………………………………………………………………. 67 Publication list ……………………………………………………………………. 68 | |
dc.language.iso | en | |
dc.title | 類固醇轉錄因子SF-1對中心體複製調控機制之研究 | zh_TW |
dc.title | The Role of Steroidogenic Factor 1 in Regulating Centrosome Homeostasis | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 鍾邦柱(Bon-chu Chung) | |
dc.contributor.oralexamcommittee | 唐堂(Tang-K Tang),張智芬(Zee-Fen Chang),陳瑞華(Ruey-Hwa Chen) | |
dc.subject.keyword | 中心體,類固醇,轉錄因子,細胞週期,基因組損傷, | zh_TW |
dc.subject.keyword | centrosome,SF-1,DNA-PK,Akt,DNA damage, | en |
dc.relation.page | 68 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-06-21 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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