博碩士論文 etd-0910107-105059 詳細資訊

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姓名 林敬智(Ching-chih Lin) 電子郵件信箱 irvin1971@hotmail.com
畢業系所 生物科學系研究所(Biological Sciences)
畢業學位 博士(Ph.D.) 畢業時期 95學年第2學期
論文名稱(中) 肝醣合成激酶-3β(Glycogen synthase kinase-3beta) 多重特性功能及其相關蛋白質之探討
論文名稱(英) Multiple tasks of Glycogen synthase kinase-3beta (GSK-3β ) and its partners
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    摘要(中) 肝醣合成激酶3 (Glycogen synthase kinase-3) 在許多訊息傳遞途徑中扮演著重要的角色。在大多數的真核細胞亦發現相似的肝醣合成激酶。因為肝醣合成激酶3在細胞中具有許多調控的功能，因此本研究利用酵母菌雙雜合系統 (yeast two-hybrid system) 由人類testis cDNA library進行肝醣合成激酶3β (GSK3β) 結合蛋白的篩選。在篩選出的GSK3β結合蛋白中，本論文選取兩個結合蛋白進一步來探討其功能，一是中心體蛋白質 hNinein，另一個則是新發現可抑制 GSK3β 活性的結合蛋白質 (GSK3β interaction protein; GSKIP)。
    本論文第一部份研究發現中心體蛋白質 hNinein 具有四種不同C端區域 (CCII-termini) 的異構體 (isoforms)，其中hNinein isoform 6 為本研究的新發現；且 hNinein isoform 6 其分布情形具有組織特異性。GSK3β 對於四種不同C端區域的 isoforms 亦具有不同的磷酸化作用。此外切除 hNinein 的N端或 CCII 區域都會造成 hNinein 結構上的改變而影響其在細胞內的分布情形，進而造成另一個中心體蛋白質 γ-tubulin 的位置改變。進一步將細胞內所有 hNinein isoforms 移除後發現 γ -tubulin 在中心體的含量也相對減少。利用功能區域交換 (domain swapping) 的實驗，發現 CCIIX-CCIIY region 提供了一個 γ-tubulin 的結合位置。當細胞過度表達全長或 CCIIX-CCIIY region 的hNinein 蛋白質都會顯著影響微管束 (microtubules) 的生成。綜上所述，hNinein 具有中心體坐落標的訊號 (centrosomal targeting signals)，不僅可調控 hNinein 本身結構變化並提供與 γ-tubulin 的結合區域，進而影響其在細胞內分佈的情形。
    本論文第二部份，就肝醣合成激酶3beta 的作用蛋白 (GSK3β interaction protein; GSKIP) 可抑制 GSK3β 對 non-primed 受質磷酸化的活性，利用神經母細胞瘤 (neuroblastoma SH-SY5Y) 當作神經分化的模式來進一步研究其功能。實驗發現當過度表達 GSKIP 可抑制 retinoic acid 誘發神經母細胞瘤 SH-SY5Y 神經軸 (neurite outgrowth) 的生長。此現象與利用 GSK3β 專一性抑制劑 LiCl 或 SB415286 進行相同實驗結果一致。進一步研究發現 GSKIP 可能藉由蛋白質交互作用 (protein-protein interactions) 而非其他蛋白質修飾作用(post-modulation) 來調控 GSK3β 的活性；且 GSKIP 可能藉由抑制 GSK3β 對 tau 蛋白質特定位點的磷酸化而影響神經軸的生長。此外經由細胞生長曲線及 MTT assay 分析發現 GSKIP 可促進細胞週期循環加速。同時 GSK3β的活性受 GSKIP 抑制進而造成細胞內 β-catenin 和 cyclin D1 總量增加。根據上述結果，GSKIP 在 retinoic acid 誘發神經母細胞瘤 SH-SY5Y 神經分化的模式中具有兩種調控功能，不僅抑制神經軸的生長亦促進細胞數的增生。而這兩種功能可能都是藉由對 GSK3β的活性的抑制所導致。
    摘要(英) Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase which plays a key role in several signaling pathways and its homologues have been identified in most eukaryotes. Since GSK3βis an essential protein kinase that regulates numerous functions within the cell, an effort to survey possible GSK3β- interacting proteins from a human testis cDNA library using the yeast two-hybrid system is made. Two interesting candidates are chosen to characterize their functions in this study. One is a centrosomal protein, hNinein, and the other is a novel inhibitor of GSK3β, designated as GSKIP (GSK3β interaction protein).
