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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華(Reuy-Hwa Chen) | |
| dc.contributor.author | Wei-Chein Yuan | en |
| dc.contributor.author | 袁維謙 | zh_TW |
| dc.date.accessioned | 2021-06-07T17:47:28Z | - |
| dc.date.copyright | 2013-07-25 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-06-24 | |
| dc.identifier.citation | References
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Binding of cargo sorting signals to AP-1 enhances its association with ADP ribosylation factor 1-GTP. J Cell Biol 180, 467-472. Lee, J.S., Kim, Y., Kim, I.S., Kim, B., Choi, H.J., Lee, J.M., Shin, H.J., Kim, J.H., Kim, J.Y., Seo, S.B., et al. (2010a). Negative regulation of hypoxic responses via induced Reptin methylation. Mo | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15525 | - |
| dc.description.abstract | KLHL20 是一個BTB-Kelch蛋白，在我們實驗室中發現它可以做為一個Cul3-based E3接合酶的受質接收器。KLHL20主要位於高基氏體中，但是也有一小部分的KLHL20會分布於PML-NB，因此這暗示著在細胞中不同位置的KLHL20可能具有不同的功能。在這本論文的第一個部分，我們發現KLHL20可以促進PML的泛素化。PML是一個腫瘤抑制因子，它的表現量在各式人類癌症中被抑制。在我們的研究中發現PML必須被Pin1於其S518位置進行異構化後才能被KLHL20所辨認並且促進PML的降解，進而抑制PML所參與的各式功能，包括促進細胞凋亡和老化以及抑制細胞形變及癌化。因此，KLHL20可以透過促進PML的降解，進而幫助細胞存活及癌化。除此之外，我們也發現在缺氧的情況下HIF-1會增加KLHL20的表現，進而促進PML的降解。此降解路徑在缺氧情況下以雙負回饋機制誘發HIF-1a表現，進而促進許多腫瘤缺氧反應。在人類前列腺癌中，HIF-1a、KLHL20及Pin1為過量表現，而PML的表現量則降低，後者表現量與前三者為負相關，PML降解路徑的高度活化則與腫瘤之進程息息相關，於晚期腫瘤細胞中更為顯著。我們的研究顯示KLHL20所參與的PML降解與HIF-1a的自動調控機制在腫瘤進程中扮演舉足輕重的角色。
在本論文的第二個部分，我們發現KLHL20也可以藉著幫助後高基氏體囊泡的生成進而促進從TGN至細胞膜以及核內體的貨物運送。Cul3-KLHL20泛素接合酶可以催化Crn7的K33類型泛素化作用，此類型的泛素化並不會促進降解作用，而是幫助Crn7與Eps15結合進而促進Crn7坐落於TNG。當抑制Crn7的泛素化或是阻斷它與Eps15的作用時，會減少位於TGN的肌動蛋白點(actin foci)形成，因此抑制管狀囊泡的產生。我們的研究發現KLHL20所參與的Crn7上K33類型的泛素化，在後高基氏體囊泡運送中扮演著舉足輕重的角色，因此解開了K33類型泛素鍊的重要性，可以在後高基氏體囊泡形成的過程中用來連接clathrin接受器Eps15與位於TGN的肌動蛋白改建(actin-remodeling)過程。 | zh_TW |
| dc.description.abstract | KLHL20, a BTB-Kelch protein, has been shown to function as a substrate adaptor of Cul3-based E3 ubiquitin ligase in our laboratory. Intriguingly, KLHL20 mainly localizes at the Golgi apparatus, while a small portion localizes at PML-NBs, thus suggesting the multiple functions of KLHL20 in different subcellular compartment. In the first part of this dissertation, we show that KLHL20 is responsible for the ubiquitination of PML, a tumor suppressor downregulated in various human cancers. Targeting PML to KLHL20 requires Pin1-mediated prolyl cis/trans isomerization of PML at the S518-P519. The Pin1/KLHL20 pathway induces PML proteolysis, thereby attenuating multiple PML biological functions, including promotion of apoptosis and senescence and suppression of cell transformation and tumorigenesis. Accordingly, KLHL20 potentiates cell survival and tumorigenesis partly through PML degradation. Additionally, we also show that KLHL20, which is induced by HIF-1, coordinates with the action of Pin1 to mediate hypoxia-induced PML proteasomal degradation. Furthermore, this PML destruction pathway constitutes a double negative feedback mechanism to amplify HIF-1a expression, thereby triggering multiple tumor hypoxia responses. In human prostate cancer, overexpression of HIF-1a, KLHL20, and Pin1 correlates with PML downregulation, and hyperactivation of the PML destruction pathway is associated with disease progression. Our study identifies a key pathway that controls PML protein stability and suggests a contribution of this pathway to aberrant PML downregulation in human cancers.
