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研究生：	廖婉玲 Liao, Wan-Lin
論文名稱：	人類細胞質磷脂水解酵素A2α及c-Jun 基因表現的後轉錄機制之探討 Characterization of the post-transcriptional regulation mechanism on cytosolic phospholipase A2α and c-Jun
指導教授：	曾大千 Tseng, T. Joseph
學位類別：	博士 Doctor
系所名稱：	生物科學與科技學院 - 生物資訊與訊息傳遞研究所 Insitute of Bioinformatics and Biosignal Transduction
論文出版年：	2011
畢業學年度：	100
語文別：	英文
論文頁數：	132
中文關鍵詞：	後轉錄調控
外文關鍵詞：	post-transcriptional regulation, cPLA2α, HuR, IRES, c-Jun
相關次數：	點閱：126 下載：0
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基因須受到正確的調控才能使細胞適應外界環境的變化。基因的調控可發生在許多層面，除了廣為人知並且已被詳細探討的轉錄方面的調控之外，後轉錄調控機制目前也逐漸地受到重視。後轉錄調控機制的研究層面包括了探討mRNA 的穩定性及蛋白質轉譯的調控。在我們的研究工作中，也針對了這兩方面的調控分成兩個研究主題以期對後轉錄調控有更進一步的了解。首先，在第一部分的研究工作中，我們發現在Interleukin-1β(IL-1β)的刺激下會增加cytosolic phospholipase A2α(cPLA2α) mRNA 的穩定度，透過進一步的研究，我們發現RNA 結合蛋白HuR 會結合到cPLA2α mRNA 的3’端非轉譯區(3’UTR) 且在IL-1β的刺激下會增加HuR 與cPLA2α mRNA 的結合。並且以si-RNA 的技術確認了HuR 在IL-1β所誘導的cPLA2α mRNA 穩定度的增加的確是扮演一重要角色。接著我們也發現 p38 mitogen-activated protein kinase(MAPK) 對於ＨuR T118位置的磷酸化在影響HuR 與cPLA2α mRNＡ的結合是重要的。透過以上的發現讓我們對於調控
cPLA2α mRNA 穩定度的機制有更進一步的了解。而在第二部分的研究中我們則發現人類c-Jun 的5’端非轉譯區 (5’UTR) 具有internal ribosome entry site(IRES)，並且在兩株來自同一病人身上，一株取自原位而另一株取自淋巴轉移的大腸直腸癌的細胞株中發現兩株細胞中c-Jun 蛋白質顯著不同的表現是因為兩株細胞中c-Jun IRES 活性不同所造成的。而在進一步的研究中，我們也發現了RNA結合蛋白hnRNPA2/B1 及hnRNPA1 會影響c-Jun 蛋白質的生合成。在此研究中，我們提出了c-Jun 亦可透過IRES 來調控其蛋白合成而執行其對細胞生理功能的影響。

Cells need to integrate and coordinate at different regulatory layers for precise gene expression and then accommodate the change of environment. Except for the well-known transcriptional regulation, the post-transcriptional regulation is now identified as an indispensible mechanism to fine-tune gene expression.
Post-transcriptional regulation encompasses the regulation of transcript stability and that of translation for protein synthesis. In our studies, we divided our work into two parts. In the first part, we studied the mechanism of interleukin-1β (IL-1β)-induced increase of cytosolic phospholipase A2α(cPLA2α)mRNA stability. In this study, we identified that an RNA-binding protein, HuR, could bind to cPLA2α 3’untranslated region (3’UTR) and found that IL-1β treatment increased the binding between HuR and cPLA2α 3’UTR. Next, we confirmed the functional role of HuR on affecting IL-1β-induced increase of cPLA2α mRNA. Finally, we found that the site of HuR T118 which was phosphorylated by p38MAPK under IL-1β treatment was important to the binding to cPLA2α 3’UTR. Thus,through this work, mechanism on the regulation of cPLA2α mRNA stability was elucidated. In the second part of our work,we focused on the translational regulation of c-Jun protein synthesis. In this study, we identified that the 5’untranslated region (5’UTR) of human c-Jun contained the property of internal ribosome entry site (IRES) by a series of bicistronic reporter assays. And this IRES activity of c-Jun 5’UTR was physiologically significant since it resulted in the difference of c-Jun protein expression between the original portion and the metastatic lymphoid portion of colorectal cancer cell. Next, we found that hnRNPA2/B1 and hnRNPA1, which belong to members of heterogeneous nuclear ribonucleoprotein played functional roles in the synthesis of c-Jun protein. This part of work addressed that the protein synthesis of human c-Jun could be through IRES-dependent translation mechanism and this functional phenomenon has never been mentioned until now.

