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系統識別號 U0026-0812200911251365
論文名稱(中文) 轉錄因子α-Pal/NRF-1 在神經細胞可塑性功能之探討
論文名稱(英文) Functional Study of the Transcription Factor α-Pal/NRF-1 in Neuronal Plasticity
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 93
學期 1
出版年 94
研究生(中文) 邱榮敬
研究生(英文) Rong-Jing Chiou
學號 s3691107
學位類別 碩士
語文別 英文
論文頁數 78頁
口試委員 指導教授-黃阿敏
召集委員-吳豐森
口試委員-莊季瑛
中文關鍵字 轉錄因子  神經腫瘤細胞  神經突生長 
英文關鍵字 α-Pal/NRF-1  neurite outgrowth 
學科別分類
中文摘要   神經突生長對於神經分化是非常重要,在神經突生長的過程中已知有許多分子參與其中,例如神經滋養因子(Neurotrophins)、引導因子(Guidance factors)、細
胞附著分子(Cell adhesion molecules)和細胞骨架分子(Cytoskeleton molecules)等以及Ca2+、MAPK 和PKA 等訊息傳導路徑相關分子。此外,轉錄因子也扮演很重要的角色,這些轉錄因子目前已知的有CREB 和c-fos 等。本實驗室最近的研究發現,轉錄因子α-Pal/NRF-1 可以調控神經突生長。α-Pal/NRF-1 是調控記憶相關基因IAP 的重要轉錄因子,因此本研究的主要目的在探討α-Pal/NRF-1 是否透過其下游基因IAP 而參與神經突生長,另外也要探討何種訊息路徑參與其中。我們採用常用的細胞模式,一種是以不含血清方式誘發人類神經腫瘤細胞IMR-32 細胞突生長,另一種是以神經生長因子NGF 誘發老鼠腎源母腫瘤細胞PC12 細胞神經突生長。再利用EMSA、半定量反轉錄聚合酶連鎖反應(RT-PCR)、
啟動子分析等技術研究軸突生長過程中IAP 基因的表現。首先在IMR-32 細胞方面,結果顯示無血清所誘發的神經突生長過程中,α-Pal/NRF-1 與IAP 啟動子DNA片段結合的活性增加,IAP 啟動子的活性增加,IAP mRNA 含量也增加。結果也顯示,MEK 抑制劑U0126 或PD98059 抑制α-Pal/NRF-1 與DNA 結合的活性,IAP 啟動子的活性及IAP mRNA 表現量也受到抑制。此外U0126 也抑制α-Pal/NRF-1 促進神經突生長的現象。其次在PC12 細胞以NGF 誘發神經突生長的模式中,結果顯示NGF抑制α-Pal/NRF-1 與DNA片段結合的活性, IAP mRNA表現量也受到抑制,同時處理U0126 則反轉NGF 的效果。最後,本研究也初步探討α-Pal/NRF-1 在大腦中的可能角色。結果發現α-Pal/NRF-1 與DNA 結合的活性在小腦腦區特別強,原位雜合法發現IAP 基因在小腦腦區表現也特別多,顯示在腦中α-Pal/NRF-1 的功能與IAP 基因表現相關。综合以上可以得知轉錄因子α-Pal/NRF-1 參與神經軸突生長,在IMR-32 細胞中此現象與MAPK 路徑活化及
其下游基因IAP 表現增加有關,而在PC12 細胞中,則與α-Pal/NRF-1 的活性和IAP 基因表現下降有關。α-Pal/NRF-1 與IAP 在此兩種細胞模式中參與神經突生
長的差異性有待進一步探討。

英文摘要   Neurite outgrowth is a fundamental event in neuronal differentiation. Many extracellular factors and cytosolic signaling molecules such as Ca2+, MAPK, and PKA are known to be involved in neurite outgrowth. Transcription factors, such as CREB and c-fos, also play important roles in this process. Our recent findings suggest that a novel transcription factor α-Pal/NRF-1 is involved in neurite outgrowth. α-Pal/NRF-1 is a critical regulator of a memory-related gene integrin-associated protein (IAP).
