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研究生:林莆鏵
研究生(外文):Pu-Hua Lin
論文名稱:TRC8藉由促進第一型血基質氧化酶泛素化和裂解進而抑制腫瘤生長
論文名稱(外文):TRC8 mediates tumor suppression through promoting heme oxygenase-1 ubiquitination and degradation
指導教授:趙麗洋
指導教授(外文):Lee-Young Chau
學位類別:博士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:91
中文關鍵詞:第一型血基質氧化酶泛素腫瘤細胞週期自由基
外文關鍵詞:HO-1TRC8ubiquitintumorcell cycleROS
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第一型血基質氧化酶 (Heme oxygenase-1, HO-1) 可以催化血基質的分解而釋放出一氧化碳、膽綠素和游離鐵離子。 這個酵素反應的代謝物,具有許多重要的生理功能,如抗氧化、抗發炎以及促進血管新生等作用。 然而,研究顯示HO-1在許多種類的癌細胞會大量表現且會影響癌細胞生長和轉移,具有增進癌細胞癌化的能力。 因此,抑制HO-1的表現被視為是一種有潛力的癌症治療方法。 由於HO-1蛋白是經由泛素-蛋白酶體系統裂解,而目前對於促使HO-1泛素化的E3接合酶則不清楚。 本論文利用泛素基因體cDNA微陣列分析找到參與HO-1泛素化的E3接合酶TRC8 (translocation in renal cancer from chromosome 8)。 HEK293T細胞大量表現TRC8能減少HO-1蛋白的表現且TRC8影響HO-1表現是在轉譯後 (post-translational) 蛋白階段。 TRC8促進HO-1蛋白裂解可以被蛋白酶體抑制劑阻斷且TRC8能促使HO-1泛素化。 另外,利用胞內 (in vivo) 和胞外 (in vitro) 泛素化修飾分析法確認HO-1是TRC8的直接作用受質。 免疫沉澱法結果顯示TRC8與HO-1有交互作用。 這些結果確認TRC8是E3接合酶,能專一性的促使HO-1泛素化及裂解。 於HeLa癌細胞大量表現HO-1會增加癌細胞增生、遷移 (migration) 以及侵入性 (invasion) 能力,這些增加的效果在細胞大量表現TRC8後即會消失。 另一方面,TRC8表現減少 (knockdown) 的U2OS細胞株具有較高表現量的內生性HO-1,且具有較高的增生速率、遷移以及侵入能力。 利用小干擾核糖核酸方法抑制內生性HO-1表現後這些增加的效果隨即會消失。 HO-1表現減少的A498細胞株其增生速率較慢。 此外,流式細胞儀分析顯示減少HO-1表現的細胞會導致細胞週期G2/M期延遲。 細胞週期延遲是因為減少HO-1表現會導致細胞內具有較高含量的自由基且會導致細胞週期檢查點蛋白Chk1 (checkpoint kinase 1) 以及CDC25C (cell division cycle 25 homolog C) 活化。 這些結果顯示HO-1能促進癌細胞的癌化作用;而TRC8可經由促進HO-1泛素化而加速其裂解,來抑制癌症的進展。
Heme oxygenase-1 (HO-1) catabolizes heme degradation to carbon monoxide, biliverdin, and free iron. These byproducts exert important biological functions, including anti-oxidant, anti- inflammatory, and proangiogenic effects. HO-1 is upregulated in tumor tissues and facilitates tumor progression. Inhibition of HO-1 is a potential strategy for cancer therapy. HO-1 protein turnover is regulated by ubiquitin-proteasome system. However, specific E3 ligase for HO-1 protein ubiquitination has not been identified. By screening an Ubiquitin Genome-wide Full-length cDNA (GFC)-Transfection Array, we identified TRC8 (translocation in renal cancer from chromosome 8) as a specific E3 ligase to facilitate HO-1 protein degradation. We showed that TRC8 overexpression in HEK293T cells downregulated HO-1 expression primarily at the protein level but not at mRNA level. Furthermore, TRC8-induced HO-1 protein degradation was blocked by cotreatment of cells with the proteasome inhibitor. In additions, both in vivo and in vitro ubiquitination assays demonstrated that TRC8 promoted HO-1 ubiquitination. Coimmunoprecipitation experiments demonstrated that TRC8 interacted with HO-1. HO-1 overexpression in Hela cells promoted cell growth and migration/invasion, which were abolished by TRC8 gene transduction. On the other hand, TRC8 downregulation significantly increased endogenous HO-1 level and further increased cell proliferation and migration/invasion in U2OS cells. These effects could be reversed by HO-1 depletion. HO-1 downregulation in renal carcinoma cells induced a mitotic delay at G2/M phase by increasing the intracellular level of reactive oxygen species and the DNA damage, which subsequently induced checkpoint kinase activation. These results support that HO-1 has a role in promoting tumor progression, and TRC8 exerts tumor suppressive effect through targeting HO-1 for ubiquitination and degradation.
一、摘要
中文摘要……………………………………………………….3
英文摘要……………………………………………………….4
二、緒論…………………………………………………………….6
三、研究動機與目的……………………………………………….16
四、材料與方法…………………………………………………….17
五、實驗結果……………………………………………………….44
六、討論…………………………………………………………….50
七、結論…………………………………………………………….57
八、參考文獻……………………………………………………….58
八、實驗圖表……………………………………………………….76

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