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系統識別號 U0026-2008201015463200
論文名稱(中文) 載脂蛋白AI磷酸化修飾的功能性分析
論文名稱(英文) The Functional Analysis of Phosphorylation on Apolipoprotein A-I
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 洪淑婷
研究生(英文) Shu-Ting Hung
學號 t3697104
學位類別 碩士
語文別 英文
論文頁數 93頁
口試委員 指導教授-楊孔嘉
口試委員-傅子芳
召集委員-黃暉升
口試委員-高照村
中文關鍵字 載脂蛋白AI  磷酸化  肝醣合成激酶 
英文關鍵字 apoAI  phosphorylation  secretion  GSK3β 
學科別分類
中文摘要 載脂蛋白AI (apoAI) 為小腸及肝臟所製造及分泌,為主要組成高密度脂蛋白 (HDL) 的蛋白質成份。磷脂質及膽固醇從周邊細胞運送回肝臟的過程稱為膽固醇的逆運轉,高密度脂蛋白參與在此過程中。血液循環中低量的載脂蛋白AI被視為是一個心血管疾病的危險因子並且與血液中高密度脂蛋白的減少有密切的相關性。我們實驗室先前所做的蛋白質體研究中,載脂蛋白AI上有存在新發現的後轉譯修飾 (PTM) -磷酸化 (phosphorylation)。磷酸化修飾被發現在載脂蛋白AI的第31號、142號,228號絲胺酸 (serine) 位點上,以及在第161號、197號蘇胺酸 (threonine) 位點上。因此本研究的特定目的想要探討磷酸化修飾對於載脂蛋白AI分泌的影響。人類載脂蛋白AI (prepro-apoAI) 與C端FLAG-tag接合產生一個融合蛋白(AI-FLAG)並且可在HepG2細胞中表現。利用丙胺酸 (alanine) 置換於五個可能的位點上並且在不同的細胞株中表現,包含了CHO-K1、HEK 293T以及Huh7細胞。實驗結果發現AI-FLAG融合蛋白在這些細胞中的表現及分泌量有不同的差異。這樣的結果代表著載脂蛋白的表現及分泌會受到特定細胞類型的因子所調控。接著不同的丙胺酸 (alanine)或麩酸(glutamic acid)置換於可以避免被辨認載脂蛋白AI小髮夾RNA (shRNA) 辨認的AI-FLAG (AI-FLAG-3+4R)上。將這些突變送進內生性載脂蛋白AI被降低的HepG2細胞中後發現到第31號及228號絲胺酸 (serine) 位點的磷酸化或許會影響載脂蛋白的分泌功能。而磷酸化的載脂蛋白AI可被辨認磷酸化-絲胺酸的抗體以免疫沉澱的方式所偵測到,這結果顯示了載脂蛋白AI的磷酸化修飾是位於絲胺酸位點上。在利用激酶與載脂蛋白AI共轉染的實驗中顯示超量表現肝醣合成激酶 (GSK3β)會降低載脂蛋白AI的分泌。這樣的結果代表著載脂蛋白AI可能為肝醣合成激酶的標的或者肝醣合成激酶間接調控。綜合以上結果,我們的實驗發現第31號及228號絲胺酸位點的磷酸化會調控載脂蛋白AI的分泌並且發現到肝醣合成激酶(GSK3β) 會調控載脂蛋白AI的分泌。
英文摘要 Apolipoprotein A-I (apoAI), expressed and secreted by intestine and liver, is the major protein component of high-density lipoprotein (HDL) which participates in transportation of phospholipid and cholesterol from peripheral cells back to liver (a process called reverse cholesterol transport). Low circulating apoAI levels were considered to be an independent risk factor for cardiovascular disease and are closely associated with low HDL cholesterol levels. Previous proteomic studies in our lab have identified novel post-translational phosphorylations of apoAI at Ser31, Ser142, Thr161, Thr197, and Ser228 sites. The specific aim of this study was to elucidate the effects of phosphorylation modification on apoAI functions in terms of protein secretion. Human prepro-apoAI (267 amino acids) fused with a C-terminal FLAG-tag. Ala substitutions were conducted to the five candidate sites and expression in different cell lines, including CHO-K1, HEK 293T, and Huh7. The expression and secretion of the mutated AI-FLAG were different in these cells. The results suggested that expression and secretion of apoAI are influenced by cell-type specific factors. Ala or Glu substitutions were further introduced to the shRNA-resistant AI-FLAG mutant construct which could avoid targeting by shAI-3 and shAI-4. Expression of these mutated AI-FLAG in endogenous apoAI knockdown HepG2 cells showed that phosphorylation on Ser31 and Ser228 residues may play a major role in regulation of apoAI secretion. The phophorylated apoAI could be immunoprecipitated with antibodies recognizing phosphorylated serine, indicating that apoAI was phosphorylated at Ser residues. In an experiment with co-transfection of apoAI and kinases showed that overexpression of GSK3β decreased the secretion level of apoAI, indicated that apoAI may be the target of this kinase or GSK3β might regulate apoAI secretion via an indirect mechanism. In conclusion, this study has identified two phosphorylation sites (Ser31, and Ser228) which might regulate the secretion ability of apoAI and GSK3β might participate in the control of apoAI secretion.
