TTK/hMps1在異常細胞分裂中調控p53蛋白之機制探討

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研究生：	黃億富 Huang, Yi-Fu
論文名稱：	TTK/hMps1在異常細胞分裂中調控p53蛋白之機制探討 The role of the spindle checkpoint kinase TTK/hMps1 in p53-dependent post mitotic checkpoint
指導教授：	張大慈 Chang, Margaret Dah-Tsyr 謝小燕 Shieh, Sheau-Yann
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子與細胞生物研究所 Institute of Molecular and Cellular Biology
論文出版年：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	65
中文關鍵詞：	細胞分裂、檢查點、抑癌蛋白p53
外文關鍵詞：	TTK/hMps1, p53, spindle checkpoint
相關次數：	點閱：1 下載：0
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在一些不良的條件下，細胞被迫長時間停在有絲分裂期而無法走出，最終細胞會嘗試適應這樣的環境，而在沒有細胞分裂之下就離開了有絲分裂期。這樣的過程會產生含有四倍數染色體的細胞，如此的細胞是不正常的，可藉由細胞凋亡的機制來消除這些不正常的細胞。此外，透過紡錘絲檢查點以及p53蛋白的作用，也可以讓那些不正常的細胞停在G1期而無法繼續增生。p53是一個抑癌蛋白，也是一個轉錄因子，透過轉錄活化它的下游基因，p53不但能阻止癌細胞的生長也能促使癌細胞走向死亡。Nocodazole和Taxol (紫杉醇)這一類破壞紡錘絲的藥物會活化p53，但是它們怎麼去活化p53的機制仍然不清楚。本研究發現在紡錘絲被破壞時，紡錘絲檢查點中的蛋白質激酶TTK/hMps1有活化p53 的功能。在試管中，TTK/hMps1磷酸化p53第15和第20位置的絲胺酸 (Serine) 以及第18位置的酥胺酸 (Threonine)。在細胞內，少了TTK/hMps1會減少因紡錘絲被破壞所引起的p53酥胺酸18的磷酸化; 相反的，在細胞內過表現TTK/hMps1會增加p53的磷酸化。這樣因TTK/hMps1所造成的p53磷酸化破壞了MDM2和p53之間的結合，也減少了MDM2所造成的p53降解，使得p53更為穩定。此外，紡錘絲被破壞時TTK/hMps1會和p53結合。當細胞長時間受到破壞紡錘絲的藥物攻擊時，少了TTK/hMps1如同少了p53一樣，都會讓細胞走向含有多倍數染色體的狀態，而這些可能都與TTK/hMps1所調控的p53第18位置的磷酸化加強了p53活化它的二個下游 p21以及Lats2的能力有關。進一步分析此磷酸化的功能，若是將p53第18位置的酥胺酸置換成天冬胺酸 (Aspartic acid) 以模擬磷酸化，或是將酥胺酸以丙胺酸 (Alanine)取代達到阻斷磷酸化的反應，前者模擬磷酸化的p53更能夠抑制含有四倍數染色體的細胞增生。綜合前面研究的結論，在紡錘絲被破壞時，透過磷酸化p53，紡錘絲檢查點中的蛋白質激酶TTK/hMps1和p53能夠共同去阻止細胞走向含有多倍數染色體的狀態，使得基因體的穩定性得以維持。

