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系統識別號 U0026-0812200914083183
論文名稱(中文) Integrin αvβ3及Fas在A群鏈球菌熱原性外毒素B引發A549細胞凋亡所扮演的角色
論文名稱(英文) Role of integrin αvβ3 and Fas in the streptococcal pyrogenic exotoxin B-induced apoptosis in A549 cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 蔡宛樺
研究生(英文) Wan-Hua Tsai
電子信箱 s5890109@ccmail.ncku.edu.tw
學號 s5890109
學位類別 博士
語文別 中文
論文頁數 151頁
口試委員 指導教授-林銘德
召集委員-莊偉哲
口試委員-林以行
口試委員-吳俊忠
口試委員-劉世東
口試委員-賴明宗
中文關鍵字 A549細胞  熱原性外毒素B  A群鏈球菌  蛋白酶  細胞凋亡  鈣離子  接受體 
英文關鍵字 Fas  integrin αvβ3  Ca2+  caspase  apoptosis  SPE B  A549 cells  protease 
學科別分類
中文摘要 本研究深入分析A群鏈球菌熱原性外毒素B (SPE B)造成A549細胞凋亡時所扮演的角色及其路徑。SPE B重組蛋白(rSPE B)、不具蛋白酶活性之突變蛋白C192S和帶有RSD片段的突變蛋白G308S,是以大腸桿菌表達系統表達,並利用親和性管柱純化,並進一步研究他們與A549細胞之作用方式。我們的結果顯示SPE B造成A549細胞凋亡是與其劑量成正相關的,而C192S並無法造成A549細胞凋亡。當細胞以低濃度rSPE B (2 μg/ml)預先處理細胞短時間,再給予28 kDa-C192S則會使得細胞凋亡;42 kDa-C192S則不會。這些結果顯示SPE B的蛋白酶活性及其大小,對於其引起細胞凋亡非常重要。分析SPE B引發細胞凋亡的訊息傳遞可以發現以下分子的參與:caspase-8的活化(1.5小時)、t-Bid的產生(2.5小時)、Bax移至粒線體(3小時)、cytochrome c從粒線體釋出(6小時)、caspase-9活化(7小時)及caspase-3活化(8小時)。而細胞大量表現Bcl-2可以抑制SPE B引發之粒線體膜電位下降及細胞凋亡。
此外,rSPE B會造成細胞內鈣離子增加。細胞外螯合劑EGTA和細胞內螯合劑BAPTA均會抑制SPE B造成細胞內鈣離子增加及死亡。接著也發現SPE B造成μ-和m-calpain活化。Calpain之抑制劑ALLN會抑制SPE B引發caspase-8、caspase-3活化及細胞凋亡。這些結果推論Ca2+/calpain活化,為SPE B造成細胞凋亡較早期的訊號。進一步的研究顯示,SPE B會造成粒線體中鈣離子的減少,而對內質網則沒有影響。加入粒線體Na+/Ca2+ exchanger抑制劑CGP37157可抑制SPE B造成粒線體中鈣離子的減少及凋亡。這些結果表示SPE B造成細胞內鈣離子增加來自於粒線體釋出。
我們進一步發現integrin αvβ3及Fas為SPE B之接受體。SPE B刪除RGD motif之蛋白或是具RSD motif之突變蛋白,兩者所引發細胞凋亡的程度低於SPE B所引發的,推測SPE B引發細胞凋亡時,其RGD motif十分重要。利用FITC-SPE B結合試驗及免疫沉澱方法證實SPE B會特異的與αvβ3結合。Anti-αvβ3抗體能部分抑制SPE B引發之細胞凋亡,而對於G308S引發之細胞凋亡則沒有影響。利用親和性管柱及免疫沉澱方法分析發現,Fas能夠與SPE B結合。Anti-Fas抗體抑制SPE B及G308S引發之細胞凋亡是與其劑量相關的,顯示SPE B經由Fas引發細胞凋亡之過程,是不需要RGD motif參與的。同時給予anti-αvβ3及anti-Fas抗體對於SPE B引發之凋亡具有加成性抑制效果。比較SPE B與G308S引發凋亡之訊息傳遞路徑,發現他們活化相同的分子。然而,G308S造成訊息活化的時間均有延後的現象。當SPE B與αvβ3結合後,會造成細胞表面的αvβ3的量降低,但是Fas則沒有明顯改變。西方點墨法的結果也顯示,SPE B造成αvβ3由細胞表面移動至細胞質。當proteasome抑制劑MG132存在時,SPE B降低細胞表面αvβ3的情形就能回復,顯示SPE B造成αvβ3經endocytosis進入細胞後分解的過程受到ubiquitin-proteasome所調節。總而言之,我們的結果證實SPE B引發細胞凋亡經由αvβ3及Fas具有加成性。
英文摘要 This study is to dissect the role of streptococcal pyrogenic exotoxin B (SPE B) in the apoptotic process of A549 cells and to elucidate the SPE B-induced apoptotic pathway. Recombinant SPE B (rSPE B), C192S, a mutant of SPE B without protease activity, and G308S, a mutant with RSD motif, were expressed in Escherichia coli, purified by using an affinity column and used to study their interaction with A549 cells. Our results showed that SPE B induced apoptosis in a dose- dependent manner, whereas C192S did not. When cells were pretreated with rSPE B (2 μg/ml) for short time and then incubated with C192S of 28 kDa, an apoptosis that is proportional to the period of pretreatment was observed but not with C192S of 42 kDa. These results suggest that the extracellular protease activity of rSPE B is required