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研究生:田孝威
研究生(外文):Shiaw-Wei Tyan
論文名稱:第一型血清及糖皮質素誘導激酶藉由調節SRF和CREB1促進zif268基因表現及與空間記憶形成的關係
論文名稱(外文):Serum- and Glucocorticoid-Inducible Kinase 1 Enhances zif268 Gene Expression through the Mediation of SRF and CREB1 in Association with Spatial Memory Formation
指導教授:李小媛李小媛引用關係
指導教授(外文):Eminy H. Y. Lee
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:296
中文關鍵詞:第一型血清及糖皮質素誘導激酶記憶
外文關鍵詞:SGK1zif268SRFElk-1CREB1memory
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第一型血清及糖皮質素誘導激酶 (serum- and glucocorticoid-inducible kinase 1,簡稱 SGK1) 在先前的實驗中被發現在大鼠的空間記憶形成過程中扮演重要的角色,但其分子作用機制尚不清楚。本研究試探討 SGK1 是否調節另一個已知在記憶形成過程中扮演重要角色的基因 ─ zif268 之基因表現,找出 SGK1 可調控的訊息傳遞路徑。此外,也探討轉錄因子 SRF、Elk-1 與 CREB1 是否參與 SGK1 調節 zif268 基因表現的過程。本研究發現將顯著抑制型突變種之 SGK1 ─ SGK1 S422A 轉染於大腦海馬迴 CA1 區域,會顯著地降低經水迷津學習實驗測試的大鼠其被誘導生成的 zif268 基因之傳訊核糖核酸 (mRNA) 含量。本研究發現 SGK1 可磷酸化 SRF 的氨基酸位置 Ser73、Ser75 和 Ser99,以及磷酸化 CREB1 的氨基酸位置 Ser133。將 SRF 與 CREB1 上受到 SGK1 磷酸化的氨基酸突變成 alanine 以抑制 SGK1 對其磷酸化,可以有效地降低 SGK1 促進 zif268 基因表現的效果。SGK1 亦可磷酸化 Elk-1 的氨基酸位置 Ser159 和 Thr160,但此磷酸化並不影響 SGK1 促進 zif268 基因的表現。將 Elk-1 上受到 SGK1 磷酸化的氨基酸突變成 aspartate 以模擬其被磷酸化,會降低 Elk-1 的活性,顯示 SGK1 可能負面調節 Elk-1,以排除其對 SGK1 促進 zif268 基因表現的影響。此外,大鼠的大腦海馬迴 CA1 區域之 SGK1 氨基酸位置 Ser422 的磷酸化會在水迷津學習實驗測試後增加,同時,SRF 氨基酸位置 Ser99 與 CREB1 氨基酸位置 Ser133 的磷酸化也會伴隨增加。將 SGK1 S422A 轉染於大腦海馬迴 CA1 區域,則會降低這些效果。這些結果顯示 SGK1 會藉由調節 SRF 與 CREB1,促進 zif268 的基因表現,而此訊息傳遞路徑可能參與空間記憶形成的機制。
Serum- and glucocorticoid-inducible kinase 1 (SGK1) has been shown to play an important role in spatial memory formation, but the underlying molecular mechanism is not known. In the present study, the hypothesis that SGK1 regulates transcription of the immediate early gene zif268, a transcription factor that is essential for memory formation, was tested. The mechanism for SGK1-regulated zif268 expression in relation to the transcription factors, SRF, Elk-1, and CREB1, was also studied. Results revealed that transfection of the dominant negative mutant of SGK1, SGK1 S422A, to rat hippocampal CA1 area significantly decreased the mRNA level of zif268 induced by water maze learning. SGK1 was found to phosphorylate SRF at Ser73, Ser75 and Ser99, and phosphorylate CREB1 at Ser133. Inhibition of phosphorylation at these residues with alanine substitution significantly diminished SGK1-enhanced zif268 expression. SGK1 also phosphorylated Elk-1 at Ser159 and Thr160, but it did not affect SGK1-enhanced zif268 expression. Substitution of these residues with aspartate to mimic SGK1 phosphoryltion of Elk-1 decreased the transcriptional activity of Elk-1, suggesting that SGK1 may negatively regulate Elk-1. Moreover, phosphorylation of SGK1 at Ser422 was increased in rat hippocampal CA1 area after water maze learning, accompanied by increased phosphorylation of SRF at Ser99 and CREB1 at Ser133. These effects were antagonized by transfection of SGK1 S422A. These results suggest that SGK1 enhances zif268 expression through the mediation of SRF and CREB1. These signaling pathways are probably involved in spatial memory formation.
目錄
正文目錄
圖目錄
附錄目錄
中文摘要
英文摘要
正文
第一章 緒言
第二章 研究目標與策略
第三章 材料與方法
第四章 結果
第五章 討論
第六章 結論
第七章 參考文獻

附錄
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