- 學位論文
訊息蛋白SH2B1β誘導之STAT3轉錄活性和電刺激分別對促進神經軸突生長之調控機制
The enhancement of neurite outgrowth by SH2B1β-mediated transcriptional activity of STAT3 and by electrical stimulation
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摘要
在神經分化及神經再生中，神經軸突的生長是必要的過程。因此了解神經軸突 生長的分子機制及細胞調控，有益於罹患神經性疾病和損傷之病人。訊息接合蛋 白SH2B1β已知會促進神經分化、在細胞核及細胞質間穿梭來回移動、和調控一 系列神經營養蛋白所誘導的基因表現。在此論文中，我提供證據顯示SH2B1β會 與轉錄因子STAT3 鍵結，影響STAT3 在細胞中的分佈，增加STAT3 的絲胺酸 磷酸化及轉錄活性，因而促進纖維細胞生長因子所誘導的STAT3 下游基因表 現，如:Egr1 和Cdh2。這些研究結果都確立SH2B1β在神經分化過程中透過鍵結 與調控STAT3 複合物，傳遞訊息到活化基因轉錄之重要角色。 電刺激也已經被指出可促進神經分化及再生。在此論文第二部份，電刺激所調 控的分子機制將被探討。我們的研究結果指出，同時給予PC12 細胞100 mV/mm 的電刺激及神經生長因子能有最好的促進神經軸突生長的效果。電刺激透過修飾 ERK1/2 活性而促進神經生長因子所誘導的神經軸突生長。這研究結果指出結合 電刺激及神經生長因子提供一個很有前途的策略促進神經軸突生長。綜合以上結 果，此篇論文研究提出訊息接合蛋白SH2B1β和電刺激正向調控PC12 細胞之神 經分化。
並列摘要
Neurite outgrowth is an essential process during neuronal differentiation as well as regeneration. Thus, understanding the molecular and cellular control of neurite outgrowth will benefit patients with neuronal diseases and injury. SH2B1β was known to enhance neuronal differentiation, undergo nucleocytoplasmic shuttling and regulate a subset of neurotrophin-induced genes. In this thesis, I provide evidence suggesting that SH2B1β interacts with the transcription factor, signal transducer and activator of transcription 3 (STAT3), by affecting the sub-cellular distribution of STAT3, and increasing serine phosphorylation and the transcriptional activity of STAT3, thus the expression of STAT3 target genes Egr1 and Cdh2 during neuronal differentiation. These findings establish a central role of SH2B1β in orchestrating signaling events to transcriptional activation through interacting and regulating STAT3-containing complexes during neuronal differentiation. Electrical stimulation (ES) has also been shown to enhance both neurite outgrowth and nerve regeneration. In the second part of this thesis, the molecular mechanism is investigated. Our data suggest that ES of 100 mV/mm together with nerve growth factor (NGF) provides optimal effect on promoting neurite outgrowth of PC12 cells. ES promotes NGF-induced neurite outgrowth through modulating the activity of extracellular signal-regulated kinase. These data suggest that combining ES and NGF provides a promising strategy for promoting neurite outgrowth. Taken together, this thesis shows the positive regulation of SH2B1β and ES on neurite outgrowth of PC12 cells.
參考文獻
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延伸閱讀
- 周瑀涵（2009）。訊息蛋白SH2B1β增進PC12細胞之神經修復能力〔碩士論文，國立清華大學〕。華藝線上圖書館。https://www.airitilibrary.com/Article/Detail?DocID=U0016-1111200916025851
- Lien, S. C. (2013). 轉化生長因子-beta家族之訊息傳遞對物理性與化學性刺激調節細胞功能之機制探討:TGF-β1與流體剪力對平滑肌細胞分化與癌細胞程序性死亡之影響 [doctoral dissertation, National Tsing Hua University]. Airiti Library. https://www.airitilibrary.com/Article/Detail?DocID=U0016-2511201310224455
- Salim, S. A. (2013). 漢丁頓關聯蛋白-1在神經細胞分化中調控斷裂點叢集區域蛋白的活性 [master's thesis, Taipei Medical University]. Airiti Library. https://doi.org/10.6831/TMU.2013.00029
- Chen, C. J. (2014). 訊息蛋白SH2B1β透過與IRSp53及Eps8交互作用促進海馬迴神經細胞的絲狀偽足形成及樹突分支 [doctoral dissertation, National Tsing Hua University]. Airiti Library. https://doi.org/10.6843/NTHU.2014.00182
- 蔡艷柔（2008）。The Influence of Static Magnetic Field on Neuronal Outgrowth of PC12 cells〔碩士論文，臺北醫學大學〕。華藝線上圖書館。https://doi.org/10.6831/TMU.2008.00110