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研究生:葉旭華
研究生(外文):Shiuh-Hwa Yeh
論文名稱:TSA降低Eps8表現量及抑制v-Src引發癌化之研究
論文名稱(外文):TSA can downregulate Eps8 expression and inhibit v-Src-induced transformation
指導教授:馬明琪
指導教授(外文):Ming-Chei Maa
學位類別:碩士
校院名稱:中山醫學院
系所名稱:生物化學研究所
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:2001
畢業學年度:89
語文別:中文
論文頁數:65
中文關鍵詞:癌化上皮生長因子接受器
外文關鍵詞:Eps8TSAv-Src
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Eps8是上皮生長因子接受器 (epidermal growth factor receptor ; EGFR) 的受質。當Eps8在細胞中過量表現時,會促進藉由EGF刺激後的細胞分裂。而Eps8不僅會受到EGFR的磷酸化,也會受到其他酪胺酸激酶接受器 (例如:PDGFR、FGFR) 的磷酸化。Eps8也被證實了不論在in vivo或是in vitro的情況下,都會受到non-receptor tyrosine kinases (例如:Src) 的磷酸化。而Eps8持續性高度酪胺酸磷酸化的現象,也廣見於一些人類癌細胞株。最近更有報導指出, Eps8是一個致癌蛋白,當其過量表達時,會促進腫瘤的形成。已知chromatin結構的histone acetylation受到兩個相互拮抗酵素:histone acetyltransferase (HAT) 與histone deacetylase (HDAC) 所調控,而chromatin的結構則與基因的活化有密切的關係。 早期研究中發現,TSA是Streptomyces 的代謝產物,且可以做為一個 antifungal antibiotic。先前文獻曾指出,TSA除了會促進Friend erythroleukemia cells的分化,也能夠專一性抑制正常鼠類纖維母細胞的生長,並且可以使腫瘤細胞恢復正常型態。最近的研究更指出,TSA是一個高效能且高專一性的HDAC抑制劑。為了探討TSA對v-Src transformation的影響,我們以TSA處理或不處理v-Src transformed (IV5) 的老鼠纖維母細胞,來探討TSA對其生長的影響。我們發現TSA會抑制IV5的生長及其在soft agar中形成colony的能力,並使細胞恢復正常型態。有趣的是,TSA能夠降低Eps8的表現,但卻不影響v-Src的蛋白量及其kinase activity。當我們以TSA處理IV5細胞24小時,再移走TSA時,我們發現受抑制的細胞又恢復生長,而且Eps8也逐漸回復原來的表現量。再進一步做RT-PCR以及Northern blotting analysis,我們證實了,相較於未處理TSA的IV5細胞,TSA會影響eps8的轉錄作用,使eps8 mRNA的量顯著降低。由於過量表現Eps8時,會造成細胞的增生及癌化;而TSA可以影響IV 5細胞的eps8轉錄作用,因此我們推測,TSA對IV5 細胞生長的抑制現象,部分的原因可能歸之於TSA造成Eps8量的降低所致。未來的研究課題將著重於如何找出eps8 promoter 內的TSA-responsive elements,並深入探討 TSA在eps8轉錄作用所扮演的角色。

Eps8 is a recently identified substrate of the epidermal growth factor receptor (EGFR). Its overexpression can enhance EGFR-mediated mitogenesis in different cells. Eps8 can be efficiently phosphorylated by several other receptor tyrosine kinases (RTKs). Previous studies have indicated that Src can also phosphorylate Eps8 both in vitro and in vivo. Constitutive phosphorylation of Eps8 was detected in many tumor cell lines. Further studies have indicated that Eps8 is an oncoprotein and can promote tumor formation. The dynamics of chromatin folding is important for the regulation of gene expression. Histone acetylase (HAT) and histone deacetylase (HDAC) are two crucial components determining the acetylation of histone that is supposed to regulate the chromatin structure and transcription activity. Previous studies have reported that Trichostatin A (TSA), a Streptomyces product, is as an antifungal antibiotic. TSA was found to cause the induction of Friend leukemia cell differentiation and specific inhibition of the cell cycle of normal rat fibroblasts at very low concentration. Several further studies have demonstrated that TSA can cause the morphological reversion of transformed cells. Accumulating evidence has suggested that it is a potent, specific inhibitor of HDAC. To study the effect of TSA to v-Src transformed cells (IV5), we treated IV5 cells with or without TSA and observed that TSA could effectively inhibit the growth of IV5 cells. In addition, TSA could abrogate the ability of IV5 cells to form colonies in soft agar. Interestingly, we found that TSA could downregulate the expression of Eps8, but the amount and kinase activity of v-Src were not affected. Furthermore, removal of TSA from 24 hr treated culture could restore the expression of Eps8. RT-PCR and Northern blotting analysis of the abundance of eps8 mRNA revealed the significant reduction of eps8 transcript in TSA-treated IV5 cells relative to control. Since overexpression of Eps8 can enhance the mitogenic signaling of EGFR and cause cellular transformation. Our results implicated the TSA- repressed Eps8 expression might attribute to TSA-induced reversion of v-Src transformed cells. Albeit the mechanisms of eps8 transcriptional regulation in TSA-treated v-Src transformed cells are still unknown, it is deserved to further investigate and identify the TSA- responsive elements in eps8 promoter and their binding transcriptional factors in our future study.

中文摘要 i
英文摘要iii
縮寫檢索表 v
第一章 緒論 1
第二章 實驗材料及方法11
第三章 結果 31
第四章 討論40
參考文獻48
圖表58

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賴俊儒 (1997) eps8在細胞生長與v-Src導致細胞轉型功能上的研究 國立成功大學藥理學研究所碩士論文

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