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系統識別號 U0026-2208201410442400
論文名稱(中文) 探討缺氧環境下HuR調節FGF9表現量的機制
論文名稱(英文) Study the mechanism of HuR-mediated regulation on FGF9 expression under hypoxia
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 102
學期 2
出版年 103
研究生(中文) 巫毓娟
研究生(英文) Yu-Chuan Wu
學號 T16011082
學位類別 碩士
語文別 英文
論文頁數 69頁
口試委員 指導教授-孫孝芳
口試委員-曾大千
口試委員-洪良宜
中文關鍵字 缺氧  人類第九纖維母細胞因子  富含腺核苷酸及尿核苷酸序列  富含腺核苷酸及尿核苷酸序列結合蛋白  轉錄後調控  轉譯調控 
英文關鍵字 Hypoxia  FGF9  ARE  ARE-BP  Post-transcriptional regulation  Translation regulation 
學科別分類
中文摘要 人類第九號纖維母細胞生長因子 (Fibroblast growth factor 9; FGF9)為一種自體分泌及旁分泌的生長因子且參與在許多生理功能之中。已知FGF9表現必須受到嚴格的調控而且FGF9基因異常表現常被發現與許多包括癌症在內的疾病有關連性。我們先前的研究證實AU-rich element binding protein 1 (AUF1)是一個富含腺核苷酸及尿核苷酸序列結合蛋白 (AU-rich element binding protein; ARE-BP)。它可以結合上FGF9三端未轉譯區造成FGF9 mRNA的穩定性下降。Human antigen R (HuR)是另一個ARE-BP,其功能是在壓力環境下作為一個穩定因子調控mRNA降解及轉譯效率。我們假設HuR在缺氧環境下可能會與FGF9 ARE結合,進而去調控FGF9的表現。本研究的目的即是探討在缺氧環境下HuR調節FGF9表現的機制。利用RNA免疫沉澱法和蛋白沉澱實驗,結果顯示HuR可以特異性結合上FGF9的第二AUUUA序列。此外,螢光素酶活性分析及酵素免疫分析法結果顯示在缺氧環境下HuR過度表達會造成FGF9報導基因的酵素活性及內源性FGF9的表現增加。另外利用mRNA穩定性分析,我們的結果顯示改變HuR會影響FGF9 mRNA的半衰期,而缺氧環境下則會改變HuR與FGF9 mRNA之間的動態關係。由於HuR是一種穿梭蛋白,它可以與所結合的RNA在細胞核與細胞質中穿梭往返,因此我們更進一步的分析在正常氧和缺氧條件下HuR的細胞分布情形。我們發現在缺氧環境下,細胞質中HuR表現量有明顯增加的趨勢。為了探討AUF1和HuR兩者間的相互關係如何調控FGF9的表現,利用RNA干擾技術抑制HuR表現,我們發現在正常氧分壓下HuR可以與AUF1合作控制FGF9的表達,然而缺氧環境下則會改變HuR與AUF1之間的關係進而相互競爭控制FGF9的表達。目前為止我們的研究結果認為HuR在缺氧情況下可以與FGF9 ARE結合,進而攜帶FGF9 mRNA到細胞質進行轉譯。從本研究結果可進一步瞭解在缺氧環境下,FGF9如何透過轉錄後調控微調FGF9 mRNA,來達到維持動態平衡的目的。
英文摘要 Fibroblast growth factor 9 (FGF9) is an autocrine/paracrine growth factor and involved in many important physiological processes. The expression of FGF9 is known to be under tightly controlled and aberrant expression of FGF9 was associated with many human diseases including cancers. Our pervious study showed that AUF1, an AU rich element binding protein (ARE-BP), binds to FGF9 3’UTR and decreases FGF9 mRNA stability. HuR is another ARE-BP that functions as a stabilizing factor to regulate mRNA turnover and translational efficiency in stress conditions. We hypothesized that HuR may bind to FGF9 ARE to increase FGF9 expression under stress conditions like hypoxia. The objective of this study is to characterize the mechanism of HuR-mediated regulation on FGF9 expression under hypoxia. Using RNA-Immunoprecipitation and pull down assays, our data demonstrated that HuR specifically binds to the second AUUUA element of FGF9 ARE. Furthermore, firefly luciferase reporter assay and ELISA showed that overexpression of HuR increased the FGF9 3’UTR-mediated reporter gene activity and endogenous FGF9 expression under hypoxia. Using mRNA stability assay, our data showed that changing the expression of HuR influences FGF9 mRNA half-life, but the dynamic interaction between HuR and FGF9 mRNA was changed under hypoxia. As HuR is a shuttle protein to carry HuR-bound RNA transporting between nuclear and cytoplasm, we examined cellular distributions of HuR in normoxia and hypoxia conditions and our data showed that cytoplasm HuR was significantly increased in response to hypoxia. Using RNA interference to knockdown HuR, we demonstrated that HuR and AUF1 are collaboratively control FGF9 expression under normoxia. However, hypoxia altered the interplay between HuR and AUF1 and these two proteins turns to compete for FGF9 ARE binding and consequently, HuR carries FGF9 mRNA to the cytoplasm for translation and thus increase FGF9 protein expression. Results from this study provide more insights on post-transcriptional regulation of FGF9 mRNA to fine tune FGF9 homeostasis under hypoxia.
