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系統識別號 U0026-1208201022305000
論文名稱(中文) 含雙色胺酸功能區氧化還原酶在mTOR訊息傳遞的角色
論文名稱(英文) The role of WW domain-containing oxidoreductase in mTOR signaling
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 98
學期 2
出版年 99
研究生(中文) 黃琮智
研究生(英文) Tsung-Chih Huang
學號 s4697110
學位類別 碩士
語文別 中文
論文頁數 97頁
口試委員 指導教授-徐麗君
口試委員-林以行
口試委員-張南山
口試委員-詹明修
中文關鍵字 含雙色胺酸功能區氧化還原酶 
英文關鍵字 WW domain-containing oxidoreductase 
學科別分類
中文摘要 人類WWOX基因位在第16對染色體易脆裂 (fragile) 的位置上,可轉錄出產生腫瘤抑制蛋白質-含雙色胺酸功能區氧化還原酶(WW domain-containing oxidoreductase 也稱作WWOX、FOR或WOX1)。近期研究指出,WWOX/WOX1可能扮演調控細胞生長以及存活的角色,然而WWOX/WOX1蛋白質在調控細胞生長訊息傳遞的角色仍然不清楚。我們的實驗結果發現,SCC-15和HeLa Tet-On細胞高量表現WWOX/WOX1蛋白質後,會增加AKT、ERK、mTOR、p70 S6K和4E-BP1蛋白質磷酸化程度,當細胞處在養分缺乏狀態下,會減弱WWOX/WOX1促使上述蛋白質磷酸化增加的現象。為了更進一步了解WWOX/WOX1如何調控mTOR蛋白質活化,我們使用了專一性蛋白質抑制劑進行實驗。在PI3K抑制劑wortmannin和mTOR抑制劑rapamycin的作用之下,WWOX/WOX1蛋白質促使p70 S6K蛋白質磷酸化增加的現象皆會受到抑制,顯示WWOX/WOX1可能透過活化PI3K/AKT/mTOR訊息傳遞路徑,來促使p70 S6K蛋白質磷酸化增加。當SCC-15細胞高量表現WWOX/WOX1蛋白質時,會促使ERK蛋白質磷酸化增加,在加入MEK抑制劑U0126作用15分鐘之後,即明顯減少ERK蛋白質磷酸化,但是WWOX/WOX1促使SCC-15細胞中p70 S6K蛋白質磷酸化增加的現象,須要到U0126作用6小時之後才會明顯降低。高量表現WWOX/WOX1蛋白質會導致AMPKα 蛋白質Thr172磷酸化程度增加,顯示WWOX/WOX1蛋白質並非藉由抑制AMPKα 活性,而導致mTOR活化。總結所有實驗結果,我們認為WWOX/WOX1蛋白質可以促使AKT/mTOR/p70 S6K訊息傳遞路徑的活化,而這些作用在細胞處於養分缺乏的情況下,則會受到抑制。
英文摘要 Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (designated WWOX, FOR or WOX1). Recent studies suggested that WWOX/WOX1 may have a role in cell growth and survival. However, the regulatory role of WWOX/WOX1 in cell growth signaling remains largely unclear. In this study, ectopic overexpression of WWOX/WOX1 in SCC-15 and HeLa Tet-On cells upregulated protein phosphorylation of AKT, ERK, mTOR, p70 S6K and 4E-BP1, and starvation reduced these effects. WWOX/WOX1-induced phosphorylation of p70 S6K was prevented by PI3K inhibitor wortmannin and mTOR inhibitor rapamycin, suggesting that WWOX/WOX1 may upregulate p70 S6K phosphorylation via PI3K/AKT/mTOR pathway. MEK inhibitor U0126 suppressed WWOX/WOX1-induced ERK phosphorylation within 15 min. However, significant downregulation of p70 S6K phosphorylation by U0126 treatment was observed after 6 h in SCC-15 cells overexpressing WWOX/WOX1. WWOX/WOX1 upregulated AMPKαphosphorylation at Thr172, suggesting that WWOX/WOX1 may not stimulate mTOR activation via inhibition of AMPKα activity. Taken together, our results suggest that WWOX/WOX1 may upregulate AKT/mTOR/p70 S6K signaling and these effects can be prevented by starvation.
論文目次 中文摘要 I
英文摘要 II
誌謝 III
總目錄 IV
圖目錄 VI
緒論 1
材料與方法 11
1. 材料
A-1 細胞株 11
A-2 試劑藥品 11
A-3 抗體 14
A-4 耗材 15
A-5 儀器 16
2. 方法
B-1細胞培養與培養液製備 17
B-2質體DNA備製 18
B-3-1細胞RNA萃取 19
B-3-2反轉錄聚合酶連鎖反應 (Reverse transcription polymerase chain reaction (RT-PCR) 20
B-3-3定量PCR連鎖反應 (real-time PCR) 21
B-4基因植入細胞 (transfection)-電穿孔法 (electroporation) 23
B-5以Dox誘導HeLa Tet-On細胞表現特定蛋白質 24
B-6-1細胞蛋白質萃取 24
B-6-2蛋白質濃度定量 26
B-6-3聚丙烯醯胺膠體電泳 (SDS-PAGE) 26
B-6-4西方墨點法 (Western Blotting) 28
B-7穀胱苷肽S-轉移酶 (GST, glutathione S-transferase) 融合蛋白質萃取 29
B-8穀胱苷肽S-轉移酶沉澱試驗 (GST pull-down assay) 30
B-9共同免疫沉澱 (coimmunoprecipitation) 32
B-10PP2A磷酸酶活性測定 (PP2A phosphatase activity assay)33
B-11酵母菌雜合試驗 (Yeast two-hybrid assay) 34
B-12構築載體的製備 35
B-13大腸桿菌轉型 (E.coli transformation) 40
B-14S1、S2、S3試劑萃取質體DNA 41
實驗結果 43
討論 52
參考文獻 58
圖附錄 70
附錄 93
自述 97
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