    In the first part of the present thesis we describe the identification of four diverse CCII-termini of human hNinein isoforms, including a novel isoform 6, by differential expression in a tissue-specific manner. In a kinase assay, the CCII region of hNinein isoforms provides a differential phosphorylation site by GSK3β. In addition, either N-terminal or CCIIZ domain disruption may cause hNinein conformational change which recruits γ-tubulin to centrosomal or non-centrosomal hNinein-containing sites. Further, depletion of all hNinein isoforms caused a significant decrease in the γ-tubulin signal in the centrosome. In domain swapping, it clearly shows that the CCIIX-CCIIY region provides docking sites for γ-tubulin. Moreover, nucleation of microtubules from the centrosome is significantly affected by the overexpression of either the full-length hNinein or CCIIX-CCIIY region. Taken together, these results show that the centrosomal targeting signals of hNinein have a role not only in regulating hNinein conformation, resulting in localization change, but also provide docking sites to recruit γ-tubulin at centrosomal and non-centrosomal sites.
    In the second part of the thesis we describe another candidate, GSK3βinteraction protein (GSKIP), to characterize its functions in neuron differentiation. We use human neuroblastoma SH-SY5Y cells as a model of neuronal cell differentiation. When overexpression of GSKIP prevents neurite outgrowth from RA-mediated differentiation, this result is similar to the presence of LiCl or SB415286, an inhibitor of GSK3β. Further, GSKIP regulates the activity of GSK3β through protein-protein interactions rather than post-modulation and GSKIP may affect GSK3β on neurite outgrowth via inhibiting the specific phosphorylation site of tau. In addition to inhibition of neurite outgrowth, GSKIP overexpressed in SH-SY5Y cells also promotes cell cycle progression by analyzing cell proliferation with cell growth and MTT assay. Furthermore, GSKIP raises the level of β-catenin and cyclin D1 through inhibition of GSK3β activity in RA-mediated differentiation SH-SY5Y cells. Taken together, the data suggest that GSKIP, a dual functional molecule, is able to inhibit neurite outgrowth and promote cell proliferation via negative regulation of GSK3β activity in RA-mediated differentiation of SH-SY5Y cells.
    關鍵字(中)
  • 肝醣合成激酶3beta 的作用蛋白
  • 中心體蛋白質
  • γ-tubulin 的結合區域
  • 神經軸
  • 肝醣合成激酶3
  • 神經母細胞瘤
    		• 關鍵字(英)
  • neurite
  • Glycogen synthase kinase-3
  • neuroblastoma
  • centrosomal protein
  • GSKIP
  • gamma-tubulin docking sites
    • 論文目次 TABLE OF CONTENTS
    TABLE OF CONTENTS  I
    ABSTRACT (Chinese)  1
    ABSTRACT (English)  3
    AN OVERVIEW OF THE GSK3  5
    PART I: Functional Characterization of Human Ninein Isoforms – hNinein is
    Regulated by Centrosomal Targeting Signals and Evidence for Docking
    Sites to Direct γ-Tubulin  8
    INTRODUCTION 9
    MATERIALS AND METHODS  15
    Isoform-specific PCR and RT-PCR  15
    Cloning and DNA sequencing 15
    Antibody production  16
    Cell culture, RNA interference, and transfections  17
    Immunofluorescence and microscopy  17
    Western blot analysis 18
    Immunoprecipitation and immunoblotting experiments 19
    In vitro kinase assay  20
    Microtubule regrowth experiment 20
    RESULTS  21
    Identification of four different human hNinein isoforms revealed a Novel hNinein
    Isoform  21
    Distribution of hNinein isoforms in the cell 22
    C-terminal region of three hNinein isoforms may be regulated by GSK3β
    phosphorylation  23
    Both the N- and C-terminus contributed to hNinein conformation resulting in
    γ-tubulin relocalization  23
    Four targeting domains in hNinein are sufficient for centrosome localization
    signals  25
    hNinein is associated with γ-tubulin via CCIIX-CCIIY docking sites 26
