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研究生:錢家珍
研究生(外文):Chia-Chen Chien
論文名稱:α微管轉譯後修飾在細胞中的分佈與功能
論文名稱(外文):Distribution and functional characterization of post-transtionally modified α-tubulin
指導教授:林奇宏林奇宏引用關係林奇宏林奇宏引用關係
指導教授(外文):Chi-Hung LinChi-Hung Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生醫光電工程研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:69
中文關鍵詞:微管修飾
外文關鍵詞:tubulinmodification
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微管是細胞骨架組成之一,其構形可隨細胞生理功能調整,具高度動態。除維持細胞形狀外,微管還作為動力蛋白的運送軌道,提供蛋白質結合,幫助染色體分配至子細胞等。真核細胞微管由α及β兩個次單元組成中空管狀,直徑約 25 nm,自 1970 年代便陸續發現其帶有多種轉譯後修飾,這些修飾主要存在α微管次單元,且多數是可逆的;其中發生頻率較高的包括 acetylation、poly-glutamylation、tyrosination、detyrosination、Δ2 modification,除 acetylation 發生在 Lys40 外,其餘均發生在接近 C 末端;不同轉譯後修飾可能改變微管與不同蛋白的親和力,藉以從事相關細胞生理功能。
本實驗利用人類細胞株 HeLa 作為模型,觀察四種發生頻率較高的修飾形式在細胞中的分佈,並觀察在細胞中大量表現突變的α微管對細胞的影響。間期細胞中 Ac-Tu、Tyr-Tu、Glu-Tu 在均呈許多由中心體向外延伸的長線條,細胞核中幾乎沒有,其中 Ac-Tu 及 Glu-Tu 在中心體附近稍微較聚集,Δ2-Tu 則呈細小點狀散佈細胞質及細胞核中,且並未連成線條,但在 lipid droplet 外圍似有聚集。細胞分裂初期 (prophase 至 prometaphase),Tyr-Tu 存在新生紡錘絲較末端,Ac-Tu 及 Glu-Tu 則存在近中心體部分,進入 metaphase 時,Tyr-Tu 主要存在星狀微管,部分存在紡錘絲,而 Ac-Tu 及 Glu-Tu 主要存在紡錘絲,Δ2-Tu 在細胞分裂過程仍為細小點狀散佈細胞中。冷處理或 nocodazole 處理後,殘留線條多帶 acetylation,中心體可見 Ac-Tu 或 Tyr-Tu 組成的圓圈狀結構,或 Glu-Tu 聚集但不呈明顯圈狀,利用西方墨點轉漬法檢驗則發現 Ac-Tu 隨冷處理時間增加或 nocodazole 濃度提高而迅速減少,其他三種形式差異不大。
在細胞中大量表現帶綠螢光蛋白的修飾形式α微管,不論模擬何種修飾者,表現後分佈均無明顯差異。大量表現後觀察細胞內粒腺體及溶酶體,結果在分佈、外形、數量上均無顯著差異,但大量表現帶 Lys40 突變時,細胞增殖較慢,且較多細胞帶有多套紡錘絲,這些細胞於 prometaphase 至metaphase 的時間大幅延長,且多數無法通過 metaphase 便死亡。利用免疫沉澱法得到 Ac-Tu 後,經西方墨點轉漬法檢驗這些產物的 C 末端,發現 Tyr-Tu 於沉澱產物中明顯減少,而 Glu-Tu 及Δ2-Tu 則提高。
Microtubule, a major component of cytoskeleton, is highly dynamic in response to its function. In eukaryotes, α and β tubulin heterodimer constitutes this hollow tube 25 nm in diameter. Since 1970s, post-translational modifications have been identified on α tubulin in which acetylation, poly-glutamylation, tyrosination, detyrosination, and Δ2 modification are more frequent and the formor three are reversible. Except Lys40 acetylation, other high frequency modifications occur near the C terminal tail. Different modifications might alter the affinity of tubulin to a variety of proteins in order to facillate specific functions.
We took a human cell line – HeLa as the model to study endogenous distribution of four major modifications and monitor the effect of overexpressing modified or mutant α tubulin. In interphase cells, Ac-Tu, Tyr-Tu, and Glu-Tu were in general filamentous-like outgrowing from the centrosome and almost absent in the nucleus. Ac-Tu and Glu-Tu were more accumulated near the centrosome. In contrast, Δ2-Tu speckled the cytoplasm and the nucleus but not forming noticeable filament. Fluorescence microscopy also showed Δ2-Tu signal surrounded lipid droplets. During M phase, Ac-Tu and Glu-Tu existed in the mitotic spindle while Tyr-Tu in the astral tubulin. After treated with cold or nocodazole, residual filaments were mostly composed of Ac-Tu and Glu-Tu and the clear circular structure of centromere was detected by Ac-Tu and / or Tyr-Tu antibody. By using Western Bloting, only Ac-Tu decreased dramatically after short-term cold or nocodazole treatment.
18 modified or mutant α tubulin were constructed and overexpressed in HeLa. Distributions of all these overexpressed forms were almost identical, which also indicated that overexpressing modified form does not totally mimic the same exdogenous modified form at least in distribution; the distribution, morphology, and quantity of mitochondria and lysosome were neither obviously affected. When overexpressing α tubulin with Lys40 mutantation, cell proliferation was noticeably decreased. Some of these cells contained multiple mitotic spindles at M phase, stocked in prometaphase, and died before metaphase. By using immunoprecipitation pulling down Ac-Tu and analysed its C terminal modification, Glu-Tu and Δ2-Tu enriched while Tyr-Tu decreased.
中文摘要 1
英文摘要 2
前言 4
材料與方法 17
結果 22
討論 29
圖與表 35
參考資料 62
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