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研究生:顏郁蓁
研究生(外文):Yu-Jhen Yan
論文名稱:探討GCIP蛋白在乳癌中抑制腫瘤生成所扮演的角色
論文名稱(外文):GCIP as a Tumor Suppressor in Breast Cancer
指導教授:張敏政張敏政引用關係
指導教授(外文):Ming-Chung Chang
學位類別:碩士
校院名稱:國立成功大學
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:2008
畢業學年度:96
語文別:中文
論文頁數:79
中文關鍵詞:抑癌基因乳癌
外文關鍵詞:GCIPId-1MCF-7breast cancer
相關次數:
  • 被引用被引用:0
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  • 下載下載:28
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GCIP 全名為 human Grap2 and Cyclin-D Interacting Protein,最早在2000年時被發現。先前的研究指出,GCIP 蛋白質會減少 RB 蛋白質的磷酸化,並且會抑制 E2F1 轉錄因子的轉錄能力,而這兩個因子目前已知為細胞週期由 G1 時期進行到 S 時期中最重要的調控步驟。先前的研究同時也指出 GCIP 蛋白質的表現量在許多人類腫瘤細胞中都有明顯減少的現象。然而,直到2006年才有第一篇正式文獻指出 GCIP 蛋白質的表現確實會減少肝腫瘤的形成,至此,GCIP 蛋白質才正式被認為是一個抑制腫瘤生成的因子。然而,本實驗室先前的研究也發現,GCIP 蛋白質其表現量與乳癌細胞癌化程度呈現負相關。除此之外,我們也對臨床乳癌病人的檢體進行定量免疫組織染色的分析,亦發現到 GCIP 蛋白質的表現量與病人的病理組織型態、病理分期及預後呈現高度正相關。因此我們推測,GCIP 蛋白質在癌化的過程中為一相當重要的調節因子。為了更加確認 GCIP 蛋白質在乳癌中作為抑制腫瘤生成的角色,我們利用核醣核酸干擾技術抑制 MCF-7 前期乳癌細胞中 GCIP 蛋白質表現量。結果發現,GCIP 蛋白質表現量下降時,細胞促進傷口癒合的能力明顯的受到改變,細胞變的較趨惡性。為了更進一步探討 GCIP 蛋白質在後期乳癌細胞表現量逐漸下降可能的機轉,我們進一步去分析 GCIP 基因上游片段的啟動子可能受到什麼轉錄因子調控。利用聚合酵素鏈鎖反應,我們成功的擴增到 GCIP 基因上游1320 鹼基對的區域,並對這段區域進行不同缺失片斷的構築,在經過啟動子活性的分析後,我們推論介於 GCIP 基因轉錄起始點上游248~135 這段區域可能是具有啟動子活性的區域。另一方面,我們也嘗試對與 GCIP蛋白質有交互作用的蛋白質進行分析,我們試圖找尋更多與 GCIP 蛋白質有交互作用的蛋白質。然而本實驗室在過去的研究發現 GCIP 蛋白質會與 Id (inhibition of DNA binding) 家族成員 Id-1、Id-2及Id-3 蛋白質在細胞內有交互作用。而根據文獻指出 Id-1蛋白質對於乳癌的生成及轉移都扮演很重要的角色。因此,本研究著重在探討GCIP 蛋白質與 Id-1 蛋白質之間的交互作用。Id-1蛋白質在結構上具有一個 HLH (Helix-loop-helix,a DNA binding motif) 區域,但,缺乏一個鹼性 DNA 結合區域,也由於此特性使得 Id-1 蛋白質在細胞核內具有負向調控鹼性轉錄因子 (basic HLH transcription factor) 的功能。而 GCIP 蛋白質在結構上也具有一個 HLH 區域,因此,我們想探討 GCIP蛋白質與 Id-1 蛋白質是否可能藉由 HLH 區域產生交互作用。我們利用免疫沉澱法的結果驗證,GCIP 蛋白質確實能與 Id-1 蛋白質在細胞內的環境下產生交互作用。除此之外,我們也發現到 GCIP 蛋白質與 Id-1 蛋白質交互作用產生的複合物主要是出現在細胞核。而利用哺乳類細胞雜交接合系統 (mammalian two hybrid),我們也初步證實了 GCIP 蛋白質確實是藉由 HLH 區域與 Id-1 蛋白質產生交互作用。因此,我們認為 GCIP 蛋白質對於乳癌的調控可能經由調控 Id-1 蛋白質所參與的訊息調控路徑。另外,我們在實驗的過程中也發現了一個很有趣的現象。過去本實驗室已證實 GCIP 蛋白質與核醣蛋白 P0 在細胞內有很強的交互作用,然而我們發現,當 P0 蛋白質在MCF-7 細胞中過度表現時 (P0-B8),會加速細胞中的 p53 蛋白質被降解。因此,我們推論 P0 蛋白除了會藉由調控 GCIP 蛋白質所參與的訊息調控路徑外,也可能會藉由影響到細胞內p53蛋白質的穩定度,進而對腫瘤生成的過程產生影響。因此,綜合上面的實驗結果,我們概括的探討了 GCIP 蛋白質在乳癌中所扮演的角色,發現它可能藉由與 P0 蛋白質和 Id-1 蛋白質產生交互作用而影響腫瘤的生成,然而,關於 GCIP 蛋白質在細胞內所調控的訊息傳導路徑則需要未來做更詳盡的探討。
GCIP is a novel human Grap2 and Cyclin-D Interaction Protein, which was found in 2000. In its function as a cyclin-D1 binding protein, GCIP is able to reduce CDK-mediated phosphorylation of RB protein and inhibit E2F-mediated transcriptional activity. Previous studies also reported that GCIP was significantly down-regulated in several different human tumors and in 2006, GCIP was first proposed to be a tumor suppressor