論文目次 Abstract (中文摘要) I
Abstract II
Acknowledgment IV
Index V
Indexs of tables and figures IX
Chapter 1: Introduction 1
1. Apolipoprotein A-I (apoAI) 2
1.1. Gene structure and transcription 2
1.2. Protein structure in the lipid-free state 3
2. The roles of apoAI in HDL function 5
3. ApoAI and HDL structure 6
4. Reverse cholesterol transport (RCT) 6
5. Naturally occurring apoAI variants 7
6. Post-translational modifications of proteins 7
7. PTM of apolipoprotein 8
8. Clinical associated references of different apoAI isoforms 9
9. Study goal and experimental design 11
Chapter 2: Materials and methods 12
1. Cell line and culture system 14
1.1 CHO-K1 cell line 14
1.2 HEK 293T cell line 14
1.3 Huh7 cell line 14
1.4 HepG2 cell line 14
1.5 Cell culture system 15
1.6 Preparation of frozen cells 15
1.7 Defrozen cells 16
2. Knockdown endogenous apoAI of HepG2 cells 17
2.1 Short haipin RNA (shRNA) targeting apoAI transiently transfected into HepG2 cells 17
2.2 Western blot analysis of apoAI in shRNA transiently transfected cells 18
2.3 Lentivirus production 21
2.4 Lentivirus transduction of HepG2 cells and calculation the multiplicity of infection (MOI) of lentivirus 22
2.5 Establish stably apoAI knockdown cell lines 23
3. Establish apoAI-TA construct 24
3.1 Total RNA extraction from HepG2 cells 24
3.2 Reverse Transcription (RT) 25
3.3 Polymerase Chain Reaction (PCR) 26
3.4 DNA eletrophoresis 27
3.5 Gel extraction 27
3.6 TA Cloning 28
3.7 Transformation 29
3.8 Minimum-scale preparation of plasmids 29
3.9 Restriction enzyme digestion 31
4. Establish apoAI-FLAG amino acid substitution vectors 31
4.1 Preparation of apoAI fragments and vector for apoAI-FLAG construction 31
4.2 Establish apoAI-FLAG expression vector 32
4.3 Site-direct mutagenesis by QuickChage II XL Site-directed Mutagenesis kit 33
4.4 Medium scale preparation of plasmids 34
5. Immunoprecipitation of phosphorylated apoAI 35
5.1 Immunoprecipitation with anti-phospho-Ser antibody 35
6. Immunofluorescence Assay (IFA) 37
Chapter 3: Results 38
1. Endogenouse apoAI was silenced by transiently transfection of lentiviral-based shRNA into HepG2 cells 39
2. Stablely knockdown of apoAI in HepG2 cells by lentiviral-mediated shRNA transduction 39
3. Construction of apoAI-FLAG and expression in cell lines 40
4. The secretion ability was affected by Ala-mutated on AI-FLAG 41
5. Introduction of mutations into shRNA target sequence on AI-FLAG construct. 42
6. Phosphorylation on Ser31 and Ser228 residues affected apoAI-FLAG secretion 42
7. ApoAI was phosphorylated at Ser residues 43
8. The effects of GSK3β and ERK1/2 on apoAI secretion 44
Chapter 4: Discussion 45
1. Construction of apoAI-FLAG 46
2. The expression of apoAI in different cell lines 47
3. The effects of amino acid variants on apoAI 48
4. Phophorylated modification plays a role in apoAI secretion 49
5. The signals involved in apoAI secretion 50
6. Conclusion 51
References: 52
Tables and Figures 61
Appendix 81
1. The preparation for experimentry reagent 83
1.1. Culture medium (1L) 83
1.2. 1X phosphate buffered saline (PBS) (1L) 83
1.3. 1X Trypsin-EDTA (50ml) 83
1.4. Frozen medium (50ml) 83
1.5. DEPC-H2O (1L) 84
1.6. IP lysis buffer (500ml) 84
1.7. IP washing buffer (500ml) 84
1.8. Lysis buffer 84
1.9. Resolving gel solution (10%) 85
1.10. Stacking gel(5%) 85
1.11. 5X running buffer (1 L) 85
1.12. 4X sample buffer dye (10 ml) 86
1.13. 10X transfer buffer(1 L) 86
1.14. 1X PBST (1 L) 87
1.15. 5% not-fat milk (100 ml) 87
1.16. 10X TBE buffer 87
1.17. 1.5% agarose gel 87
2. Reagents and Instruments 89
2.1. Reagents 89
2.2. Restric enzyme 91
2.3. Antibody 91
2.4. Instruments 91
2.5. Consumables 92
Author 93
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