    Regrowth experiment with overexpression of full length and truncated hNinein 27
    DISCUSSION 28
    hNinein isoforms have different C-terminal coiled-coil domains  28
    Redundant or distinct functions of hNinein isoforms 29
    The distinct centrosomal localization of hNinein isoforms may be regulated by
    GSK3β phosphorylation  30
    γ-tubulin localization to the centosome is hNinein-dependent 30
    Overexpression of hNinein inhibits microtubule nucleation and cell mitosis 32
    hNinein isoforms are regulated by centrosome targeting signals and docks
    γ-tubulin to the centosomal and non-centrosomal sites 33
    PART II: GSKIP , a dual functional molecule, inhibites neurite outgrowth and
    promotes cell proliferation via negative regulation of GSK3β activity
    in retinoid acid-mediated differentiation of SH-SY5Y cells 35
    INTRODUCTION  36
    MATERIALS AND METHODS 39
    Cell culture and Differentiation  39
    Cloning and DNA Sequencing  39
    Transfection  40
    Immunofluorescence and microscopy  40
    Western blotting 41
    Cell growth cure and MTT assay  41
    RESULTS  42
    RA-mediated differentiation in human neuroblastoma SH-SY5Y cells 42
    The inhibition of GSK3β prevents neurite outgrowth from RA-mediated
    differentiation  42
    GSKIP may affects GSK3β on neurite outgrowth via phosphorylated on specific
    site of tau 43
    GSKIP overexpression promotes cell cycle progression in SH-SY5Y cells  44
    Overexpression of GSKIP raised the level of β-catenin and cyclin D1 
    REFERENCES 50
    LIST OF FIGURES
    Figure 1. Identification of a novel human hNinein isoform 65
    Figure 2. The distribution of four hNinein isoforms in cells  68
    Figure 3. Phosphorylation of four C-terminal fragments of hNinein isoforms by
    GSK3β, Aurora A and PKA  72
    Figure 4. C- and N-terminal domain disruptions of GFP-tagged hNinein isoform 5
    were over-expressed in HeLa cells  73
    Figure 5. Four centrosome localization signals in hNinein  76
    Figure 6. hNinein is associated with γ-tubulin using the CCIIX-CCIIY docking
    sites  79
    Figure 7. Microtubules regrowth assay  82
    Figure 8. Model for the structure and the role of hNinein in position, anchoring
    and microtubule nucleation by the centrosome organization 85
    Figure 9. Morphological changes in SH-SY5Y human neuroblastoma cells
    differentiated by treatment with 10μM retinoic acid for 5 days  87
    Figure 10. Inhibition of GSK3β activity blocks neurite outgrowth in SH-SY5Y
    human neuroblastoma cells  88
    Figure 11. Overexpression of GSKIP inhibits neurite outgrowth in SH-SY5Y
    human neuroblastoma cells  90
    Figure 12. GSKIP has no effects on phosphorylation of GSK3β  91
    Figure 13. GSKIP affects GSK3β to phosphorylate tau on specific site  92
    Figure 14. GSKIP overexpression promotes cell cycle progression in SH-SY5Y
    cells  93
    Figure 15. Overexpression of GSKIP increase the level of β-catenin and cyclin D1 94
    Figure 16. Overexpression of GSKIP results in cyclin D1 acumination in nucleus 95
    LIST OF TABLES
    Table 1. Summary of subcellular localization, intrinsic targeting signals, γ-tubulin
    docking site and phosphorylation site of various hNinein isoforms 96
    Table 2. Summary of different hNinein portions when overexpressed in transfected
    cells. 97
    Table 3. Summary of GSK3β inhibitors affect on neurite outgrowth in RA-mediated
    differentiation SH-SY5Y cells 98
    APPENDIX I The centrosome structure  99
    APPENDIX II The Centrosome Duplication Cycle 100
    APPENDIX III ABBREVIATIONS 101
    APPENDIX IV Antibody for immunofluorescenc 102
    APPENDIX V 103
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    口試委員
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  • 楊倍昌 - 委員
  • 洪義人 - 指導教授
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