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研究生:劉雅娟
研究生(外文):Ya-Chuan Liu
論文名稱:鈣離子與鎘誘導金屬硫蛋白基因表現之相關研究
論文名稱(外文):The Role of Calcium in Cadmium Induced Metallothionein Gene Expression
指導教授:林立元林立元引用關係
指導教授(外文):Lih-Yuan Lin, Ph.D.
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生命科學系
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:2002
畢業學年度:90
語文別:中文
論文頁數:79
中文關鍵詞:鈣離子金屬硫蛋白
外文關鍵詞:calciumcadmiummetallothionein
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中文摘要
金屬硫蛋白(metallothionein;MT),是會受到重金屬誘導表現的小分子量蛋白質,具有金屬解毒的功用。本篇研究主要是探討細胞質鈣離子以及其下游蛋白質和MT基因表現的關係。首先我們確定鎘會造成大鼠腦下垂體GH3細胞的MT mRNA表現,並且處理鎘之後也會在短時間內造成細胞質鈣離子含量上升。當分別以會增加細胞質鈣離子的藥物,A23187、ionomycin或thapsigargin和鎘共同處理細胞,則可以增加鎘誘導的MT mRNA表現量。若將GH3細胞處理以細胞內鈣離子螯合劑BAPTA-AM,則會抑制鎘造成的MT mRNA表現。由此可知,細胞質鈣離子含量的變化,是鎘誘導MT基因活化的重要因子。同時我們也觀察到PKC的廣泛抑制劑H7,會抑制鎘所誘發的MT mRNA。若是以各種不同PKC isoform的抑制劑處理GH3細胞,只有PKCδ的專一抑制劑 rottlerin,可以隨著處理劑量的增高而逐漸降低MT基因表現。Rottlerin在抑制MT mRNA的同時,也會造成進入細胞內的鎘離子含量下降。接著我們也觀察到當GH3細胞加入鎘之後2.5分鐘時,PKCδ的活性會有大量升高的現象。此外我們發現處理calmodulin antagonist,W7可以降低鎘造成的MT mRNA。並且進一步觀察到Ca2+/calmodulin-dependent protein kinaseⅡ(CaMKⅡ)的專一抑制劑KN93,可以減少部分的MT基因表現量。並且CaMKⅡ的活性會在加入鎘之後3分鐘會增加到最表現大量。綜合以上結果,我們推測重金屬鎘誘發GH3細胞的MT基因表現,是需要透過細胞質鈣離子含量的增加,並且和PKCδ和CaMKⅡ活性有關。

Abstract
Metallothioneins (MTs) are small molecular-weight proteins that could be induced by heavy metals. MTs are involved in the metal detoxification. In our study, we observed that cadmium (Cd) induced MT mRNA expression and increased the cytosolic calcium (Ca2+) in GH3 cells. By using chemicals increasing intracellular Ca2+ content, such as A23187, ionomycin or thapsgargin, and intracellular Ca2+ chelator, PBAPTA-AM, we found that Cd-induced MT mRNA was affected by intracellular Ca2+ concentration. We also observed that H7, a non-specific PKC inhibitor, abrogated MT mRNA induction after Cd treatment. However using specific inhibitors of various PKC isoforms, only PKCδ inhibitor, rottlerin reduced MT gene expression. The PKCδ activity increased after Cd treatment. Rottlerin not only inhibited Cd-induced MT mRNA, but also attenuated the accumulation of intracellular Cd. We also found that calmodulin antagonist, W7 decreased the Cd-induced MT mRNA. When using the inhibitor KN93 to further investigate the effect of Ca2+/calmodulin dependent protein kinaseⅡ on MT gene expression, we found that KN93 partially inhibited MT gene expression. After GH3 exposed to Cd, CaMKⅡ activity increased and reached the highest level within 3 minutes. We conclude that Cd-induced MT gene expression is through the increase of cytosolic Ca2+, and activation of PKCδ and CaMKⅡ.

目次
英文摘要……………………………………………………………1
中文摘要……………………………………………………………2
緒言…………………………………………………………………4
材料與方法……………………………………………………… 17
結果……………………………………………………………… 28
討論……………………………………………………………… 39
參考文獻………………………………………………………… 48
附圖……………………………………………………………… 59

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