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研究生:林秋宏
研究生(外文):Chiou-Hong, Lin
論文名稱:TACC3透過Aurora-A的磷酸化調控紡錘體穩定性的機制
論文名稱(外文):The mechanism of Aurora-A-mediated TACC3 phosphorylation in regulating mitotic spindle stability
指導教授:施修明
指導教授(外文):Hsiu-Ming, Shih
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:55
中文關鍵詞:紡錘體
外文關鍵詞:SpindleTACC3Clathrin
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中文摘要
在細胞分裂的過程中,形成良好排列的紡錘體對於能否正確分配已複製的染色體到二個子細胞中扮演相當關鍵的角色。然而,要形成穩定排列、具有正確兩極結構的紡錘體,需要許多蛋白質的參與。Aurora-A是一個相當重要的激酶,它可藉由磷酸化數個參與調節紡錘體形成的蛋白質來幫助維持遺傳物質的恆定。其中,TACC3便是需要Aurora-A的磷酸化修飾,才能正確的座落在紡錘體上並發揮穩定紡錘體的功能。TACC3可將與其結合的ch-TOG帶到紡錘體上。憑藉著ch-TOG促進紡錘絲聚合的能力,TACC3-ch-TOG複合體得以幫助形成穩定的紡錘體結構。在果蠅及牛蛙的系統中,TACC3如何透過Aurora-A的磷酸化來調節紡錘體的功能已有深入的研究。然而,我們並不了解TACC3究竟是經由何種機制來調控它與紡錘體形成連結。在本篇論文當中,我們利用含有Aurora-A磷酸化的胺基酸的TACC3蛋白質片段來搜尋可能參與此調控的蛋白質。經由質譜儀分析的結果,我們發現一個參與胞膜運輸的蛋白質在此過程中扮演著相當重要的角色。被Aurora-A磷酸化的TACC3可藉由Clathrin heavy chain (CHC) 與紡錘體形成連結。我們亦找到位於CHC上能夠直接與TACC3形成結合的區段。進一步透過RNA干擾法來降低TACC3或CHC的表現量導致相似程度的細胞分裂缺失。同樣的結果也出現在同時降低TACC3與CHC的細胞中。這些現象包含了尚失ch-TOG與紡錘體結合的能力、紡錘體結構的異常以及染色體排列不均。因此,我們的實驗結果幫助我們了解Aurora-A如何透過磷酸化TACC3來建立正確的紡錘體結構,並同時解開了CHC參與細胞分裂的機制。
Abstract
Mitotic spindles play essential roles in chromosome congression and segregation during mitosis. Aurora-A, a mitotic kinase, regulates spindle assembly in part via phosphorylating human TACC3 on S558, which triggers TACC3 relocalization to mitotic spindles and stabilizes microtubules. TACC3 involved in spindle regulation is through recruiting ch-TOG protein for microtubule stabilization. While phosphorylation of human TACC3 at Ser-558 by Aurora-A is crucial for TACC3 spindle targeting, factor(s) responsible for spindle recruitment of phospho-TACC3 remains unclear. Here, we identified clathrin heavy chain (CHC) as an adaptor protein to recruit S558-phosphorylated TACC3 onto the spindle during mitosis for microtubule stabilization. CHC binds phospho-S558 TACC3 via its linker domain and first CHC repeat. CHC depletion or mutation on phospho-TACC3 binding abrogates TACC3 spindle relocalization. Depletion of either or both CHC and TACC3 yields similar defective phenotypes: loss of ch-TOG on spindles, disorganized spindles and chromosome misalignment with comparable mitotic delay. Our findings elucidate the association between Aurora-A phosphorylation and spindle apparatus, and demonstrate that regulation from Aurora-A is mediated by CHC in recruiting phospho-TACC3 and subsequently ch-TOG to mitotic spindles.
