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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 張智芬 | |
dc.contributor.author | Sui-Chih Tien | en |
dc.contributor.author | 田穗稺 | zh_TW |
dc.date.accessioned | 2021-06-16T13:32:29Z | - |
dc.date.available | 2013-09-24 | |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-07-19 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62184 | - |
dc.description.abstract | 過去的研究顯示當Shp2失去調節時會造成ERK高度活化而使細胞生長異常,我的實驗發現表現致癌性Shp2會降低微小管的穩定度而使ERK活化。將HDAC6基因靜默或加強RhoA-Dia訊息皆可以增加微小管的穩定度避免致癌性Shp2所引發的ERK高度活化,而且也會減緩細胞的增生。我的結果證實致癌性Shp2可藉由降低RhoA-Dia-EB1的訊息路徑促使HDAC6所調控的微小管乙醯化減少,進而影響ERK的調節。研究機制的結果指出:在血清的刺激反應下,致癌性Shp2可維持ERK的活化但不影響ERK活化的程度。同樣地,抑制HDAC6可降低ERK持續活化的情形。在人類癌症細胞中抑制Shp2或HDAC6也一樣可以增加微小管的乙醯化並降低ERK磷酸化。重要的是抑制Dia即可恢復Shp2受抑制時所產生的影響,這證實微小管的調控在致癌過程中扮演著關鍵的角色。
此外,表現致癌性Shp2可以損害上皮細胞的方向性與正常囊腔的形成,這不僅與ERK高度活化有關,ROCK的高度活化也參與其中,而且同時將ROCK與ERK活性抑制即可增加微小管的乙醯化並恢復其細胞的方向性;不論是單獨抑制HDAC6或增加Dia表現也可恢復細胞的方向性。我們先前的研究指出:Shp2將ROCKII Y722去磷酸化後可增加ROCK與RhoA的親合力,因此,致癌性Shp2不僅可以增加RhoA-ROCK也同時降低RhoA-Dia訊息。在此研究中,我發現當ROCKII Y722失去磷酸化時,細胞會表現出與致癌性Shp2相同的不正常現象,而這些現象也皆可透過增加微小管乙醯化而被恢復。根據這些觀察,我們推測致癌性Shp2在細胞生長與形態發育所引起的異常可能是由於ROCK/Dia訊息失去平衡所導致。 | zh_TW |
dc.description.abstract | Deregulation of Shp2, a non-receptor tyrosine phosphatase, causes hyper-activation of extracellular signal-regulated kinase (ERK), leading to growth abnormality. I found that oncogenic Shp2 expression decreased microtubule (MT) stability to up-regulate ERK activation. Silencing of histone deacetylase 6 (HDAC6), or enforcing RhoA-Dia (Diaphanous) signal to increase MT stability prevented oncogenic Shp2-induced ERK hyper-activation and slowed down cell proliferation. I provided evidence that down-regulation of RhoA-Dia-EB1 (end-binding 1) pathway by oncogenic Shp2 leaded to HDAC6-mediated reduction in MT acetylation, in turn affecting ERK regulation. The mechanistic study indicated that oncogenic Shp2 sustained ERK activation in response to serum stimulation rather than affecting the magnitude of ERK activation. Consistently, HDAC6 inhibition diminished sustained activation of ERK. Accordingly, blocking Shp2 or HDAC6 inhibition in human cancer cells increased MT acetylation and decreased ERK phosphorylation. Importantly, inhibition of Dia was sufficient to overcome Shp2 inhibition effects, supporting that MT regulation as a key that mediates the oncogenic process.
In addition, expression of oncogenic Shp2 was sufficient to impair epithelial polarity and normal lumen formation, which was not only associated with ERK but also Rho-associated kinase (ROCK) hyper-activation. Simultaneous inhibition of ROCK and ERK elevated MT acetylation with cell polarity restoration. Either inhibition of HDAC6 or elevation of Dia expression also rescued cell polarity phenotype. We have previously reported that ROCK dephosphorylated at Y722 by Shp2 increases its affinity to RhoA. Therefore, gain-of-function of Shp2 might increase RhoA-ROCK while attenuating RhoA-Dia. In this study, I found that the loss of ROCKII Y722 phosphorylation recapitulated all abnormal phenotypes that could be rescued through increasing MT acetylation as seen in cells expressing oncogenic Shp2. Based on these observations, we hypothesize that it is the imbalance of ROCK/Dia signal responsible for oncogenic Shp2-induced abnormalities in growth and morphogenesis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T13:32:29Z (GMT). No. of bitstreams: 1 ntu-102-D94442005-1.pdf: 7490017 bytes, checksum: 2a5a5a7c6b50d19e2b7405452c358eb6 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員審定書………………………………………………………………………i
中文摘要……………………………………………………………………………....ii Abstract…………………………………………………………………………….....iii Table of contents…………………………………………………………………...…iV Chapter I - Rationale and Overview…………………………………………….…..…1 Rationale of this research…………………………………………………………….2 Part I : The role of Shp2 in Ras/Raf/ERK pathway……………………………….....3 Part II : The RhoA GTPase signaling pathway……………………………………....5 Part III : Microtubule dynamics and modification…………………………………...7 Chapter II – Oncogeneic Shp2 disturbs microtubules regulation to cause HDAC6- dependent ERK hyper-activation……………………………………….10 Introduction…………………………………………………………………………11 Materials and Methods……………………………………………………………...12 Results……………………………………………………………………………....14 Discussions…………………………………………………………………….……18 Figures and Legends…………..……………………………………………………20 Chapter III - Epithelial polarity requires Shp2-regulated MT stability………………35 Introduction…………………………………………………………………………36 Materials and Methods…………………………………………………………...…38 Results…………………………………………………………………………..…..40 Discussions………………………………………………………………………….44 Figures and Legends……………………………..…………………………………46 References……………………………………………………………………………59 Appendix……………………………………………………………………………..67 | |
dc.language.iso | en | |
dc.title | RhoA訊息與微小管穩定性在致癌性Shp2引發上皮細胞損害之探討 | zh_TW |
dc.title | The involvement of RhoA signaling and microtubule stability in oncogenic Shp2-induced epithelial defects | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 張明富 | |
dc.contributor.oralexamcommittee | 李芳仁,陳瑞華,周祖述 | |
dc.subject.keyword | 微小管,蛋白酪氨酸磷酸?組蛋白去乙醯化?, | zh_TW |
dc.subject.keyword | microtubule,Shp2,RhoA,ROCK,Dia,HDAC6, | en |
dc.relation.page | 67 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-07-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
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ntu-102-1.pdf 目前未授權公開取用 | 7.31 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。