Therefore, we hypothesized that α-Pal/NRF-1 involved in neurite outgrowth through the regulation of its downstream IAP gene. Two different cell models were used, the serum starvation-induced neurite outgrowth in human IMR-32 cells and the NGF-induced neurite outgrowth in rat PC12 cells. Promoter assay, EMSA, and semi quantitative RT-PCR were used to investigate IAP gene expression. In IMR-32 cells,results showed that the DNA binding activity of α-Pal/NRF-1 and the IAP promoter activity were enhanced by serum starvation. The IAP mRNA level was also increased. MEK inhibitors U0126 or PD98059 inhibited the effects of serum starvation. Enhancement of neurite outgrowth by α-Pal/NRF-1 was also inhibited by U0126. In
PC12 cells, results found that NGF treatemnt reduced the DNA binding activity of α-Pal/NRF-1 and decreased IAP mRNA expression. These effects were reversed by the treatment of U0126. Finally, the possible role of α-Pal/NRF-1 in the adult brain was explored. The α-Pal/NRF-1 binding activity was very strong in the rat cerebellum. Interestingly, the strong activity was correlated with very high expression of IAP gene in the cerebellum as revealed by in situ hybridization Taken together, these results
indicate that the enhancement of neurite outgrowth by α-Pal/NRF-1 was meditated by the MAPK pathway and its downstream IAP gene in IMR-32 cells. In contrast, in PC12 cells, the activity of a-Pal/NRF-1 and the expression of IAP gene are negatively correlated with in NGF-induced neurite outgrowth. The differential role of α-Pal/NRF-1 and IAP in these two cell models remains to be further characterized.

論文目次 Acknowledgments...............................................................I
Table of Contents...........................................................III
List of Tables and Figures....................................................V
Abstract in Chinese...........................................................1
Abstract......................................................................2
Introduction..................................................................3
Materials and Methods........................................................16
Cell Culture.................................................................16
Transient transfection and Dual luciferase assay.............................16
Nuclear protein extraction...................................................18
Gel electrophoretic mobility shift assay (EMSA)..............................19
Minipreparation of plasmid DNA...............................................20
Total RNA extraction and DNase I treatment...................................21
Semi-quantitative reverse transcription PCR (RT-PCR).........................23
Measurement of neurite outgrowth.............................................23
Animals......................................................................24
Radioactive In situ hybridization (ISH)......................................24
Statistics...................................................................26
Results......................................................................27
Involvement of α-Pal/NRF-1 and its downstream integrin- associated protein (IAP) gene in the serum starvation-induced neurite outgrowth in human neuroblastoma IMR-32 cells...................................................27
Serum starvation enhanced the DNA binding activity of α-Pal/NRF-1 in IMR-32
cells........................................................................27
Serum starvation enhanced the IAP promoter activity in IMR-32 cells..........27
Serum starvation increased the expression of IAP transcripts.................28
PD98059 inhibits the binding activity of α-Pal/NRF-1.........................28
U0126 inhibits the IAP promoter activity enhanced by α-Pal/NRF-1.............28
U0126 inhibits the enhancement of neurite outgrowth by α-Pal/NRF-1 in IMR-32 cells........................................................................29
Involvement of α-Pal/NRF-1 in the nerve growth factor (NGF) -induced neurite outgrowth in rat pheochromocytoma PC12 cells.................................29
NGF decreased the DNA binding activity of α-Pal/NRF-1 in PC 12 cells.........29
NGF decreased the expression of IAP mRNA.....................................30
NGF reduced the expression of α-Pal/NRF-1 transcripts........................30
Overexpression IAP form 4 increased NGF induced neurite outgrowth and antisense IAP cDNA inhibited neurite outgrowth induced by NGF in PC 12 cells.30
Exploring the function of α-Pal/NRF-1 in vivo................................31
DNA binding activity of α-Pal/NRF-1 in the adult rat brain...................31
Correlation of the DNA binding activity of α-Pal/NRF-1 and mRNA expression of IAP gene.....................................................................31
Discussion...................................................................32
References...................................................................41
Appendix.....................................................................71
About of the Author..........................................................78
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