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研究生：	魏任宣 Wei, Renn-Shiuan
論文名稱：	癌症轉移相關的NDPK-A藉由eEF1Bα參與在轉譯作用中 Metastasis-associated NDPK-A is involved in translation via eEF1Bα
指導教授：	張玲 Chang, Christina Lin
學位類別：	碩士 Master
系所名稱：	醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	112
中文關鍵詞：	腫瘤轉移、NM23-H1 、NDPK-A 、核苷二磷酸激酶 A 、eEF1Bα 、eEF1β 、轉譯延長
外文關鍵詞：	Metastasis, NM23-H1, NDPK-A, Nucleoside diphosphate kinase A, eEF1Bα, eEF1β, Eukaryotic translation elongation factor 1
相關次數：	點閱：147 下載：0
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腫瘤轉移是導致患者病情惡化並造成死亡的主要因素，但目前對於腫瘤轉移的分子機制尚未完全瞭解。一種核苷二磷酸激酶 A (NDPK-A) 被發現與腫瘤轉移有關，此蛋白質由 NM23-H1基因負責製造。本實驗室專注於與NDPK-A 相互作用的蛋白質，想藉此瞭解 NDPK-A 在腫瘤轉移中所扮演的角色；在前人酵母菌雙雜合系統和免疫沉澱的實驗中，發現一轉譯延長因子 (eEF1Bα) 會與 NDPK-A 交互作用。我運用聚組胺酸沉澱蛋白質的方法，証實了此二種蛋白質的交互作用。另外在冷光酶酵素活性實驗中，我觀察到在神經母細胞瘤中，正常的NDPK-A會提高50%的典型轉譯效能，但失去磷酸轉移酶的活性的突變株則無此現象；更重要的是，一種與轉移相關的突變 NDPK-A 會促使典型的轉譯效能增加兩倍，且內部核醣體進入位的轉譯效能增加一倍半。另外，此種突變的 NDPK-A也會增加蛋白質的新合成，並在缺乏養分的情況下會維持轉譯的功能。總而言之，此種與轉移相關的突變 NDPK-A更能提升轉譯效能，且磷酸轉移酶的活性似乎是 NDPK-A 增加轉譯效能的必要的因素。我的實驗結果提出一種新的概念：顯示出腫瘤轉移與轉譯調控之間的聯繫。

Metastasis is a major cause of death in cancer patients, however, its molecular mechanism remain largely unclear. The nm23-H1 gene encoding nucleotide diphosphate kinase A (NDPK-A) was first discovered as a metastasis-associated gene. Our lab further identified the S120G mutation in patients with advanced neuroblastoma. To understand the molecular mechanism of NDPK-A in tumor metastasis, we have found that NDPK-A interacted with a translation elongation factor, namely eEF1Bα, by yeast two-hybrid system and immunoprecipitation. In this thesis, a nickel pull-down assay also confirmed such an interaction. In an in-vivo dual-luciferase reporter system, NDPK-A and its S120G mutant (NDPK-AS120G) increased cap-dependent translation by 1.5 and 2 folds respectively. Moreover, NDPK-AS120G but not wild type NDPK-A enhanced IRES-dependent translation by 1.5 folds. However, an enzymatically inactive NDPK-AH118F did not show detectable effect on translation efficiency. NDPK-AS120G also increased new protein synthesis, while retaining translation during early period of serum starvation. Overall, NDPK-AS120G was more effective than its wild type in enhancing translation, and the phosphotransferase activity was required for NDPK-A mediated translation. Our findings suggest a novel link between tumor metastasis and translation control.