In the second part of this dissertation, we show that KLHL20 is also crucial for the cargo trafficking from trans-Golgi network (TGN) to plasma membrane and endosomes by promoting the biogenesis of post-Golgi carriers on the basis of its Golgi localization. The Cul3-KLHL20 complex catalyzes a non-degradable, K33-linked polyubiquitination on coronin 7 (Crn7), which contributes to Crn7 TGN localization through an interaction with Eps15. Blockage of Crn7 ubiquitination or its interaction with Eps15 impairs the formation of F-actin foci at TGN, thereby inhibiting the generation of tubular carriers. Our study reveals a role of KLHL20-mediated K33-ubiquitination of Crn7 in post-Golgi transport, provides a cellular decoding mechanism for this ubiquitin chain type, and reveals the importance of this ubiquitination in linking clathrin adaptor Eps15 to the TGN actin-remodeling process during post-Golgi carrier biogenesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T17:47:28Z (GMT). No. of bitstreams: 1 ntu-102-D97b46009-1.pdf: 14960318 bytes, checksum: 8797d86f3d7a51b9611999100b9e08bc (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | Table contents
Abbreviations 9 Abstract 11 中文摘要 12 Literature Review 13 1. Ubiquitination 13 1.1 The cascade of ubiquitination 13 1.2 The different topologies of ubiquitination 13 1.3 The multiple functions of ubiquitination 14 1.4 The diversity of E3 ubiquitin ligases 14 1.5 BTB-kelch protein and KLHL20 16 2. Ubiquitin binding proteins 18 2.1 Binding with ubiquitin 18 2.2 Eps15 19 3. Ubiquitin and cancer 21 4. Hypoxia responses 22 4.1 Hypoxia and Cancer 22 4.2 Regulation of hypoxia-inducible factors (HIFs) 22 4.3 HIFs in cancer progression 24 5. PML 25 5.1 PML and PML nuclear body 25 5.2 PML tumor suppressive functions 26 5.3 Regulation of PML expression and stability 28 6. Golgi complex 30 6.1 Golgi structure, dynamics, and functions 30 6.2 TGN and post-Golgi carrier formation 32 7. Ubiquitin and membrane trafficking 36 7.1 Clathrin-dependent or -independent internalization 36 7.2 ESCRT-mediated MVB sorting 37 7.3 Regulation of endocytic proteins by ubiquitination 37 8. Coronin family 38 8.1 Coronin family 38 8.2 Coronin protein as actin regulator 38 8.3 Coronin 7 40 Experimental rationale 42 Chapter I 43 The KLHL20-Cullin3 ubiquitin ligase links the activities of CDK and Pin1 to control the degradation of PML tumor suppressor 43 Introduction 44 Results 45 KLHL20 colocalizes with PML in PML-NBs and regulates the abundance of PML-NBs. 45 KLHL20 promotes PML ubiquitination and proteasomal degradation. 46 Regulation of KLHL20-mediated PML degradation by CDK1/2. 46 KLHL20 mediates cell cycle-dependent regulation of PML. 47 S518 phosphorylation by CDK1/2 targets PML to KLHL20-based E3 ligase. 48 Pin1 potentiates the recruitment of CDK-phosphorylated PML to KLHL20-based E3 ligase. 48 S518 mutation enhances the tumor suppressive functions of PML. 49 KLHL20 promotes cell survival and tumorigenesis through a PML-dependent manner. 50 KLHL20-mediated PML destruction amplifies tumor hypoxia responses. 51 KLHL20-mediated PML destruction promotes tumor angiogenesis and growth in vivo. 52 HIF-1a/KLHL20/Pin1/PML pathway is manifested in human prostate cancer and is upregulated in high-grade tumors. 