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研究生:龔明祥
研究生(外文):Ming-Hsiang Kung
論文名稱:山羊 ß-酪蛋白近端起動子與第一內含子於不朽化山羊乳腺上皮細胞株之功能性研究
論文名稱(外文):Functional study of proximal goat ß-casein promoter and intron 1 in immortalized caprine mammary epithelial cells
指導教授:朱有田朱有田引用關係姜延年姜延年引用關係
口試委員:黃木秋林志生吳希天李宜儒
口試日期:2015-03-25
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:動物科學技術學研究所
學門:農業科學學門
學類:畜牧學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:111
中文關鍵詞:山羊乳腺上皮細胞ß-酪蛋白起動子第一內含子泌乳素
外文關鍵詞:goatmammary epithelial cellß-casein promoterintron 1prolactin
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山羊 ß-酪蛋白起動子被廣泛應用於轉基因山羊中驅動重組醫藥蛋白的表現,然而,山羊 ß-酪蛋白起動子活性受泌乳激素調控之順式作用元件與反式作用因子的研究,目前仍然缺乏在山羊乳腺上皮細胞中進行研究的直接證據;因此,本研究使用不朽化山羊乳腺上皮細胞株(CMC)作為研究平台,進一步證實泌乳激素刺激山羊 ß-酪蛋白基因轉錄作用之分子調控機制。
為了研究山羊 ß-酪蛋白起動子至第一內含子(–4,047 至 +2,054)受泌乳激素調控的順式作用元件,本研究首先建構了數個以山羊 ß-酪蛋白基因5’ 端側區系列刪除的起動子與有或無第一內含子序列驅動螢火蟲冷光素酶報導基因之重組質體,並利用雙重冷光系統分析在CMC細胞中之起動子活性變化。研究結果指出,所有不同長度的起動子重組質體活性受到泌乳素活化,而所有的起動子活性對泌乳素與氫皮質酮之協同作用具有加乘作用,其中 –1.68 kb之山羊 ß-酪蛋白起動子序列內即具有可受泌乳激素誘導活化的調控元件,然而,起動子包含第一內含子序列會顯著降低起動子的基礎活性,此抑制作用並不會受泌乳激素刺激而減輕,經由第一內含子3’ 端系列刪除的研究猜測此抑制作用元件可能位於 +393 至 +501的區域,這個發現有別於過去其他物種的研究。
本研究使用CMC細胞與數個專一性訊息抑制劑研究3條訊息傳導途徑在泌乳激素刺激 –1.68 kb山羊 ß-酪蛋白起動子活性的角色,經由處理AG490抑制劑研究發現,Janus kinase 2/訊息傳導及轉錄活化因子 5a(signal transducer and activator of transcription 5a,STAT5a)訊息傳導途徑在泌乳素刺激起動子活性作用扮演一個重要的角色,而同時添加氫皮質酮會提升並延長STAT5a與山羊 ß-酪蛋白起動子之活性;然而,在兩種泌乳激素同時添加的CMC細胞中,當分別處理抑制劑PD98059與LY294002分別抑制mitogen/extracellular signal-regulated kinase/extracellular signal-regulated protein kinase與phosphatidylinositol 3-kinase/protein kinase B訊息傳導途徑會導致山羊 ß-酪蛋白起動子活性STAT5a磷酸化程度的上升;這些結果指出,山羊 ß-酪蛋白起動子活性受到這些訊息傳導途徑的調控,而轉錄因子STAT5a是主要的調節者。
為了分析受泌乳激素刺激活化所需的最小片段長度之山羊 ß-酪蛋白起動子,以 –1.68 kb 山羊 ß-酪蛋白起動子建構數個5’ 端側區DNA系列刪除的起動子重組質體進行分析研究,結果指出重要的順式作用元件位於山羊 ß-酪蛋白起動子的近端位置(–300 至 –90),而此新發現的山羊近端起動子功能並不存在於牛和人類的起動子中。另外,為了確認在 –1.68 kb起動子預測的STAT5a結合位置與醣皮質素受體反應元件之角色,以內部刪除突變與STAT5a結合位置的單一核苷酸定點突變,證實了一個STAT5a結合位置(–102 至 –82)與其中 –90鳥苷酸(guanosine)序列保留性對泌乳激素作用的重要性,並以染色質免疫沉降分析法進一步確認STAT5a與該序列受泌乳激素刺激的結合作用;另外也發現,泌乳激素的誘導作用並不需要依賴醣皮質素受體反應元件。
綜合以上的發現證實了 –300 bp的近端山羊 ß-酪蛋白起動子包含了一個可反應泌乳激素刺激作用的STAT5a結合位置(–102 至 –82),另外,第一內含子也許是山羊乳腺組織或發育時期專一表現所必需的調節序列。

口試委員會審定書 i
致 謝 ii
中文摘要 iii
英文摘要 v
圖目錄 xiv
表目錄 xvi
一、前言 1
二、文獻檢討 2
