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研究生(外文):Yu-Chen Chang
論文名稱(外文):Cep55 subcellular distribution in mouse testes and its regulation mechanism by p53
指導教授(外文):P. Ouyang
外文關鍵詞:Cep55intercellular bridgep53Plk1
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Cep55蛋白質對於細胞分裂的完成很重要,它在間期(interphase)細胞會存在於中心體(centrosome),而在胞質分裂(cytokinesis)時則會存在於中體(midbody)。先前的北方墨點實驗顯示Cep55在睪丸會大量表現且在多數的人類癌症中可以發現Cep55蛋白質會過度表現與p53蛋白質的失去功能,這引起我們討論這兩個基因相關的可能性。在這個論文中我們首先檢驗在老鼠睪丸成熟過程中Cep55蛋白質的空間與時間的表現形態,其次我們評估p53對於Cep55調控的角色。我們發現Cep55和另一個中心體蛋白質pericentrin會存在於連接生殖細胞(spermatogenic cells)之細胞間橋(intercellular bridges)。我們也發現誘發p53生成會同時抑制Cep55和Plk1蛋白質之表現。Plk1的過度表現與抑制p53表現(knockdown)兩者皆會增強Cep55轉譯後(post-translational)之蛋白質穩定度。我們的結果顯示在精子生成(spermatogenesis)過程中需要Cep55和pericentrin形成生殖細胞間之穩定細胞間橋。我們也發現p53會經由Plk1負向調控Cep55之表現,而Plk1本身則會正向調控Cep55之蛋白質穩定度,這些資料顯示有p53-Plk1-Cep55調控軸的存在。
Centrosomal protein 55 (Cep55), located in the centrosome in interphase cells and recruited to the midbody during cytokinesis, is essential for completion of cell abscission. Northern blot previously showed Cep55 is predominantly expressed in the testis. Upregulation of Cep55 and inactivation of p53 occur in the majority of human cancers, raising the possibility of a link between these two genes. In the present thesis, we first examined the spatial and temporal expression patterns of Cep55 during mouse testis maturation and then we evaluated the role of p53 in Cep55 regulation. We found that Cep55, together with pericentrin, another centrosomal protein, were localized to the intercellular bridges interconnecting spermatogenic cells in a syncytium. We also demonstrated that downregulation of expression of Cep55 was accompanied by repression of polo-like kinase 1 (Plk1) levels due to p53 induction. Overexpression of Plk1 and knockdown of p53 expression both enhanced the post-translational protein stability of Cep55. Our results, therefore, indicate Cep55 and pericentrin are required for the stable bridge between germ cells during spermatogenesis and demonstrate the existence of a p53-Plk1-Cep55 axis in which p53 negatively regulates expression of Cep55 through Plk1 which, in turn, is a positive regulator of Cep55 protein stability.
誌謝 i
摘要 ii
1.1 Centrosomal Protein 55 kDa (Cep55) 1
1.1.1 Identification of Cep55 1
1.1.2 Gene functions of Cep55 3
1.1.3 Cep55 and cancers 5
1.2 Centrosome, cytokinesis, midbody, and intercellular bridges (IBs) 7
1.3 Testis and spermatogenesis 9
1.4 p53 10
1.5 Specific aims 11
2.1.1 Antibody production 13
2.1.2 Northern blot analysis 14
2.1.3 Western blot analysis 14
2.1.4 Cell culture and synchronization 15
2.1.5 Immunohistochemistry 16
2.1.6 Preparation of enzyme-dissociated testicular cells 17
2.1.7 Immunofluorescence microscopy 18
2.2.1 Cell culture, plasmids, and transfection 19
2.2.2 Growth rate assay 20
2.2.3 UV irradiation 20
2.2.4 Luciferase and -galactosidase assays 20
2.2.5 Cell treatment and Western blot analysis 21
3.1.1 Characterization of monoclonal anti-Cep55 antibodies 23
3.1.2 Expression analysis of Cep55 in developing and adult testes 24
3.1.3 Localization of Cep55 to germ cell intercellular bridges in adult murine testes 26
3.1.4 Coexpression of Cep55 as well as pericentrin with MKLP1 at germ cell intercellular bridges in developing and adult testes 27
3.1.5 Cep55 and pericentrin form an inner ring in stable intercellular bridges from dissociated male germ cells 29
3.2.1 Correlation of Cep55 protein expression levels and ovarian cancer cell growth 29
3.2.2 Cep55 expression is negatively regulated by p53 31
3.2.3 Stability of Cep55 protein is influenced by p53 33
3.2.4 Repression of Cep55 by p53 is through Plk1 34
PART I - Characterization of centrosomal proteins Cep55 and Pericentrin in intercellular bridges of mouse testes 37
PART II - Cep55 stability is negatively regulated by p53 through Plk1 43

Fig. 1. Model for Cep55 phosphorylation during mitosis. 54
Fig. 2. Spermatogenesis in testis. 55
Fig. 3. Mouse stages in the cycle of the seminiferous epithelium (I-XII). 56
Fig. 4. Characterization of Cep55 monoclonal antibodies (mAbs). 58
Fig. 5. Expression of Cep55 in adult and developing testes. 59
Fig. 6. Immunohistological localization of Cep55 in adult mouse testis. 61
Fig. 7. Subcellular distribution of Cep55, MKLP1, and pericentrin in quiescent and dividing HeLa cells. 62
Fig. 8. Subcellular localizations of Cep55, MKLP-1, and pericentrin in mouse testes at different maturation stages to adult. 64
Fig. 9. Immunofluorescent localization of Cep55, MKLP-1, and pericentrin in dissociated cells from adult mouse testis. 65
Fig. 10. Cep55 expression contributes to cell proliferation. 67
Fig. 11. Repression of Cep55 protein expression in response to p53 induction. 69
Fig. 12. Cep55 promoter activity is suppressed by expression of p53. 71
Fig. 13. Cep55 stability is influenced by p53. 72
Fig. 14. Plk1 regulates Cep55 expression and protein stability. 74
Fig. 15. p53-dependent Cep55 expression is mediated by Plk1 phosphorylation. 77
Fig. 16. Expression patterns of Cep55 and Plk1 in isogenic cell lines with or without p53 expression. 78
Fig. 17. Model for regulatory pathway of Cep55. 79

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