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系統識別號 U0026-0608201314410200
論文名稱(中文) 探討 Aurora A/hBora 複合物和 Pin1 之交互作用 對於進入有絲分裂期之調控
論文名稱(英文) The interplay of Aurora A/hBora complex with Pin1 in the regulation of mitotic entry
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 李育誠
研究生(英文) Yu-Cheng Lee
電子信箱 u8905109@hotmail.com
學號 S58961476
學位類別 博士
語文別 英文
論文頁數 156頁
口試委員 指導教授-呂佩融
口試委員-賴明德
召集委員-劉校生
口試委員-蕭宏昇
口試委員-黃奇英
中文關鍵字 脯胺酸異構酶  細胞週期  G2/M 過渡期  Aurora A/hBora 複合物  後轉譯修飾 
英文關鍵字 prolyl isomerase  G2/M transition  cell cycle, Aurora A/hBora complex  post-translational modification 
學科別分類
中文摘要 Pin1 是脯胺酸異構酶中,第一個被證明在酵母菌及哺乳類細胞中,與細胞分裂
相關。有趣的是,Pin1 對於G2 時期,扮演著負向調控之角色,而其機制仍不清楚。
此外,Pin1-WW domain 中Ser16 位點之磷酸化,其生理意義與細胞中哪一個激酶負
責此位點之磷酸化也尚未知道。在此研究,針對細胞週期G2/M 過渡期中,探討Pin1
Ser16 位點磷酸化與Aurora A/hBora 複合物調控細胞進入有絲分裂期之關係進行探
討。我們發現在G2 時期,GSK3β 能磷酸化hBora 於Ser274 及Ser278 兩個位點上,
其磷酸化可促進細胞進入有絲分裂期; 此外,Aurora A 可磷酸化Pin1 於Ser16 位點
上,其磷酸化能抑制Pin1 與其受質結合的功能,而降低Pin1 在G2/M 過渡期的功能。
有趣的是,hBora Ser274 及Ser278 的磷酸化位點,恰為Pin1 的結合位點。當過度表
現Pin1 於細胞中,Pin1 能戰勝細胞中Aurora A 對Pin1 的抑制結果,藉由結合hBora
而促使hBora 經由β-TrCP 而提早降解,導致Aurora A/hBora 複合物活化Plk1 之能力
下降,而延遲細胞進入有絲分裂期。而當細胞進入有絲分裂期時,抑制Pin1 表現或
活性,則會導致hBora 蛋白的累積而伴隨著有絲分裂進行的延遲,意味著Pin1 可以
回饋調控有絲分裂期中hBora 蛋白的降解,而確保有絲分裂期的進行及離開。總結而
言,此研究藉由探討Aurora A-Pin1-hBora-GSK3β 分子間的後轉譯修飾及交互作用,了解細胞如何調控進入以及離開有絲分裂期。
此外,當細胞受到損害,Pin1 能調控p53 的穩定性,並增加p53 在DNA 損害
下G2/M 檢查點之功能。Pin1 和Aurora A 已被報導過度表現於人類癌細胞當中,且
皆參與G2/M 過渡期的調控。而Pin1-Ser16 磷酸化的表現,在癌細胞中尚未被分析。
因此,Aurora A 造成Pin1-Ser16 之磷酸化,是否對於癌細胞中G2/M 檢查點功能之缺失,以及其是否與細胞易產生癌化之相關性,值得未來進一步探討。
英文摘要 Pin1 is the first prolyl isomerase to be identified that is involved in cell division in
both yeast and mammalian cells. Interestingly, the mechanism of Pin1 acts as a negative
regulator of mitotic activity in G2 remains unclear. Besides, the biological significant and
which kinase is responsible for Pin1-Ser16 phosphorylation in vivo also remain unknown.
In this study, the functional link of Ser16 phosphorylation with Aurora A/hBora
complex-mediated mitotic entry is investigated at the G2/M transition. We uncovered a
suppressed role of Pin1 in regulating Aurora A/hBora complex activity. GSK3β-mediated
Ser274 and Ser278 phosphorylation of hBora is involved in mitotic entry and that is
characterized as a novel Pin1 binding protein. Aurora A phosphorylates Pin1 at Ser16 and
suppresses Pin1 G2/M function to prevent the premature hBora degradation mediated
by β-TrCP, whereas Pin1 overexpression can override the suppressed role of Pin1 by
Aurora A and therefore delays mitotic entry. Furthermore, Pin1 depletion or inhibition
results in marked hBora accumulation and concomitant with delayed mitotic progression,
indicating that Pin1 feedback promotes hBora degradation in mitosis to ensure mitotic
progression and exit. In conclusion, the cell cycle progression control from mitotic entry to
exit is regulated by the post-translational modification and interaction of Aurora
A-Pin1-hBora-GSK3β axis.
