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系統識別號 U0026-0812200914000667
論文名稱(中文) 辨認纖連蛋白胺基端區域中與第四型雙胜肽蛋白水解酶的結合位點
論文名稱(英文) Identification of Dipeptidyl Peptidase IV Binding Site(s) in N-Terminal Region of Fibronectin
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) of Biochemistry and Molecular Biology
學年度 95
學期 2
出版年 96
研究生(中文) 王毓瑄
研究生(英文) Yu-husan Wang
電子信箱 s1694111@mail.ncku.edu.tw
學號 s1694111
學位類別 碩士
語文別 中文
論文頁數 71頁
口試委員 指導教授-鄭宏祺
口試委員-凌斌
召集委員-張敏政
口試委員-莊偉哲
中文關鍵字 纖連蛋白  第四型雙胜肽蛋白水解酶  癌症轉移 
英文關鍵字 Metastasis  DPPIV  Fibronectin 
學科別分類
中文摘要 癌症轉移是癌症病患致死的主要原因。在沒有辦法有效治療癌症的情況之下,提供一個有效阻斷癌症細胞擴散至全身各處將為病患帶來最大利益。癌細胞上的多聚體纖連蛋白(poly-fibronectin; poly-FN)與肺臟的血管內皮細胞膜上的細胞黏著接受器第四型雙胜肽蛋白水解酶(Dipeptidyl peptidase IV DPPIV; CD26)結合,是造成肺臟之臟器特異性轉移主因之ㄧ。我們試圖以阻斷DPPIV與FN兩個蛋白質的結合作為抑制癌症的策略之ㄧ,期望達到抑制癌細胞轉移的最終目的。之前我們已經在FN的羧基端找到一個保留性胺基酸序列之DPPIV結合位點,並且利用人工合成這段保留性序列,可以阻斷DPPIV與FN的結合並在動物實驗中有效抑制癌症細胞在肺部的轉移聚落。雖然抑制轉移的效果顯著,但是並沒有完全抑制轉移的聚落形成。我們探討眾多不能完全抑制轉移的原因,其中一個是癌細胞表面上FN存在有其他DPPIV的結合位點。的確,在還原狀態(reducing condition) 的Far-western 實驗中,FN 的胺基端水解片段(proteolytic FN) 29kDa[第一至第五個第一型重複區域(FNI(1-5)) ; N-29kDa]與45kDa [第六個第一型、第一個第二個第二型重複性區域及第七個至第九個第一型重複性區域FNI(6)II(1-2)I(7-9) ; N45kDa]的區域中也具有與DPPIV結合的能力。為了找出這些結合位點,我們利用Maltose binding protein (MBP)重組蛋白去表現 FN的N端片段,來篩選出具有DPPIV結合能力之片段。首先我們證實FN重組蛋白與FN水解片段同樣具有與DPPIV的結合能力。由此我們便可利用此系統去縮小FN上可以與DPPIV結合的位點。在實驗結果中顯示,在N-29kDa的區域中,FNI(1)、FNI(2)、FNI(3)、FNI(4);N-45kDa的區域中,FNI(6)、FNI(7)、FNI(8)可與DPPIV結合。這些DPPIV結合能力全部屬於第一型重複區域。未來的工作乃是一一把這些重複區域中的位點或一個保留性位點序列找出,盼望將來能藉此設計有效藥物來抑制FN的N端、C端與DPPIV的結合,以提供阻斷癌症轉移的新策略。
英文摘要 Most cancer mortality is attributed to metastatic disease rather than the primary tumor. To metastasize successfully, the cancer cells traveling in the circulation must first adhere to blood vessel wall in an organ specific manner. We have demonstrated that Dipeptidyl peptidase IV (DPPIV; CD26) expressed on lung endothelial cells serves as an adhesion receptor of polymeric fibronectin (poly-FN) on the surfaces of metastatic breast cancer cells (MTF7) in a lung-specific rat breast cancer metastasis model. Blocking the binding between DPPIV and FN is an ideal strategy of pulmonary metastasis prevention. We have previously identified a novel consensus DPPIV-binding site (DBS) in the C-terminal of FN, according to the sequence of which a recombinant DPPIV-binding peptide was purified for in vivo breast cancer cell colonization inhibition. Although the inhibitory effect was significant, this peptide did not completely impede the tumor colony formation. One possible explanation for this incompleteness is the existence of other DPPIV-binding regions in FN. The fact that, during testing the DPPIV-binding activity of FN fragments by far-western assay, we accidentally found additional DBS(s) in the N-terminal of the proteolytic FN fragments of 29kDa [FNI(1-5); N-29kDa] and of 45kDa [FNI(6)II(1-2)I(7-9);N45kDa] under reducing condition strengthen the above-mentioned possibility. By conducting additional far-western assay, we were able to narrow down the DBS(s) in the recombinant Maltose-Binding Protein [MBP]-fusion N-terminal FN fragments. We also demonstrated the DPPIV-binding activity of the recombinant FN is similar to that of proteolytic FN. In our results, both the individual fragments of N-29kDa [FNI(1), FNI(2), FNI(3) and FNI(4)] and N-45kDa [FNI(6), FNI(7) and FNI(8) ] can interact with DPPIV. In the future, we determine to find out either various DBS(s) or a consensus motif in these fragments, from which we hope to design specific inhibitors to effectively inhibit cancer metastasis by abolishing the interaction between C,N terminal domain of FN and DPPIV.
論文目次 中文摘要------------------------------------------------------------------------------------------I
英文摘要-----------------------------------------------------------------------------------------II
誌謝----------------------------------------------------------------------------------------------IV
目錄-----------------------------------------------------------------------------------------------V
表目錄-----------------------------------------------------------------------------------------VIII
圖目錄-------------------------------------------------------------------------------------------IX
第一章 緒論
1-1癌症轉移之研究-----------------------------------------------------------------------1
1-2癌症轉移之假說-----------------------------------------------------------------------1
1-3組織特異性癌症轉移-----------------------------------------------------------------2
1-4 FN/DPPIV與組織特異性癌症轉移-----------------------------------------------4
1-5第四型雙胜肽蛋白水解酶(Dipeptyl peptidase IV;DPPIV;CD26)----------5
1-6 纖連蛋白(Fibronectin;FN) --------------------------------------------------------6
1-7 研究動機------------------------------------------------------------------------------7