Table of Contents
Table of Contents…………………………………………………………….……..I
List of Figures…………………………………………………………...………...IV
中文摘要………………………………………………………………………………1
Abstract…………………………………………….…...…………………………...2
Introduction…………………………………….……………………………..........3
Mitotic spindle……………………………………………………………………3
Regulation of spindle microtubules stability………………………………....3
Microtubule-associated proteins……………………………………………...4
Aurora-A……………………………………………..……………...…………....5
Aurora-A and cancer……………….……………………………………...…..6
Mitotic function of Aurora-A…………………………………..……………….6
Substrates of Aurora-A………………………………………………………...7
TACC3……………………………………………………………………………..8
TACC3 and cancer……………………………………………………………..8
Mitotic function of TACC3……………………………………………………...9
TACC3 and Aurora-A…………………………………………………………10
Clathrin…………………………………………………………………………..10
Endocytosis……………………………………………………………………11
Mitotic function of clathrin…………………………………………………….11
Clathrin heavy chain (CHC)………………………………………………….12
Specific Aim…………………………………………….………………...…….13
Materials and Methods…………………………………………………………..14
Plasmid constructs……..………………………………………………………..14
siRNAs………………………..…………………………………………………..14
Antibodies………………..………………………………………………………14
Cell culture, synchronization, and drug treatment……………………………15 Transfection…………………………………………………………………..….15
Immunoprecipitation and Western analysis…………………………………..15
GST pull-down assays……………………………………………………….....16
In vitro aster assembly and MT binding assays………………………..……..16
Immunofluorescence and cold shock treatment……………………………...17
Live-cell imaging……………………………………………………………..….17
Mitotic index…………………………………………………………………...…18
Image quantification and statistical analysis……………………………...…..18
Results……………………………………………………………………………...20
TACC3 interacts with Aurora-A…………………………………………………20
Aurora-A phosphorylates TACC3 S558 during mitosis……………..……….20
TACC3 targeting to mitotic spindle is phospho-S558-dependent…………..20
CHC is identified as a phospho-S558 TACC3-interacting protein……...…..21
TACC3 interacts with CHC in vivo……………………………………………..22
TACC3 colocalizes with CHC at mitotic spindles…………………………..…23
TACC3 loses spindle localization in CHC-depleted HeLa cells……………..23
CHC mediates TACC3 spindle MTs-association…………………….……….24
Prolonged mitosis and chromosome alignment defect in CHC and/or
TACC3 depleted cells………………………………………………..…….25
CHC and TACC3 cooperate to regulate spindle stability…………………....25
CHC mediates TACC3-ch-TOG complex to mitotic spindles………………..26
CHC fragments containing 331-542 residues interact with phospho-S558 TACC3…………………………………………………………………….…27
CHC WT but not ∆(331-542) mutant or 331-542 fragment rescues the localization of TACC3 in CHC-depleted cells…………………………....27
CHC WT but not ∆(331-542) mutant rescues the phenotypes caused
by CHC depletion…………………………………………………………..28
Discussion…………………………………………………………………………29
The phosphorylation of S558 per se is essential for TACC3 spindle
Localization………………………………………………………………....29
What molecule(s) mediates CHC spindle localization?...............................29
Moonlighting proteins work for endocytosis and mitotic function………...…30
Figures……………………………………………………………………………...32
References…………………………………………………………………………48
























List of Figures
Figure 1. TACC3 interacts with Aurora-A and is a substrate of Aurora-A…….32
Figure 2. TACC3 spindle localization depends on Aaurora-A
phosphorylation………………………………………………………….33
Figure 3. CHC associates with phosphor-S558 TACC3………………………..34
Figure 4. The interaction of CHC with TACC3 is S558 phosphorylation dependent………………………………………………………………..35
Figure 5. TACC3 and CHC colocalize to mitotic spindles………………………36
Figure 6. The specificity of both antibodies in recognizing phosphor-S558 TACC3……………………………………………………………………37
Figure 7. CHC is essential for TACC3 localization to the spindle……………..38
Figure 8. CHC depletion does not alter Aurora-A localization and kinase activity……………………………………………………………………39
Figure 9. TACC3 and CHC cannot directly bind to microtubules……………...40
Figure 10. Depletion of CHC and/or TACC3 causes comparable mitotic delay and chromosome alignment defect………………………………….41
Figure 11. Depletion of CHC and/or TACC3 causes aberrant spindles………42
Figure 12. CHC depletion renders a loss of ch-TOG spindle targeting……….43
Figure 13. CHC and/or TACC3 depletion decreases spindle polymerization ability after cold shock………………………………………………...44
Figure 14. The CHC 331-542 region is important for TACC3 interaction……..45
Figure 15. The CHC 331-542 region is important for TACC3 spindle recruitment……………………………………………………………..46
Figure 16. The CHC 331-542 region is important for TACC3 mitotic spindle functions……………………………………………………………......47
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