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標題: | 表皮生長因子促進 Cten 基因表現之機制探討 Elucidating the Mechanism of EGF-Induced Cten Gene Expression |
作者: | Chia-Chung Chang 張佳鈞 |
指導教授: | 廖憶純(Yi-Chun Liao) |
關鍵字: | 表皮生長因子,細胞遷移,集中點附著體,基因轉錄,表觀基因調控機制, EGF,EGFR signaling,focal adhesion,Tensin,Cten,U0126,cis-acting element,RNA stability,epigenetic regulation,histone modification,Trichostatin A,Anacardic acid, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | EGFR signaling 是調控細胞遷移的訊息傳導路徑之一,而癌細胞中不正常活化的 EGFR signaling 會促進腫瘤的侵入性或癌細胞轉移。已知 EGFR signaling 可透過調控 focal adhesion 中 tensin 家族的 tensin3 及 Cten 蛋白質含量的消長,使蛋白質含量增加的 Cten 取代 tensin3,進而拆卸 actin fiber 增強乳癌細胞遷移的能力,且 EGF 誘導大量表現的 Cten 還可進一步延長 EGFR signaling 的活化時間,但 EGFR signaling 調控 Cten 表現上升的機制目前仍不清楚。本研究於 Cten 啟動子中並未發現與 EGF 調節有關的 cis-acting elements,且 EGF 的刺激也不會增加 Cten mRNA 之穩定性,進一步分析 Cten 啟動子上 nucleosome positioning 及 histone modification 等表觀基因調控方式,實驗結果發現 EGF 可促使 Cten 啟動子區域的 chromatin 結構變得較鬆散,並增加 Cten 啟動子上 histone tail 的 acetylation 修飾,而 histone acetyltransferase p300 的抑制劑 anacardic acid 可降低 EGF 誘導的 Cten 表現量,因此推測 EGF signaling 可能是藉由 histone acetyltrasnsferase p300 增加 Cten 啟動子區域 histone 的 acetylation 進而活化 Cten 基因的表現。 Epidermal growth factor receptor (EGFR) signaling is involved in regulation of cell migration. Aberrant activation of the pathway contributes to the tumor invasion and metastasis. Recent studies showed that EGF-driven breast cancer cells migration is mediated by a tensin3-Cten switch mechanism. EGF-induced up-regulation of Cten displaces tensin-3 from cytoplasmic tail of integrin and causes actin fiber disassembly then promotes cell migration. Furthermore, elevated expression of Cten by EGFR activation can prolong EGFR signaling. However, the molecular mechanism underlying EGFR signaling regulates the increased expression of Cten is still incompletely understood. Our results have shown that no EGF-responsive cis-acting elements were found within Cten promoter and Cten mRNA stability was not increased by EGF. Nonetheless, analyses of nuclesome positioning and histone modification within Cten promoter demonstrated that EGF stimulation increased the chromatin accessibility of Cten promoter and enhanced histone acetylation. Moreover, anacardic acid, a histone acetyltransferase p300 inhibitor, suppressed EGF-induced Cten expression, which suggested that the histone acetyltransferase p300 may be involved in the regulation of EGF-induced Cten expression. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/5922 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 生化科技學系 |
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