52 Discussion 53 Materials and Methods 56 Plasmids 56 Antibodies and reagents 56 Cell culture, transfection, and establishment of stable cell lines 56 Lentivirus production and infection 57 In vitro and in vivo ubiquitination 57 Apoptosis assay 58 Cell migration assays 58 Tissue specimens and IHC analysis 58 Soft-agar colony-formation assay and Xenotransplantation. 59 Immunoprecipitation and GST pull down 59 Senescence assay 60 Immunofluorescence analysis 60 qPCR analysis 60 Immunofluorescence analysis 60 IHC analysis on xenograft tumors 61 Chapter II 62 Atypical ubiquitination of Crn7 by Cul3-KLHL20 complex regulates F-actin at TGN to promote post-Golgi trafficking 62 Introduction 63 Results 64 KLHL20 is localized to Golgi through an Arf1-dependent mechanism and contributes to Golgi ultrastructure. 64 Cul3-KLHL20 complex contributes to anterograde transport 65 KLHL20 depletion impairs the formation of TGN tubular carrier precursors 66 Cul3-KLHL20 targets Crn7 for K33-linked polyubiquitination 66 KLHL20-mediated Crn7 ubiquitination contributes to the post-Golgi trafficking. 67 KLHL20-mediated Crn7 ubiquitination contributes to the assembly of TGN-associated F-actin 68 Ubiquitinated Crn7 interacts with Eps15 at Golgi 69 Interaction with Eps15 enhances the TGN-localization of Crn7 to promote F-actin assembly. 70 Discussion 70 Materials and Methods 73 Plasmids 73 Antibodies and reagents 73 Cell culture, transfection, and establishment of stable cell lines 73 RNA interference 74 Immunoprecipitation and GST pull down 74 Isolation of Golgi fractions 75 Transmission electron microscope 75 Immunofluorescence analysis 75 VSVG transport assay 76 GPI-GFP and MPR transport assays 76 CTxB and STxB transport assays 76 Quantitative analysis 76 Time-lapse fluorescence microscopy 77 In vivo ubiquitination assay 77 Yeast two-hybrid screen and assay 77 Nanoflow HPLC-MS/MS 78 Actin cosedimentation assays 78 Figures 79 Fig. 1. Endogenous KLHL20 and PML are colocalized in PML-NBs. 79 Fig. 2. KLHL20 and PML colocalize in the periphery of PML-NBs. 80 Fig. 3. Overexpression of KLHL20 downregulates PML-NBs and PML immunofluorescent intensity. 81 Fig. 4. KLHL20 siRNA upregulates PML-NBs and PML immunofluorescent intensity. 82 Fig. 5. Ubiquitination of PML-I in vivo by KLHL20-Cul3. 83 Fig. 6. Sumoylation is dispensable for PML ubiquitination mediated by KLHL20. 84 Fig. 7. PML-IV ubiquitination in vivo is stimulated by overexpression of KLHL20 and Cul3. 85 Fig. 8. Overexpression of KLHL20, but not KLHL20m6, promoted the turnover of both PML-I and PML-IV. 86 Fig. 9. Overexpression of KLHL20, but not KLHL20m6, reduced the abundance of most, if not all, PML isoforms detected in HeLa cells. 87 Fig. 10. KLHL20 siRNA decreases PML ubiquitination. 88 Fig. 11. KLHL20 depletion upregulates endogenous PML. 89 Fig. 12. serum starvation of A431 cells caused a concomitant elevation of PML steady-state level and an enrichment of G1 population. 90 Fig. 13. Androgen is required for KLHL20-dependent PML downregulation in LNCaP cells. 91 Fig. 14. serum starvation of DU145 cells caused a concomitant elevation of PML steady-state level. 