in heptoma. In our previous studies, our preliminary data suggest that GCIP may be a tumor suppressor in breast cancer and thus, we speculate that loss of GCIP expression plays a role in development or progression of breast cancer. To confirm this hypothesis, in this study, we established stable GCIP-shRNA cells in MCF-7 and determined their tumorigenetic properties. Here we found that depletion of GCIP resulted in an increase of the migration capacity, indicating that GCIP expression level was negatively associated with cell migration. To investigate the mechanism of downregulation of GCIP in aggressive/invasive breast cancers, the -1320 bp upstream region sequence of GCIP gene was cloned and the putative promoter region of GCIP was characterized as well as potential transcriptional regulators of GCIP was investigated. Using promoter reporter assay, I discovered that the 248~135 upstream of GCIP transcription start site is an essential region for the basal promoter activity of GCIP. On the other hand, our previous data revealed that GCIP might interact with the Id (Inhibition of differentiation and inhibition of DNA binding) family proteins, in this study, using a mammalian two-hybrid system, interactions between GCIP and Id proteins were assayed quantitatively with luciferase activity. Among these GCIP-associated Id family proteins, I focused my study on demonstrating that GCIP could interact with Id-1 in breast cancer cell lines, because of Id-1 was recently recognized as a very important oncogenic protein for breast tumorigenicity and lung metastagenicity. Immunoflorescence assay indicated GCIP protein and Id-1 protein were co-localized in the nucleus. Furthermore, we found GCIP-Id-1 complex were detected in the nucleus by using nuclear extracts in immunoprecipitation. We also proved that GCIP can interact with Id-1 via its HLH domain. These data suggest that GCIP might be involved in the regulation of breast cancer through Id-1 mediated signaling pathway. An interesting finding is that I discovered the tumor suppressor P53 is downregulated in stable MCF-7 cells overexpressing P0, P0-B8. Further study revealed that p53 degradation in P0-B8 cells is more rapid than that in control cells. Thus, I suspect P0 might be involve in the regulation of breast cancer not only through GCIP mediated signaling pathway but also via regulating p53 expression level in cells. Taken together, this study indicated that GCIP can regulate tumorigenesis pathway in breast cancer through interacting with Id-1 and ribosomal protein P0. However, the detail mechanisms of GCIP mediated suppression in breast cancer need further studies.