中文摘要................................................I
Abstract...............................................II
Acknowledgment.........................................III
Contents...............................................IV
Figure index...........................................VIII
Appendix index........................................ X
Abbreviations..........................................XI
Chapter 1. The post-transcriptional regulation mechanism on cPLA2α
Introduction
I. Gene regulation.......................................1
1. Post-transcriptional regulation.......................1
2. mRNA turnover.........................................1
3. Cis-acting elements regulate mRNA decay...............2
II. RNA-binding proteins.................................4
1. RNA-binding proteins targets on AREs..................5
2. Hu family of RNA-binding proteins, HuR................5
III. Physical functions of cytosolic phospholipase A2α...9
1. Families of phospholipase A2..........................9
2. Physiological functions of cPLA2α.....................9
3. Regulation of cPLA2α..................................10
IV. Research aims........................................11
Materials and methods
I. Materials.............................................12
II. Methods
1. Cell culture and IL-1β treatment......................17
2. Reverse Transcription and PCR.........................17
3. Plasmid construction..................................18
4. RNA electrophoresis mobility shift assay (RNA-EMSA)...18
5. Biotin-labeled probe pull-down assay..................19
6. RNA immunoprecipitation assay.........................19
7. RNA interference assay................................19
Results
I. IL-1β signaling increases mRNA stability of the cPLA2α gene…....................................................20
1. IL-1β induces the expression of cPLA2α mRNA and protein..................................................20
2. No significant effect of IL-1β on cPLA2α promoter activity.................................................20
3. IL-1β increases the stability of cPLA2α mRNA..........20
II. The cPLA2α mRNA 3’UTR binds with cytosolic protein complexes................................................21
1. Construction of four different segments of cPLA2α 3’UTR into pGEM-T easy vector..................................21
2. Cytosolic proteins binding to the cPLA2α mRNA 3’UTR...21
III. HuR binds to the 3’UTR of cPLA2α mRNA...............22
1. To identify RNA-binding proteins binding to the cPLA2α
mRNA 3’UTR...............................................22
2. HuR binds to the cPLA2α mRNA 3’UTR....................22
3. Dissection of binding region between HuR and cPLA2α mRNA
3’UTR....................................................23
IV. IL-1β signaling increases the binding between HuR and the 3’UTR of cPLA2α mRNA.................................23
V. Reduction of HuR protein expression decreases the cPLA2α gene expression..........................................24
VI. p38 MAPK pathway mediates cPLA2α mRNA stability through HuR phosphorylation......................................25
1. p38 MAPK regulates IL-1β induced cPLA2α mRNA..........25
2. Phosphorylation of the site of HuR T118 by p38 MAPK
regulates the binding of HuR to cPLA2α mRNA..............25
VII. Effect of HuR T118A phosphorylation on the inflammatory-related gene COX-2..........................26
VIII. IL-1β signaling regulates cPLA2α mRNA in other cell line.....................................................26
1. IL-1β induces cPLA2α mRNA in HeLa cells...............26
2. Reduction of HuR expression inhibits the IL‐1β induced
cPLA2α mRNA expression...................................27
3. IL‐1β signaling increases the binding between HuR, cPLA2α and COX‐2 mRNAs in HeLa cells....................27
Discussion
I. The stability of mRNA influences the induction of genes encoding inflammatory molecules..........................28
II. ARE containing genes in inflammation.................29
III. ARE-mediated signaling pathways in inflammation.....30
IV. Effect of p38 MAPK on HuR............................31
V. Coordination of post-transcriptional events...........32
VI. The regulation of HuR on inflammatory related gene is not an exclusive event...................................33
Chapter 2. The molecular mechanism regulating c-Jun protein synthesis
Introduction
I. Mechanism of protein synthesis in eukaryotic cells.....35
1. Canonical cap-dependent translation initiation.........35
2. Alternative internal route of translation initiation...36
3. Structure of cellular IRES elements....................37
4. Cellular IRES-mediated translation.....................38
5. The role of ITAFs in cellular IRES-mediated translation...............................................38
6. HnRNPA2/B1.............................................39
7. HnRNPA1................................................40
II. Physiological significance of c-Jun...................40
1. History of c-Jun.......................................40
2. Functional roles of c-Jun..............................41
3. Regulation of c-Jun expression.........................42
III. Research aims........................................43
Materials and methods
I. Materials..............................................44
II. Methods
1. Cell culture...........................................49
2. Preparation cell lysates...............................49
3. Reverse transcription-PCR/qPCR.........................49
4. Plasmid construction...................................50
5. Transient transfection.................................50
6. Biotin pulled -down assay..............................50
7. Mass spectrometry analysis.............................51
8. RNA immunoprecipitation assay..........................51
9. RNA-interference assay.................................51
10. Blockade of Akt activity..............................52
Results
I. Difference of c-Jun protein expression between SW480 and SW620.....................................................53
1. Detection of c-Jun mRNA and protein level in SW480 and
SW620.....................................................53
2. Comparison of c-Jun protein stability between SW480 and
SW620.....................................................53
II. 5’UTR of c-Jun contains IRES activity.................54
III. The activity of c-Jun IRES is higher in SW620 compared with that in SW480........................................55
IV. c-Jun IRES activity is induced during mitosis.........55
V. Detection of the ITAFs binding on c-Jun IRES element...56
1. Identification of hnRNPA2/B1 binding on c-Jun IRES in vitro.....................................................56
2. Interaction between hnRNPA2/B1 and c-Jun in cells......57
3. Both expression level and binding affinity of hnRNPA2/B1
affect more binding to c-Jun in SW620.....................57
4. Identification of hnRNPA1 binding on c-Jun IRES in vitro.....................................................58
VI. Characterization the role of hnRNPA2/B1 and hnRNPA1 in c-Jun protein expression..................................58
1. Silencing of endogenous hnRNPA2/B1 in SW620 reduces c-Jun
protein expression........................................58
2. Silencing of endogenous hnRNPA1 increases c-Jun protein
expression................................................59
VII. Correlation between Akt activity and c-Jun protein expression in SW480 and SW620.............................59
1. Identification of Akt status in SW480 and SW620........59
2. Blockade of Akt activity by pharmacological inhibitor increases c-Jun protein expression in SW480...............59
Discussion
I. The physiological role of c-Jun IRES...................61
II. HnRNPA2/B1 and hnRNPA1 regulate c-Jun protein expression................................................62
III. The correlation of c-Jun protein and AKT activity....64
Thesis conclusion.........................................66
References................................................67
Figures...................................................85
Appendices...............................................116
Publications.............................................130
Curriculum vitae.........................................131
                                    

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