92 Fig. 15. The upregulation of endogenous PML by KLHL20 siRNA was observed in Pml+/+ and Pml-/- MEFs. 93 Fig. 16 . siRNA-mediated downregulation of KLHL20 and/or PML in PC3 cells. 94 Fig. 17. KLHL20 can destabilize PML 3KR mutant. 95 Fig. 18. KLHL20 binds PML 3KR as efficiently as WT PML. 96 Fig. 19. Sumoylation of PML at K490 does not affect its degradation induced by KLHL20. 97 Fig. 20. Overexpression of CDK2-cyclin E or CDK1-cyclin B, but not CDK6-cyclin D enhanced PML downregulation by KLHL20. 98 Fig. 21. CDK-mediated phosphorylation enhances PML ubiquitination by KLHL20-based E3 ligase in vitro. 99 Fig. 22. PML directly interacts with KLHL20 through an S518 phosphorylation-dependent manner. 100 Fig. 23. S518 mutation stabilizes PML. 101 Fig. 24. The S518 and P519 residues (indicated by asterisks) are conserved among various vertebrates. 102 Fig. 25. S518 phosphorylation is required for PML interaction with Pin1 in vivo. 103 Fig. 26. Pin1 binds CDK-phosphorylated PML in vitro. 104 Fig. 27. Pin1 enhances KLHL20-mediated ubiquitination of CDK-phosphorylated PML. 105 Fig. 28. Pin1 silencing abolished PML-I interaction with KLHL20 and ubiquitination by KLHL20-Cul3. 106 Fig. 29. Pin1 promotes KLHL20-induced PML degradation. 107 Fig. 30. Pin1 is required for CDK-dependent PML degradation. 108 Fig. 31. Pin1 is critical for KLHL20-mediated PML degradation. 109 Fig. 32. Pin1 promotes PML ubiquitination through KLHL20. 110 Fig. 33. Pin1 promotes PML degradation through KLHL20. 111 Fig. 34. S518 mutation enhances the pro-apoptotic function of PML in MEF cells. 112 Fig. 35. S518 mutation increases the senescence-induction capability of PML. 113 Fig. 36. S518 mutation enhances the functions of PML in suppressing cell transformation. 114 Fig. 37. Depletion of KLHL20 sensitizes cells to apoptosis through a PML-dependent manner. 115 Fig. 38. KLHL20 promotes cell transformation through PML degradation. 116 Fig. 39. KLHL20 promotes tumor growth through PML degradation. 117 Fig. 40. Hypoxia treatment of control siRNA-expressing PC3 cells resulted in a decrease of apoptosis induced by doxorubicin, and this effect was enhanced by PML knockdown. 118 Fig. 41. The chemoresistance effect of hypoxia was abrogated by KLHL20 silencing and rescued by KLHL20 and PML double knockdown. 119 Fig. 42. EMT assays for PC3 cells expressing indicated siRNAs cultured in normoxia or hypoxia for 24 hr. 120 Fig. 43. PC3 cells expressing indicated siRNAs were assayed for migration under normoxia or hypoxia for 12 h (top) or 16 h (bottom). 121 Fig. 44. PML S518A blocks tumor hypoxia responses 122 Fig. 45. In vitro proliferation rate (A) and soft agar colony-formation ability (B) of the indicated cells. 123 Fig. 46. KLHL20-Mediated PML Destruction Promotes Tumor Growth 124 Fig. 47. KLHL20-Mediated PML Destruction Promotes Tumor Angiogenesis. 125 Fig. 48. Western blot analysis of the expression of PML, KLHL20, and HIF-1a in tumors derived from indicated cells. 126 Fig. 49. IHC analysis for HIF-1a, and PML using comparable-sized tumors derived from indicated cell lines. 127 Fig. 50. The effects of PML depletion on cell proliferation, soft agar colony-formation, tumor growth in vivo, and angiogenesis. 