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研究生:陳欣伶
研究生(外文):Hsin-Ling Chen
論文名稱:Cas的SH3domain抑制致癌基因v-Src所引起的腫瘤形成
論文名稱(外文):Blockade of v-Src-stimulated tumor formation by the Src Homology 3 domain of Crk-associated substrate
指導教授:陳鴻震
指導教授(外文):Hong-Chen Chen
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:75
中文關鍵詞:致癌基因腫瘤形成腫瘤轉移細胞轉型
外文關鍵詞:oncogenetumor formationinvasiontransformationv-SrcCasCas SH3 domain
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致癌基因v-Src會磷酸化細胞內許多蛋白,以致造成多種訊息傳遞的放大,導致細胞功能的改變,進而引起腫瘤的發生及轉移。許多種類的人類惡性腫瘤都有Src基因高度活化的現象。Cas(Crk-associated substae)是個會被致癌基因v-Src高度磷酸化的蛋白,同時在v-Src所引起的細胞轉型(transformation)過程中扮演重要的角色。因此本篇利用老鼠纖維母細胞(NIH3T3)及致癌基因v-Src而引起細胞轉型的老鼠纖維母細胞(3T3/v-Src),將Cas的Src homology 3 (SH3) domain送入細胞,建立此蛋白穩定表現的細胞株,來研究此SH3 domain對v-Src所引起的細胞轉型有何影響。實驗結果顯示,Cas SH3 domainu抑制了Cas原本被v-Src引起的高度磷酸化及Cas與focal adhesion kinase(FAK)的結合,但卻不影響Src活性。生物功能上的分析顯示,在in vitro中Cas SH3 domain阻止了細胞原本被v-Src活化能夠抵抗不能貼附生長所引起的細胞凋亡(anoikis),及Matrigel侵犯的能力。在動物實驗中也發現Cas SH3 domain制止了因v-Src所造成的腫瘤生長及腫瘤轉移的發生。然而生物化學上的分析顯示,Cas SH3 domain使得3T3/v-Src細胞恢復對細胞凋亡(apoptosis)的敏感性,是因為阻止原本v-Src活化的PI3K-AKT路徑,同時也藉由抑制Cas-JNK路徑而使得侵犯能力的下降。因此綜合上述結果,Cas SH3 domain抑制了v-Src所引起的細胞轉型、腫瘤的生長及轉移的能力。
The oncogene v-Src has been shown to activate a number of signaling proteins, leading to cell transformation. Many reports indicate that Src activity contributes to tumorigenesis. Cas (Crk-associated substrate) docking protein is highly phosphorylated in v-Src-transformed cells and plays a critical role in v-Src-induced cell transformation. In this study, the Cas SH3 domain was stably expressed in v-Src-transformed or normal NIH3T3 cells and its effects on v-Src-stimulated tumor formation in vivo and in vitro were examined. Our results showed that the Cas SH3 domain markedly inhibited v-Src-stimulated Cas phosphorylation and its association with focal adhesion kinase (FAK) without affecting the activity and expression of v-Src. Biological assays revealed that the Cas SH3 domain abolished v-Src-stimulated anchorage-independent cell growth and Matrigel invasion in vitro and blocks v-Src-stimulated tumor growth in vivo. Biochemical analysis revealed that the Cas SH3 domain could increase sensitivity of 3T3/v-Src cells to apoptosis by inactivating the PI3K-AKT pathway and inhibited v-Src-stimulated invasion through its inhibition on the Cas-JNK pathway. Together, our results suggest that the Cas SH3 domain inhibits v-Src-induced cell transformation, tumor growth, and metastasis.
目錄
中文摘要……………………………………………………………………Ⅲ
英文摘要……………………………………………………………………Ⅳ
Ⅰ 文獻探討
一、細胞轉型作用(Cell transformation) ……………………………......1
二、Src的介紹…………………………………………………………...3
三、Cas的介紹…………………………………………………………..7
Ⅱ 材料與方法
實驗材料
一、 細胞株………………………………………………………………11
二、 質體…………………………………………………………………11
三、 抗體………………………………………………………………....12
四、 藥品………………………………………………………………....13
五、 裸鼠………………………………………………………………....14
實驗方法
一、 細胞培養及細胞株的建立…………………………………...…….14
二、 細胞蛋白質之萃取(Collection of cell lysate)…………………….15
三、 免疫沈澱法 (Immunoprecipitation)……………………..………..16
四、 蛋白質轉印法(Western blotting)…………………………….........16
五、 生物體外激脢活性試驗(In vitro kinase assay)…………………..17
六、 Matrigel 侵犯分析(Matrigel invasion assay)………………........18
七、 細胞移動分析(cell migration assay)………………………...……19
八、 細胞軟洋菜膠生長分析(soft agar-colony formation assay)..…..19
九、 裸鼠腫瘤生長……………………………………………………….20
十、 裸鼠腫瘤淋巴節轉移分析……………………………….…………20
十一、細胞在serum deprivation 與anoikis環境底下存活率分析……21
十二、病毒的建立………………………………………………………….21
Ⅲ 結果
一、表現Cas SH3 domain會抑制v-Src所引起Cas的酪氨酸磷酸化
但不影響Src的活性及表現………………………………………….23
二、表現Cas SH3 domain抑制Cas下游蛋白Crk的磷酸化,進而
抑制JNK訊息傳遞路徑,但卻不影響ERK及STAT3的路徑…...25
三、Cas SH3蛋白表現抑制v-Src所造成的腫瘤生成…………….…....26
四、Cas SH3蛋白表現抑制v-Src所活化的PI3K-AKT路徑…..……...27
五、Cas SH3蛋白表現抑制v-Src所造成的腫瘤轉移…..………..….....29
Ⅳ 討論……………………………………………………………………..31
Ⅴ 參考文獻…………………………………………………………..……38
Ⅵ 圖………………………………………………………………………..57
附錄…………………………………………………………………………..75
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