Furthermore, when cells encounter stress, such as DNA damage, Pin1 can stabilize
p53 and increase p53-mediated G2/M checkpoint response. In addition, Pin1 and Aurora A
are overexpressed in human cancers and both of their function are related to G2/M
regulation. The status of Pin1-Ser16 phosphorylation has not yet been clarified in human
cancers. Accordingly, it is interesting to investigate whether Aurora A-mediated Pin1
III
Ser16 phosphorylation is associated with the impaired G2/M checkpoint response in
cancers and whether that can increase the susceptibility of cell transformation in the future.
論文目次 Table of Contents
中文摘要...............................................................................................................................I
Abstract...............................................................................................................................II
致謝....................................................................................................................................IV
Table of Contents...............................................................................................................VI
Table List.............................................................................................................................X
Figure List...........................................................................................................................XI
Abbreviations..................................................................................................................XIII
Chapter I. Introduction ......................................................................................................1
1. An overview of the cell cycle.............................................................................................2
2. Regulation of G2 to Mitotic phase.....................................................................................2
3. G2/M DNA damage checkpoint.........................................................................................4
4. Aurora A kinase..................................................................................................................5
5. Aurora A cofactor-hBora protein.......................................................................................7
6. Peptidyl-prolyl isomerase Pin1..........................................................................................8
Objective and Specific Aims..............................................................................................11
Chapter II. Materials and Methods..................................................................................13
1. Cells culture......................................................................................................................14
2. Transfection.....................................................................................................................15
3. Cell synchronization.........................................................................................................15
4. Plasmid constructs and Site-directed mutagenesis...........................................................16
5. Production of recombinant proteins.................................................................................17
6. In vitro kinase assays........................................................................................................18
7. Antibodies and reagents...................................................................................................19
VII
8. Cell fractionation assay and protein stability assay..........................................................20
9. LC-MS/MS-based phosphopeptide mapping analysis.....................................................21
10. Flow Cytometry analysis................................................................................................22
11. In vitro GST pull-down assay........................................................................................22
12. In vivo co-immunoprecipitation assay...........................................................................23
13. Immunofluorescence microscopy analysis.....................................................................24
14. Statistical analysis..........................................................................................................25
Chapter III. Results............................................................................................................26
1. hBora is phosphorylated in late G2 and Mitosis..............................................................27
2. Pin1 interacts with hBora in vitro and in vivo..................................................................27
3. Ser274 and Ser278 are critical hBora phosphorylation sites in vivo...............................30
4. Both pSer274 and pSer278 of hBora are major Pin1 binding sites..................................31
5. GSK3β interacts with hBora in vitro and in vivo.............................................................32
6. GSK3β
phosphorylates Ser274 and Ser278 of hBora......................................................34
7. GSK3β-mediated Ser274 and Ser278 phosphorylation of hBora is required for mitotic
entry...............................................................................................................................35
8. The negative function of Pin1 in the regulation of mitotic entry.....................................37
9. Gain of Pin1 function through overexpression delays mitotic entry through reducing the
hBora steady-state level..................................................................................................39
10. Pin1-mediated hBora degradation through a proteasome-dependent pathway..............40
11. Gain of Pin1 function causes hBora subcellular translocation.......................................40
12. Gain of Pin1 function promotes the β-TrCP-mediated ubiquitination and degradation of
hBora.............................................................................................................................41
13. The S274A/S278A mutant hBora reduces the Pin1-mediated effect on hBora.............43
14. Impaired Pin1 function causes mitotic arrest by hBora accumulation...........................43
VIII
15. Elevated Pin1-Ser16 phosphorylation levels coincides with Aurora A activity and
expression profile...........................................................................................................46
16. Aurora A interacts with and phosphorylates Pin1 at Ser16............................................47
17. Aurora A-mediated Ser16 phosphorylation suppresses the binding capacity and alters
subcellular localization of Pin1......................................................................................49
18. Pin1 S16A enhances the interaction with hBora and obviously reduces hBora
expression than wild-type and S16E Pin1......................................................................50
Chapter IV. Discussion......................................................................................................52
Conclusion………...............................................................................................................67
References..........................................................................................................................68