Upon prolonged arrest in mitosis, cells undergo adaptation and exit mitosis without cell division. These tetraploid cells are arrested in the subsequent G1 phase in a spindle checkpoint and p53-dependent manner. p53 has long been known to be activated by spindle poison such as nocodazole and taxol, although the underlying mechanism is still unclear. In this study, evidence was presented which demonstrated that stabilization and activation of p53 by spindle disruption required the spindle checkpoint kinase TTK/hMps1. Down regulation of TTK/hMPS1 diminishes p53 response after spindle damage. In vitro, TTK/hMPS1 phosphorylates p53 on Ser15, Thr 18, and Ser20. Ablation of TTK/hMPS1 in vivo reduces spindle damage-induced p53 Thr18 phosphorylation and p53 response. Conversely, overexpression of TTK/hMPS1 enhances Thr18 phosphoylation and stabilizes p53 by disrupting the interaction with MDM2 and by abrogating MDM2-mediated p53 ubiquinylation. In addition, TTK/hMPS1 coimmunoprecipitates with p53 after spindle damage. Upon prolonged treatment with spindle poisons, down regulation of TTK/hMPS1 leads to polyploidy, a phenomenon closely mimicked by p53 ablation. TTK/hMPS1-mediated Thr18 phosphorylation enhances p53-dependent activation of not only p21 but also Lats2, two mediators of the post-mitotic checkpoint. Furthermore, a phospho-mimicking substitution at Thr18 (T18D) is more capable than the phospho-deficient mutant (T18A) in rescuing the tetraploid checkpoint defect of the p53-depleted cells. Our data indicate that by phosphorylating p53 Thr18, TTK/hMPS1 works with p53 to prevent polyploidy after spindle damage.

Contents
中文摘要 .............................................................................................................1
Abstract  .………………………………………………………………………2
Ⅰ.  Introduction
 1.1 The tumor suppressor protein p53..................................................................... 3
 1.2 The regulation of p53 ………………………………………………………….3
 1.3 Mitosis and the anaphase promoting complex (APC) ………………………...4
 1.4 Aneuploidy and the spindle assembly checkpoint …………………………….5
 1.5 TTK/hMps1 …………………………………………………………………...6
 1.6 The p53-dependent postmitotic (tetraploidy) checkpoint ……………………..8

Ⅱ.  Materials and Methods
 2.1 Cell culture conditions and treatments ……………………………………….10
 2.2 Plasmids and siRNA transfection …………………………………………….10
 2.3 Cell lysis, immunoprecipitation and immunoblotting ……………….............. 11
 2.4 Recombinant proteins………………………………………………………....12
 2.5 GST pull-down assay………………………………………………………....13
 2.6 In vitro kinase assay and immunoprecipitation/kinase assay ………………...14
 2.7 In vivo ubiquitination assays ……………………………………………........14
 2.8 Luciferase Reporter Assay ………………………………………………........15
 2.9 Isolation of total RNA ………………………………………………………...15
 2.10 Reverse transcription (RT)–PCR ……………………………………………16
 2.11 Cell cycle analysis …………………………………………………………...16

Ⅲ.  Results
 3.1 Downregulation of TTK/hMps1 by siRNA attenuates the p53   response induced by spindle disruption. ………………………………………………...17
 3.2 Down-regulation of TTK/hMps1 by siRNA diminishes p53
    response after DNA damage. ………………………………………………….18
 3.3 TTK/hMps1 interacts directly with p53. ……………………………………... 18
 3.4 TTK/hMps1 stabilizes p53 through the p53 N-terminal domain. ...…………...19
 3.5 TTK/hMps1 phosphorylates the p53 N-terminal domain in vitro. ………….....20
 3.6 Downregulation of TTK/hMps1 by siRNA attenuates the p53 T18 phosphorylation induced by spindle disruption. ……………………............... 21
 3.7 Down-regulation of TTK/hMps1 by siRNA diminishes p53 T18 and S20 phosphorylation after DNA damage. ……………………………………….....21
 3.8 The stable TTK-p53 interaction is not absolutely required for
    TTK to phosphorylate p53. ………………………………………………….....22
 3.9 Overexpression of WT but not TTK /hMps1-KD protects p53 from MDM2-mediated degradation. ………………………………………………...22
 3.10 Down-regulation of TTK leads to impaired postmitotic checkpoint and
     polyploidy. …………………………………………………………………....23
 3.11 The Thr18 phosphorylation is required for p53-dependent post mitotic
     checkpoint. ……………………………………………………………………24
 3.12 MAD2 and BUB R1 participate in TTK-mediated T18
     phosphorylation of p53 after spindle damage. ……………………..................24