Table of Contents
Introduction
1. Translation	1
2. Translational Elongation Factor and Tumorigenesis	2
3. NM23/NDPK	5
4. NDPK-A and Metastasis	6
5. Hypothesis	9
Materials and methods
1. Cell line & Cell culture	10
2. Transfection	10
3. The nickel pull-down assay	12
4. Western blot analysis	12
5. Dual-luciferase assay	13
6. β-Galactosidase (β-GAL) assay	13
7. In vivo [35S] labeling for cells	14
8. Two-dimensional electrophoresis	14
9. Stable clones generation	15
Results
1. Construction	16
1.1 Maps of cloning vector and plasmids expressing NDPK-A, NDPK-AS120G & NDPK-AH118F variants	16
1.2 Expression of deletion mutants of eEF1Bα	16
2. Interaction of NDPK-A and eEF1Bα in the nickel pull-down assay	17
2.1. Interaction of exogenous eEF1Bα and exogenous NDPK-A	17
2.2. Interaction of eEF1Bα and NDPK-A variants in the nickel pull-down assay	17
2.3. Interaction of wild type NDPK-A and eEF1Bα variants in the nickel pull-down assay	18
3. Increase of translation efficiency by metastasis-associated NDPK-A	19
3.1 H118 is required for NDPK-A increased translation efficiency in NB69 cells	19
3.2 NDPK-AS120G increased both cap-dependent and IRES-dependent translation efficiency in NB69 cells	19
3.3 NDPK-AS120G increased protein synthesis in NB69 cells	20
3.4 NDPKAS120G retained the translation efficiency during early serum starvation in NB69 cells	20
3.5 NDPKAS120G enhanced the increase of cap-depend and IRES- dependent translation by serum induction in NB69 cells	21
4. Regulation of translation efficiency by eEF1Bα	21
4.1 Overexpression of eEF1Bα decreased translation efficiency in NB69 cells	21
4.2 Knock-down of eEF1Bα increased translation efficiency in NB69 cells	22
Discussion
References
Figures
Figure 1. Maps of cloning vector and plasmids expressing NDPK-A, NDPK-AS120G & NDPK-AH118F	36
Figure 2. Interaction of eEF1Bα and NDPK-A variants in the nickel pull-down assay	38
Figure 3. Interaction of NDPK-A variants and eEF1Bα in the nickel pull-down assay	40
Figure 4. Interaction of wild type NDPK-A and eEF1Bα variants in the nickel pull-down assay	42
Figure 5. H118 is required for NDPK-A increased translation efficiency in NB69 cells	44
Figure 6. NDPK-AS120G increased protein synthesis in NB69 cells	46
Figure 7. NDPKAS120G retained the translation efficiency during early serum starvation in NB69 cells	48
Figure 8. NDPKAS120G enhanced the increase of cap-depend and IRES-dependent translation by serum induction in NB69 cells	50
Figure 9. Overexpression of eEF1Bα decreased translation efficiency in NB69 cells	52
Figure 10. Knock-down of eEF1Bα increased translation efficiency in NB69 cells	54
Figure 11. Knock-down of eEF1Bα increased translation efficiency in HeLa cells	56
Abbreviations
Appendix
Appendix 1. Multipule functions of EF1A [5]	58
Appendix 2. A new unifying nomenclature of eEF1 [95]	58
Appendix 3. High similarity of the guanine exchange domain between eEF1Bα and eEF1Bδ	59
Appendix 4. “Phosphotransferase activity” and “Translation elongation”	59
Appendix 5. Protein-protein interaction in eEF1 complex [30, 95]	60
Appendix 6. Multipule functions of NM23-H1 [90]	60
Appendix 7. IRESs play critical roles in cells [96]	61
Appendix 8. A sketch of two possible interactions between eEF1Bα and NDPK-A	62
Appendix 9. Information of plasmids	63
1. pEF6-V5-His-Topo	63
2. pV5H6-NDPKA_WT	66
3. pV5H6-NDPKA-S120G	70
4. pV5H6-NDPKA-H118F	74
5. pV5H6-eEF1Bα-WT	78
6. pV5H6-eEF1Bα-N	81
7. pV5H6-eEF1Bα-C	84
8. pIRES-XbaI Plasmid	87
9. pIRES-BFP Plasmid	90
10. pIRES-R/GFP_TAA-Hyg	93
11. pIRES-R/GFP_TAG-Hyg	97
12. pDsRed1-N1-MYC (TAA)	101
13. pDsRed1-N1-MYC (TAG)	104
14. pDsRed1-N1-MYC (TGA)	107
15. pRMF Plasmid	110

                                    

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