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研究生:蔡忠穎
研究生(外文):Chung-Ying Tsai
論文名稱:肝細胞生長因子接受體Met進入細胞核機轉的探討
論文名稱(外文):Study on Mechanism by which Hepatocyte Growth Factor Receptor c-Met Tranlocates to the Nucleus
指導教授:陳鴻震
指導教授(外文):Chen-Hong 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
畢業學年度:96
語文別:中文
論文頁數:47
中文關鍵詞:肝細胞生長因子接受體
外文關鍵詞:Met
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Met,又稱為肝細胞生長因子接受體 (hepatocyte growth factor receptor),廣泛表現於各種細胞的細胞膜上,屬於receptor tyrosine kinases (RTKs) 的成員,並參與多種不同的生理功能。在許多的癌症研究顯示,Met的活化與過量表現和癌細胞的增生與侵犯能力有關聯性。在最近的研究發現RTKs會進入到細胞核內,像是表皮生長因子接受體 (epidermal growth factor receptor family)、纖維母細胞生長因子接受體 (fibroblast growth factor receptor)、胰島素接受體 (insulin receptor) 等都被發現會進入到細胞核內,做為轉錄因子 (transcriptional factor),進而調控基因表現、影響細胞功能。在本研究中,我們試圖了解Met是否會進入到細胞核內與其中的過程。我們分別利用免疫組織化學染色在肺腺癌組織或是免疫螢光染色在肺癌細胞株CL1-5中可以偵測到Met在細胞核。另外也利用fractionation技術發現到細胞核的部份 (nuclear fraction) 有一個66kDa的片段只會被辨認Met細胞內部份 (intracellular domain) 的抗體所辨認到,代表進入細胞核內的Met片段確實包含了細胞內部份。此外我們分別構築並表現不同Met細胞內部份的片段,鑑定出對於Met進入細胞核的重要序列是位於Met kinase domain內的胺基酸1189到1235。在HEK293細胞表現具活性的Met細胞內部份 (GFP-Met-cyto),發現其可進入到細胞核內,並可以明顯提高細胞核內的蛋白磷酸化程度。在細胞功能方面,在CL1-1細胞建立穩定表現的系統,發現具活性的Met細胞內部份可以增加細胞增生的能力。
Met, also named hepatocyte growth factor receptor, is a transmembrane glycoprotein that belongs to receptor tyrosine kinases (RTKs). Met is responsible for various physiological functions such as cell proliferation and differentiation. In many cancer studies, Met activation and overexpression are related to cancer cells proliferation and invasion. Recently, a number of reports find that RTKs, such as epidermal growth factor receptor (EGFR) family members, fibroblast growth factor receptor (FGFR), and insulin receptor, can translocate into nucleus and function as transcription factors to regulate gene expression and cell functions. In this study, we tried to prove that Met could translocate into nucleus and tried to clarify this nuclear translocation process. First, with immunohistochemical staining method and immunoflourescence staining method, we can detect a part of Met expressed in nucleus in lung adenocarcinoma tissues and lung cancer cell line CL1-5. Moreover, using cell fractionation method, a 66-kDa Met fragment in the nucleus fraction was detected by the antibody which specifically recognizes the intracellular domain of Met. It indicated that the Met fragment in the nucleus contains the intracellular domain of Met. Furthermore, through generating different length of Met intracellular domain-GFP fusion proteins, we demonstrated that a region in kinase domain (amino acid 1189-1235) plays an important role in Met nuclear translocation process. In addition, with expressing active GFP-Met-cyto in HEK293 cells, we found that GFP-Met-cyto not only has nuclear translocation ability, but also significantly increases protein tyrosine phosphorylation level in the nucleus. In conclusion, our study suggests that membrane bound Met could form a special fragment which contains intracellular domain and could translocate into nucleus.
一、文獻探討………………………………………………1
二、研究動機………………………………………………4
三、材料與方法...................................5
(一) 實驗材料
1. 組織檢體收集……………………………………………5
2. 商品化肺癌組織晶片……………………………………5
3. 藥品………………………………………………………5
4. 儀器………………………………………………………7
5. 細胞株……………………………………………………8
6. 抗體………………………………………………………8
7. 質體………………………………………………………9
(二)實驗方法
1. 免疫組織化學染色法 (Immunohistochemistry staining)………9
2. 細胞培養及細胞株的建立 (cell culture and stable cell line)………11
3. 細胞蛋白質之萃取 (Collection of cell lysates)……………11
4. 分離細胞核與細胞質的蛋白 (Fractionation)…………………12
5. 免疫沈澱法 (Immunoprecipitation)……………………………12
6. 西方轉印法 (Western blotting)………………………………13
7. 免疫螢光染色 (Immunofluorescence staining)………………13
8. 質體的建立 (plasmid cloning)…………………………………14
9. 細胞軟洋菜膠生長分析(soft agar-colony formation assay)........14
10. 細胞增生能力分析 (cell proliferation assay)………14 11. Matrigel侵犯分析(Matrigel invasion assay)......14
12. 細胞移動能力分析 (cell migration assay) .........15

三、結果…………………………………………………………16
一、利用免疫組織化學染色法在肺腺癌組織中可於細胞核偵測到Met。
二、利用分別辨認Met細胞內部份及細胞外部份的抗體,在CL1-5細胞做螢光染色,只有辨認細胞內部份的抗體可以偵測到核內的訊號。
三、在細胞核內發現一個66 kDa的Met片段。
四、Met的kinase domain中的胺基酸1189到1235這段序列對於Met進
入細胞核是重要的。
五、具有活性的Met細胞內部份會聚集在細胞核中,並使細胞核內蛋白
的磷酸化程度上升。
六、具有活性的GFP-Met細胞內部份增加細胞增生的能力。
討論………………………………………………………………20
參考文獻…………………………………………………………24
實驗結果圖………………………………………………………35
附錄………………………………………………………………45
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