中文摘要 I
Abstract III
誌謝 V
目錄 VI
圖表目錄 IX
縮寫表 X
第1章 緒論 1
1-1 乳癌的流行病學 1
1-2 乳癌簡介 2
1-3 GCIP蛋白簡介 6
1-4 Id蛋白簡介 7
1-5 研究動機 9
第 2 章 材料與方法 10
2-1 實驗菌株、載體與培養基配方 10
2-1-1 實驗菌株 10
2-1-2 載體 (附錄4 ) 10
2-1-3 培養基配方 10
2-2 細胞培養方法 11
2-2-1 實驗細胞株 11
2-2-2 細胞解凍 11
2-2-3 細胞繼代培養 (附著型細胞 adherent cell) 12
2-2-4 細胞計數 12
2-2-5 細胞保存 13
2-3 質體製備 14
2-3-1 聚合酶連鎖反應 14
2-3-2 構築 PCR 片段於質體中 15
2-3-3 E. coli 形質轉移 15
2-3-4 小量質體製備 16
2-4 蛋白質分析 17
2-4-1 蛋白質萃取 17
2-4-2 蛋白質定量 17
2-4-3 SDS-PAGE 蛋白質電泳 18
2-4-4 西方墨點法 19
2-5 在 MCF-7 前期乳癌細胞建立 GCIP 表現抑制的穩定細胞 20
2-5-1 GCIP shRNA 之來源 20
2-5-2 細胞轉染 20
2-5-3 利用抗生素篩選穩定細胞株 21
2-6 GCIP 表現抑制的穩定細胞株對於影響腫瘤生長能力的分析 22
2-6-1 利用 RT-RCR 分析穩定細胞株中 GCIP mRNA表現量 22
2-6-2 利用螢光染色觀察穩定細胞株之肌動蛋白及應力纖維之活動情形 22
2-6-3 利用MTT 試驗偵測穩定細胞株之生長能力 23
2-6-4 利用傷痕癒合試驗分析穩定細胞株之爬行能力 23
2-6-5 利用 Boyden chamber及市售套組分析穩定細胞株之爬行能力 24
2-7 GCIP 啟動子活性分析 25
2-7-1 從人類周邊血液抽取染色體 DNA 25
2-7-2 GCIP 基因上游啟動子區域之構築 26
2-7-3 分析 GCIP 基因上游啟動子區域的活性 26
2-8 GCIP 蛋白與 Id-1 蛋白的交互作用 27
2-8-1 Id家族成員重組基因之構築 27
2-8-2 利用mammalian two hybrid確認 GCIP 與 Id家族成員交互作用 的強弱情形 28
2-8-3 利用免疫沉澱法確認GCIP 蛋白與 Id-1 蛋白在活體之內交互作用 28
2-8-4 利用免疫螢光染色法觀察 GCIP 與 Id-1 複合物在細胞內的位置 29
2-8-5 利用細胞核質分離確認 GCIP 與 Id-1 蛋白複合物存在的位置 30
2-9 統計方法 30
第3章 實驗結果 31
3-1 在 MCF-7 前期乳癌細胞建立 GCIP 表現抑制的穩定細胞株 31
3-2 GCIP 表現抑制的穩定細胞株對於影響腫瘤生長能力的分析 32
3-2-1 利用相位差顯微鏡觀察GCIP 蛋白表現受抑制時對於細胞型態 上的影響 32
3-2-2 利用螢光染色觀察穩定細胞株之肌動蛋白及應力纖維之活動情形 32
3-2-3 利用MTT 試驗偵測穩定細胞株之生長能力 33
3-2-4 利用傷痕癒合試驗分析穩定細胞株之爬行能力 33
3-2-5 利用 Boyden chamber及市售套組分析穩定細胞株之爬行能力 33
3-2-6 觀察穩定細胞株之鈣黏著素E 蛋白 (E-cadherin) 表現的情形 34
3-3 GCIP 啟動子活性分析 35
3-3-1 從人類周邊血液抽取染色體 DNA 35
3-3-2 分析 GCIP 基因上游啟動子區域的活性 35
3-3-3 尋找 GCIP 基因上游可能具有啟動子活性的區域 35
3-4 GCIP 蛋白與 Id-1 蛋白的交互作用 37
3-4-1 利用mammalian two hybrid確認 GCIP 與 Id家族成員之交互作用 的情形 37
3-4-2 利用免疫沉澱法確認GCIP 與 Id-1 蛋白在活體內交互作用的結果 37
3-4-3 利用免疫螢光染色法觀察 GCIP 與 Id-1 複合物在細胞內的位置 38
3-4-4 利用細胞核質分離確認 GCIP 與 Id-1 蛋白複合物存在的位置 38
3-4-5 利用mammalian two hybrid 探討 GCIP 蛋白與Id-1 蛋白產生交互 作用的區域 39
3-5 核醣蛋白 P0 在細胞內對於 p53 蛋白表現的調控 40
第 4 章、實驗討論 41
4-1 GCIP 蛋白在乳癌中所扮演的角色 41
4-2 GCIP 基因上游基因的分析 42
4-3 GCIP 與Id-1 蛋白的交互作用對於乳癌細胞致癌性的影響 43
4-4 P0 蛋白在細胞內對於 p53 蛋白的調控 44
第5章、結論 46
參考文獻 47
實驗圖表 53
附錄 71
自述 79
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