128 Fig. 51. Representative IHC results for HIF-1a, KLHL20, Pin1 and PML in a BPH specimen and a prostate tumor specimen (A) as well as in a prostate tumor specimen with a benign ductal structure inside (B). 129 Fig. 52. The HIF-1a/KLHL20/Pin1/PML Pathway Is Manifested in Human Prostate Cancer and Associated with High-Grade Tumor 130 Fig. 53. Model for KLHL20-mediated PML degradation in tumor development and progression under hypoxia and normoxia conditions. 131 Fig. 54. Coordinated upregulation of KLHL20 and HIF-1/HIF-2 targets in human colon cancers. 132 Fig. 55. Hypoxia does not drastically alter PML-NBs. 133 Fig. 56. Hypoxia increases global SUMO-1 conjugation, PML SUMO-1 conjugation, and PML interaction with Daxx. 134 Fig. 57. KLHL20 is localized to Golgi. 135 Fig. 58. Localization of the endogenous and exogenous KLHL20. 136 Fig. 59. Enrichment of KLHL20 in the Golgi fraction. 137 Fig. 60. Distribution of KLHL20 and TGN46 in BFA treated Cos-1 cells. 138 Fig. 61. The Golgi morphology in KLHL20 knockdown cells. 139 Fig. 62. KLHL20-Cul3 complex potentiates anterograde trafficking of VSVG. 140 Fig. 63. KLHL20-Cul3 complex potentiates anterograde trafficking of MPR. 141 Fig. 64. KLHL20 does not affect LAMP-2 glycosylation. 142 Fig. 65. KLHL20 does not affect retrograde trafficking of CTxB. 143 Fig. 66. KLHL20 does not affect retrograde trafficking of STxB. 144 Fig. 67. The anterograde trafficking function of KLHL20 is dependent on the formation of Cul3-KLHL20 E3 ligase complex. 145 Fig. 68. Localization of the exogenous KLHL20 m6. 146 Fig. 69. Cul3 potentiates anterograde trafficking of VSVG 147 Fig.70. KLHL20 controls the formation of tubular carrier precursors at TGN. 149 Fig. 71. KLHL20 interacts with Crn7. 150 Fig. 72. KLHL20 promotes Crn7 ubiquitination. 151 Fig. 73. KLHL20 does not affect Crn7 expression and turn-over rate. 152 Fig. 74. Effects of indicated ubiquitin KR mutants or ubiquitin K-only mutants on KLHL20-mediated Crn7 polyubiquitination. 153 Fig. 75. Tandem mass spectrum of a peptide derived from ubiquitinated Crn7 showing a ubiquitin conjugation at the K33 residue of ubiquitin. 154 Fig. 76. SWISS-MODEL structural modeling of the KLHL20 kelch domain. 155 Fig. 77. Mapping the residues in KLHL20 and Crn7 involved in their interaction. 156 Fig. 78. KLHL20-3A mutant could not confer Crn7 ubiquitination, whereas the Crn7△835-865 mutant could not be efficiently ubiquitinated by KLHL20. 157 Fig. 79. KLHL20-mediated Crn7 polyubiquitination influence on post-Golgi trafficking of VSVG. 158 Fig. 80. KLHL20-mediated Crn7 polyubiquitination influence on post-Golgi trafficking of MPR. 159 Fig. 81. Depletion of K33-linked ubiquitin chain impaired post-Golgi trafficking of VSVG 160 Fig. 82. Actin sedimentation assay for the effects of Crn7 and ubiquitinated Crn7 on F-actin binding. 161 Fig. 83. KLHL20 does not affect the trafficking of GFP-GPI. 162 Fig. 84. KLHL20 depletion downregulates TGN-associated F-actin puncta. 163 Fig. 85. KLHL20 and Crn7 contributes to the assembly of TGN-associated F-actin. 164 Fig. 86. KLHL20-mediated Crn7 ubiquitination contributes to the assembly of TGN-associated F-actin. 