第二章 材料與方法
2-1實驗材料
2-1-1通透細胞(competent cell)菌株-----------------------------------------------9
2-1-2細胞株----------------------------------------------------------------------------9
2-1-3培養液----------------------------------------------------------------------------9
2-1-4緩衝液----------------------------------------------------------------------------9
2-2實驗方法
2-2-1 建構DNA質體---------------------------------------------------------------12
2-2-1-1製備通透細胞 (competent cell) ---------------------------------12
2-2-1-2聚合酶鍊鎖反應(Polymerase chain reaction,PCR) ---------12
2-2-1-3限制酶切割DNA---------------------------------------------------14
2-2-1-4接合作用(ligation) -------------------------------------------------14
2-2-1-5菌株轉型作用(transformation) -----------------------------------14
2-2-1-6 菌落聚合酶鍊鎖反應(Colony PCR)----------------------------14
2-2-2表現MBP重組蛋白----------------------------------------------------------15
2-2-3純化MBP重組蛋白(MBP-fusion protein) ------------------------------15
2-2-4硫銨沉澱法(Ammonium sulfate precipitation)粗提6A3 mAb--------15
2-2-5製作6A3 mAb beads---------------------------------------------------------16
2-2-6純化第四型雙胜肽蛋白水解酶(DPPIV)---------------------------------16
2-2-7細胞黏著試驗(Adhesion assay) -------------------------------------------17
2-2-8 Gel overlay assay(Far western assay) -------------------------------------17
2-2-9 生物素標記蛋白(Protein biotinylation)----------------------------------18
2-2-10 Affinity precipitation assay [親合性沉澱試驗; pull down (PD) assay
拉下實驗]------------------------------------------------------------------------18

第三章 實驗結果
3-1 纖連蛋白(FN)的N端與第四型雙胜肽蛋白水解酶(DPPIV)結合---------20
3-2建構並表現純化人類纖連蛋白(FN)重組蛋白---------------------------------21
3-3純化大白鼠肺臟之第四型雙胜肽蛋白水解酶(DPPIV)----------------------22
3-4 DPPIV與重組蛋白MBP-29kDa 的結核能力大於MBP-45kDa------------22
3-5表現並純化第四型雙肽胜肽水解酶(DPPIV)重組蛋白----------------------23
3-6 N-29kDa片段會與DPPIV-A結合-----------------------------------------------24
3-7建立以Far western assay篩選結合區域-----------------------------------------24
3-8表現人類纖連蛋白(FN)的 N端重複性區域-----------------------------------25
3-9篩選可以與第四型雙胜肽蛋白水解酶(DPPIV)結合之纖連蛋白(FN)的N
端重複區域---------------------------------------------------------------------------26
3-10 結論---------------------------------------------------------------------------------27

第四章 討論
4-1纖連蛋白(Fibronectin)之N端結構----------------------------------------------28
4-2纖連蛋白(Fibronectin)上之第四型雙肽胜肽水解酶(DPPIV)的結合位點28
4-3 纖連蛋白(Fibronectin)的結構改變----------------------------------------------30
4-4 雙硫鍵與纖連蛋白(Fibronectin)第一型(Type I)重複區域結構------------30
4-5癌症細胞表面的纖連蛋白(Fibronectin)的聚集(Assembly)------------------31
4-6癌症轉移與雙硫鍵異構酶(Disufide bond isomeras)的關係-----------------32
4-7 纖連蛋白(Fibronectin)上的肝素(Heparin)結合位置與第四型雙胜肽蛋白水解酶(DPPIV)結合位置---------------------------------------------------------33
4-8第四型雙胜肽蛋白水解酶(DPPIV)的雙聚體(Dimer)-------------------------34
4-9抑制癌症轉移的新策略------------------------------------------------------------35

第五章 參考文獻------------------------------------------------------------------------------36
第六章 表---------------------------------------------------------------------------------------47
第七章 圖---------------------------------------------------------------------------------------50
作者自述----------------------------------------------------------------------------------------71
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洪婷婷「定位大鼠第四型雙肽蛋白水解酶其細胞外區域中之纖連蛋白及單株抗體6A3的結合位點」,國立成功大學,碩士論文(2007)。
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