2.1 活體乳腺組織之構造與發育週期 2
2.2 內泌素調控乳腺組織的發育分化 3
2.3 泌乳期乳腺上皮細胞具分泌乳蛋白功能 4
2.4 影響 ß-酪蛋白基因表現之調控機制 5
2.4.1 胞外基質對乳腺泡發育與 ß-酪蛋白基因表現之調控 5
2.4.2 胜肽與固醇類泌乳激素對 ß-酪蛋白基因轉錄之調控機制 6
2.4.3 調控 ß-酪蛋白基因轉錄作用之訊息傳導途徑 8
2.4.4 β-酪蛋白基因順式作用元件之研究 9
2.4.4.1 近端 ß-酪蛋白啟動子 9
2.4.4.2 遠端 ß-酪蛋白啟動子 9
2.4.4.3 第一內含子於 ß-酪蛋白起動子活性調控之功能 11
2.5 轉錄因子STAT5a調控 ß-酪蛋白基因表現 11
2.5.1 STAT家族 12
2.5.2 STAT5a的介紹與在乳腺組織的功能 12
2.5.3 STAT5a與 ß-酪蛋白基因的結合作用 13
2.6 以 ß-酪蛋白基因起動子生產外源性重組蛋白之應用 13
三、材料與方法 15
3.1 以電腦軟體分析 ß-酪蛋白基因體序列保留性與預測轉錄因子作用元件 15
3.2 建構冷光素酶報導基因之重組質體 16
3.2.1 建構不同長度的山羊 ß-酪蛋白基因驅動螢火蟲冷光素酶報導基因之重組質體 16
3.2.1.1 聚合酶鏈反應 17
3.2.1.2 限制酶截切與DNA接合反應 17
3.2.1.3 電穿孔轉型 18
3.2.1.4 小量質體萃取 19
3.2.1.5 中量質體萃取 20
3.2.1.6 螢火蟲冷光素酶基因重組質體之命名與插入起動子序列位置 21
3.2.2 建構 –1.68 kb山羊 ß-酪蛋白起動子之內部刪除突變與單一核苷酸定點突變的螢火蟲冷光素酶報導基因重組質體 22
3.2.2.1 突變引子之設計 22
3.2.2.2 突變重組質體之架構策略 22
3.2.2.3 突變重組質體之架構方法 23
3.2.3 建構珊瑚蟲冷光素酶重組質體phRL/TK 24
3.2 以穩定表現人類端粒酶之不朽化山羊乳腺上皮細胞株 CMC進行山羊 ß-酪蛋白基因調控作用之研究 24
3.2.1 細胞解凍活化 24
3.2.2 細胞培養條件 25
3.2.3 細胞繼代培養 25
3.2.4 CMC細胞轉染試驗 26
3.2.5 泌乳激素誘導CMC細胞山羊 ß-酪蛋白起動子活性 26
3.2.6 專一性抑制劑的處理 27
3.2.7 雙重冷光素酶分析系統 27
3.2.8 以西方吸漬法研究訊息傳導途徑所扮演的功能 28
3.2.8.1 細胞蛋白質萃取 28
3.2.8.2 細胞蛋白質定量 29
3.2.8.3 西方吸漬法 29
3.4 建立穩定插入山羊 ß-酪蛋白起動子與螢火蟲冷光素酶基因之嵌合表現質體之不朽化山羊乳腺細胞株(H25-Luc) 31
3.4.1 構築同時帶有山羊 ß-酪蛋白起動子驅動螢火蟲冷光素酶報導基因與表現真核生物抗藥性基因hygromycin B篩選基因之p1.68k/hyg重組質體 31
3.4.2 抗生素篩選穩定插入外源性基因之CMC細胞株(H25-Luc 細胞) 31
3.4.3 H25-Luc細胞培養與泌乳激素誘導條件 32
3.4.4 單一冷光素酶分析系統 32
3.5 以染色質免疫沉降技術與定量real-time PCR研究STAT5a與山羊 ß-酪蛋白近端起動子順式作用元件(–102/–82)之相互作用 33
3.5.1 染色質免疫沉降技術 33
3.5.2 定量 Real-time PCR分析 35
3.6 統計分析 36
四、結果 38
4.1 山羊 ß-酪蛋白基因起動子和第一內含子序列在不同哺乳動物之間之保留性序列的差異 38
4.2 山羊 ß-酪蛋白起動子的 –1.68 kb序列的與第一內含子在調控起動子的活性上扮演相反的作用 39
4.3 山羊 –1.68 kb的 ß-酪蛋白起動子活性可受泌乳激素協同作用誘導 41
4.4 抑制山羊 ß-酪蛋白啟動子基礎活性之抑制元件位於第一內含子 +393至 +501區域,而此抑制作用並不受泌乳激素的影響 42
4.5 訊息傳導途徑JAK2/STAT5a、MEK/ERK與PI3K/Akt調控由泌乳激素誘導的 –1.68 kb山羊 ß-酪蛋白起動子活性 43
4.6 新發現的山羊 ß-酪蛋白近端起動子(–300 至 –90)具有足夠反映CMC細胞泌乳激素誘導作用的順式作用元件 45
4.7 以H25-Luc細胞證實泌乳激素具有正調控STAT5a與山羊 ß-酪蛋白起動子 –102至 –82區域的結合能力 48
五、討論 50
5.1 新發現的山羊 ß-酪蛋白近端起動子區域具有足夠反應泌乳激素刺激的功能性調節序列 50
5.2 山羊 ß-酪蛋白基因第一內含子具有降低山羊 ß-酪蛋白起動子基礎活性的抑制功能,而泌乳激素的刺激無法減輕此抑制 52
5.3 泌乳激素刺激STAT5a活化 –300 bp近端山羊 ß-酪蛋白起動子 54
5.4 氫皮質酮提高泌乳素誘導山羊 ß-酪蛋白起動子活性的協同作用並不需要醣皮質素受體反應元件 55
六、結論 56
參考文獻 92
附 錄 102


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