論文目次 Table of contents
摘要 ........................................................................................................................................ I
Abstract ............................................................................................................................... III
Acknowledgement ................................................................................................................. V
Introduction ........................................................................................................................... 5
1. Gene regulation ......................................................................................................... 5
1.1. Controls of gene expression .............................................................................. 5
1.2. Post-transcription regulation ............................................................................. 6
1.3. Cis-acting elements regulate mRNA decay ...................................................... 6
2. RNA-binding proteins mediated mRNA stability ..................................................... 7
2.1. RNA-binding proteins targets on AU-rich elements ......................................... 7
2.2. AU-rich element RNA binding protein1, AUF1 ............................................... 8
2.3. Hu family of RNA-binding protein, HuR ......................................................... 9
2.4. Interaction of HuR and other factors involving in post-transcriptional
regulation ..................................................................................................................... 12
3. Physiological functions of fibroblast growth factor 9 ............................................. 13
3.1. Family of fibroblast growth factor .................................................................. 14
3.2. Physiological functions of FGF9..................................................................... 14
3.3. Regulation of FGF9 ......................................................................................... 15
4. Research aims .......................................................................................................... 16
Materials and Methods ........................................................................................................ 18
1. Cell culture .............................................................................................................. 18
2. Protein preparation .................................................................................................. 18
3. Plasmid construction ............................................................................................... 19
4. Plasmid DNA extraction ......................................................................................... 19
5. Transient transfection and dual luciferase reporter assay ....................................... 20
6. Western blot analysis .............................................................................................. 20
7. Enzyme-linked immunosorbent assay ..................................................................... 21
8. In vivo transcription and pull-down assay ............................................................... 21
9. RNA-interference assay .......................................................................................... 22
10. RNA half-life measurement ................................................................................ 23
11. RNA immunoprecipitation assay ........................................................................ 23
12. Real-time quantitative PCR assay ....................................................................... 24
13. Immunofluorescence Staining ............................................................................. 24
14. Co-immunoprecipitation assay ............................................................................ 25
15. Statistical analysis ............................................................................................... 25
Result ................................................................................................................................... 26
1. HuR and AUF1 specifically bind to FGF9 mRNA at different ARE sites ............. 26
2. HuR binding prolongs FGF9 mRNA stability ........................................................ 27
3. Hypoxia changes HuR knockdown effect on FGF9 expression ............................. 27
4. HuR changes cellular distribution in response to hypoxia ...................................... 28
5. Hypoxia changes the interplay of HuR and AUF1 on control FGF9 expression .... 30
6. HuR interacts with VHL and hnRNP A1 but not AUF1 proteins. .......................... 31
Discussion ........................................................................................................................... 32
1. HuR binds to FGF9 ARE and promotes FGF9 expression ..................................... 32
2. HuR plays a broad role in regulating gene expression during stresses ................... 33
3. HuR regulated gene expression in translation level ................................................ 33
4. The interplay of HuR and AUF1 on gene expression ............................................. 34
5. Conclusion ............................................................................................................... 36
Figures ................................................................................................................................. 38
Figure 1. Schematic diagram of specific aims. ................................................................ 38
Figure 2. HuR and AUF1 specifically bind to the ARE of FGF9 3’UTR. ...................... 40
Figure 3. HuR overexpression increased the expression level of FGF9 in HEK293 cells.
......................................................................................................................................... 43
Figure 4. Hypoxia change HuR knockdown effect on FGF9 expression. ....................... 47
Figure 5. Hypoxia significantly induced the level of cytoplasmic HuR. ........................ 48
Figure 6. Short term hypoxia treatment increased cytosolic HuR ................................... 49
Figure 7. The fluorescence intensity of cytosol HuR increased in response to hypoxia . 52
Figure 8. Hypoxia changes the interplay of HuR and AUF1 on control FGF9 expression.
......................................................................................................................................... 53
Figure 9. No evidence for a direct protein-protein interaction between HuR and AUF1 in
HEK293. .......................................................................................................................... 54
Figure 10. Schematic of the working model of HuR and AUF1 physical and functional
interaction. ....................................................................................................................... 55
Figure S1. HuR and AUF1 bind to RNA probe forming band shift in pull down assay. 56
Table .................................................................................................................................... 57
Table 1. Primers used in this study .................................................................................. 57
Reference ............................................................................................................................. 58
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