Tables..................................................................................................................................78
Figures ...............................................................................................................................79
Appendix..........................................................................................................................123
1. Appendix Table 1. The nomenclature of Aurora kinases in different species...............124
2. Appendix Table 2. Classification of WW domains based on their ligand specificity....125
3. Appendix Figure 1. The different phases of the cell cycle.............................................126
4. Appendix Figure 2. The stages of mitosis......................................................................127
5. Appendix Figure 3. The major Cyclins and Cdks in cell cycle control of mammalian
cells..............................................................................................................................128
6. Appendix Figure 4. Plk1 indirectly regulates cyclin-B1/Cdk1 complex activity..........129
7. Appendix Figure 5. hBora and Aurora A cooperatively activate Plk1 and control mitotic
entry.............................................................................................................................130
8. Appendix Figure 6. G2/M checkpoint pathways that block cell cycle progression after
DNA damage stress......................................................................................................131
9. Appendix Figure 7. Human Aurora kinase structure.....................................................132
IX
10. Appendix Figure 8. Cdk1 feedback regulates hBoa degradation.................................133
11. Appendix Figure 9. Structure of human Pin1 protein..................................................134
12. Appendix Figure 10. The dynamic expression profile of Pin1-Ser16 phosphorylation
after DNA damage checkpoint recovery......................................................................135
13. Appendix Figure 11. Endogenous TPX2 expression is increased in Pin1 overexpression
mitotic cells..................................................................................................................136
14. Appendix Figure 12. Inhibition of GSK3b activity attenuates cell proliferation.........137
15. Appendix Figure 13. Gain of Pin1 function slightly increase p53 expression.............138
16. Appendix Figure 14. Inhibition of Aurora A activity can reduce Pin1-Ser16
phosphorylation and increase p53 expression..............................................................139
17. Appendix Figure 15. The interaction of endogenous Plk1 with various WW
domain-containing proteins..........................................................................................140
18. Appendix Table 1. The antibodies and their reaction conditions in this study............141
19. Appendix Table 2. Primers for site-directed mutagenesis and deletion of hBora........143
20. Side project: I. The association of Pin1 and Sp1 in Neuronal differentiation..............145
21. Side project: II. The conversion of mESC into mNSC................................................149
22. Curriculum Vitae
X
Table List
Table 1. Summary of the phosphorylation sites in hBora by LC/MS/MS-based
phosphopeptide mapping assay......................................................................................78
Appendix Table 1. The antibodies and their reaction conditions in this study..................141
Appendix Table 2. Primers for site-directed mutagenesis and deletion of hBora..............143
XI
Figure List
Figure 1. hBora is phosphorylated in late G2 and M phase.................................................79
Figure 2. hBora interacts with Pin1 in vitro and in vivo......................................................80
Figure 3. hBora colocalizes with Pin1 both at endogenous and overexpression levels.......82
Figure 4. The interaction of hBora and Pin1 is phosphorylation- dependent manner and that
is specific and selective for the WW domain of Pin1....................................................84
Figure 5. Ser274 and Ser278 are critical in vivo hBora phosphorylation sites....................86
Figure 6. hBora-Ser274 and Ser278 are major phosphorylation sites for Pin1 binding......88
Figure 7. GSK3β activity is involved in the interaction of Pin1 and hBora........................90
Figure 8. GSK3β interacts with hBora in vivo and in vitro.…............................................92
Figure 9. GSK3β phosphorylates hBora at Ser274 and Ser278...........................................93
Figure 10. S274A/S278A mutant hBora reduces the slowly migrating bands of hBora and
delays the activation of Plk1..........................................................................................94
Figure 11. Loss of GSK3β function delays the activation of Plk1 and reduces mitotic
index..............................................................................................................................96
Figure 12. Gain of Pin1 function delays Plk1 activation and entry into mitosis..................99
Figure 13. Loss of Pin1 function promotes premature mitotic entry.................................101
Figure 14. Pin1 reduces hBora expression through a proteasome-degradation pathway...102
Figure 15. Gain of Pin1 function alters the cytoplasmic translocation of hBora...............104
Figure 16. Pin1 promotes the premature degradation of hBora by β-TrCP.......................106
Figure 17. hBora S274A/S278A mutant can reduce Pin1-mediated effect on hBora…....108
Figure 18. Impaired Pin1 function induces mitotic arrest and hBora accumulation……..110
Figure 19. Pin1-Ser16 phosphorylation levels coincides with Aurora A activity and
expression during the G2/M transition.........................................................................112
Figure 20. Inhibition of Aurora A activity by pharmacological inhibitors reduces
XII
Pin1-Ser16 phosphorylation.........................................................................................113
Figure 21. Manipulation of Aurora A expression can alter Pin1-Ser16
phosphorylation............................................................................................................115
Figure 22. Pin1-Ser16 phosphorylation positively correlated with Aurora A expression in
ESCC cancer cell lines.………………........................................................................116
Figure 23. Pin1 co-localizes with Aurora A and interacts with Aurora A in vitro and in
vivo..............................................................................................................................117
Figure 24. Aurora A phosphorylates Pin1 at Ser16 by in vitro kinase assay…………….118
Figure 25. Aurora A-mediated Pin1-Ser16 phosphorylation disrupts Pin1 binding ability
and alters its subcellular localization............................................................................119
Figure 26. Pin1-S16A enhances the interaction with hBora and promotes the degradation
of hBora........................................................................................................................120
Figure 27. Mechanisms regulating the interplay of Aurora A, Pin1, hBora and GSK3β for
mitotic entry.................................................................................................................121
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