165 Fig. 87. Crn7△835-865 displayed a comparable F-actin-binding capability relative to the wild type protein 166 Fig. 88. Depletion of K33-linked ubiquitin chain downregulated TGN-associated F-actin puncta 167 Fig. 89. Ubiquitinated Crn7 binds Eps15 but not GGA3. 168 Fig. 90. Depletion of KLHL20 blocked the interaction between endogenous Crn7 and endogenous Eps15 169 Fig. 91. Depletion of K33-linked ubiquitin chain blocked the interaction between Crn7 and endogenous Eps15 170 Fig. 92. Ubiquitin-dependent interaction of Crn7 with Eps15 on Golgi membrane. 171 Fig. 93. Poly-ubiquitinated Crn7 interacts directly with full length Eps15 (A) or Eps15 UIM domains (B). 172 Fig. 94. KLHL20 depletion attenuates the TGN-localization of Crn7 173 Fig. 95. Depletion of K33-linked ubiquitin chain impairs the TGN-localization of Crn7 174 Fig. 96. Eps15 promotes the TGN-localization of Crn7 175 Fig. 97. Eps15 promotes the TGN-localization of Crn7 through its UIM domain. 176 Fig. 98. Eps15 contribute to F-actin assembly through its UIM domain. 177 Fig. 99. Eps15 promotes post-Golgi trafficking through its UIM domain. 178 Fig. 100. Model for KLHL20-mediated Crn7 ubiquitination in regulating TGN-associated F-actin assembly and post-Golgi trafficking. 179 Appendix 180 Appendix I: In vitro ubiquitination of PML by KLHL20-Cul3-Roc1 complex. 180 Appendix II: the pan-CDK inhibitor roscovitine blocked KLHL20-mediated degradation of PML-I. 181 Appendix III: CDK1/2 are required for KLHL20-mediated PML ubiquitination. 182 Appendix IV: CDK phosphorylates PML at S518 in vitro. 183 Appendix V. The specificity of p518PML antibody. 184 Appendix VI. Inhibition of CDK decreases PML S518 phosphorylation in vivo. 185 Appendix VII. DN mutant of CDK1 or CDK2 blocked PML S518 phosphorylation in vivo. 186 Appendix VIII: Overexpression of CDK1-cyclin B or CDK2-cyclin E enhanced S518 phosphorylation in vivo. 187 Appendix IX: PML S518A was defective in KLHL20-induced ubiquitination and downregulation in vivo. 188 Appendix X: EMT assays for cells cultured in normoxia or hypoxia for 24h. 189 References 190 | |
| dc.language.iso | en | |
| dc.subject | 肌動蛋白骨架 | zh_TW |
| dc.subject | 泛素化 | zh_TW |
| dc.subject | KLHL20 | zh_TW |
| dc.subject | PML | zh_TW |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | Crn7 | zh_TW |
| dc.subject | Eps15 | zh_TW |
| dc.subject | 後高基氏體囊泡運送 | zh_TW |
| dc.subject | ubiquitination | en |
| dc.subject | actin | en |
| dc.subject | post-Golgi trafficking | en |
| dc.subject | Eps15 | en |
| dc.subject | Crn7 | en |
| dc.subject | hypoxia | en |
| dc.subject | PML | en |
| dc.subject | KLHL20 | en |
| dc.title | 探討KLHL20在腫瘤進程與囊泡運送之調控分析 | zh_TW |
| dc.title | Functional characterization of KLHL20 in tumor progression and vesicular trafficking | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 張智芬(Zee-Fen Chang),李芳仁(Fang-Jen Lee),施修明(Hsiu-Ming Shih),沈孟儒(Meng-Ru Shen),王昭雯(Chao-Wen Wang) | |
| dc.subject.keyword | 泛素化,KLHL20,PML,缺氧,Crn7,Eps15,後高基氏體囊泡運送,肌動蛋白骨架, | zh_TW |
| dc.subject.keyword | ubiquitination,KLHL20,PML,hypoxia,Crn7,Eps15,post-Golgi trafficking,actin, | en |
| dc.relation.page | 218 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-06-24 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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