Ⅳ.  Discussion
 4.1 TTK/hMps1 mediates p53-dependent tetraploidy checkpoint. ………………...26
 4.2 p53 activation in response to spindle damage requires an intact spindle
    checkpoint. ………………………………………………………..................... 27
 4.3 TTK/hMps1 participates in the p53 response after DNA damage. ...………......29
 4.4 TTK/hMps1 stabilizes p53 by pathway besides Thr18   phosphorylation. ……………………………………………………………....30
 4.5 The relative contribution of the p53 N-terminal and C-terminal domains in TTK/hMps1-mediated stabilization. …………………………………………..30
 4.6 The feedback pathway between TTK/hMps1 and p53. ……………………......31
 4.7 The role of TTK/hMps1 in maintaining genome stability ……………………..32
 4.8 Future directions …………………………………………………………….....32

Ⅴ. References …………………………………………………………………35
Ⅵ. Figures
 Fig. 1. TTK/hMps1 knockdown by siRNA mitigates the p53 response after Taxol
       or nocodazole treatment. ...............................................................................43
 Fig. 2. The half-life of p53 was reduced in TTK/hMps1-downregulated cells
       treate with Taxol. ………………………………………………….............. 44
 Fig. 3. The IR-induced p53 response is diminished in TTK/hMps1-knockdown
       cells. ……………………………………….................................................. 45
 Fig. 4. TTK/hMps1 interacts with p53 in vivo after spindle disruption or DNA damage in 293T cells. ………………………………………………...……46
 Fig. 5. The p53 C-terminal domain interacts directly with TTK/hMps1 in vitro.  ………………………………………………………………..…... 47
 Fig. .6 The kinase domain of TTK/hMps1 interacts directly with p53 in vitro. ……………………………………………………………….………48
 Fig. 7. TTK stabilizes p53. ………………………………………………….….......49
 Fig. 8. TTK/hMps1 stabilizes p53 through the N-terminal domain. ……................ 50
 Fig. 9. Overexpression of WT but not TTK-KD stabilizes the p53 N-terminal
      domain (N96, amino acid 1-96) and increases Thr18 phosphorylation
      of both transfected and endogenous p53.  ……………………………... .....51
 Fig. 10. TTK/hMps1 phosphorylates the N-terminal domain of p53. …………….. 52
 Fig. 11. TTK/hMps1 phosphorylates p53 on Thr18 in vivo. ………………….... ....53
 Fig. 12. The DNA damage-induced p53 phosphorylation is diminished
        in TTK/hMps1-knockdown cells. …………………………………………54
 Fig. 13. TTK/hMps1 phosphorylates p53 in the absence of the p53
        C-terminal region. ………………………………………………………....55
 Fig. 14. MDM2-induced degradation of p53 is rescued by
        coexpression of WT but not TTK-KD. ……………………………….. ….56
 Fig. 15. TTK stabilizes p53 by preventing p53 from binding and ubiquitination
        by MDM2. …………………………………………………………….. ….57
 Fig. 16. TTK/hMps1 ablation ameliorates the postmitotic checkpoint. ............... ….58
 Fig. 17. Tetraploidy is more efficiently suppressed by the phosphomimicking
        T18D mutant than by WT or the phosphodeficient T18A mutant …….. …59
 Fig. 18. Phosphomimicking mutation at Thr18 increases p53 activity. ………... … 60
 Fig. 19. The p53 T18D mutant transactivates the endogenous p21 gene better
        than the WT and the T18A mutant. …………………………………...... ...61
 Fig. 20. MAD2 participates in the p53-dependent postmitotic checkpoint. ..........…62
 Fig. 21. MAD2 and BUB R1 are involved in the p53 Thr18
        phosphorylation in response to spindle damage. …………………….........63
 Fig. 22. Downregulation of MAD2, or BUBR1 by siRNA does not
        affect the intrinsic kinase activity of TTK. ………………………….... ....64
 Fig. 23. TTK/hMps1 mediates p53-dependent postmitotic checkpoint………....... .65

                                

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