for the initiation of apoptosis and that the size of SPE B is important for an effective induction of apoptosis. The time course analysis revealed that molecules activated in apoptosis were in the following order: caspase-8 (1.5 h), t-Bid (2.5 h), Bax (3 h), cytochrome c release (6 h), caspase-9 (7 h), and caspase-3 (8 h). It was observed that the overexpression of Bcl-2 inhibited depolarization of mitochondrial membrane, thereby inhibiting apoptosis.
In addition, rSPE B increased intracellular Ca2+ levels in a concentration dependent manner. Both EGTA, an extracellular Ca2+ chelator and BAPTA, an intracellular Ca2+ chelator, abolished the rSPE B-induced intracellular Ca2+ levels elevation and apoptosis. rSPE B induced the activation of μ- and m-calpain, Ca2+ dependent cysteine protease. Inhibitor of calpain, ALLN, influenced SPE B-induced caspase-8, caspase-3 activation and apoptosis, suggesting that Ca2+/calpain activation have an important role in the early event of SPE B-induced apoptosis. Further studies showed that SPE B caused mitochondrial Ca2+ depletion but unaffected on ER Ca2+ homeostasis. CGP37157, a blocker of mitochondrial Na+/Ca2+ exchanger significantly inhibited rSPE B induced apoptosis, suggesting that the SPE B-induced Ca2+ rise is through mitochondrial releasing.
We have also identified αvβ3 and Fas as SPE B receptors for this function. The SPE B fragment without the RGD motif and G308S, a SPE B mutant with the RSD motif, induced less apoptosis than did native SPE B, suggesting that the RGD motif is critical for SPE B-induced apoptosis. Fluorescein isothiocyanate-SPE B binding assays and immunoprecipitation analysis showed that SPE B specifically interacted with αvβ3. Anti-αvβ3 antibody could partially inhibit SPE B-induced apoptosis but had no effect on G308S-induced apoptosis. In addition, Fas binding to SPE B was verified in an affinity column and an immunoprecipitation analysis. Anti-Fas antibody inhibited SPE B- and G308S-induced apoptosis in a dose-dependent manner, suggesting that Fas-mediated SPE B-induced apoptosis also occurs RGD independently. Both anti-αvβ3 and anti-Fas antibodies synergistically inhibited SPE B-induced apoptosis. The apoptotic cascades were activated by SPE B and G308S, with a little delay by the latter. After SPE B binding, the cell surface level of αvβ3, but not of Fas, was decreased. The decreased αvβ3 level was restored by treatment with the proteasome inhibitor MG132, suggesting a SPE B-mediated endocytosis of integrin αvβ3 is regulated by the ubiquitin-proteasome system. Taken together, our results demonstrate that SPE B-induced apoptosis is mediated through αvβ3 integrin and Fas in a synergistic manner.
IX
論文目次 總目錄…………………I
考試合格證書…………V
中文摘要………………VI
英文摘要…………………VIII
致謝………………………X
圖目錄………………………XI
縮寫檢索表………………………XIII
緒論………………………1
材料與方法………………………17
實驗材料………………………17
A 試劑藥品………………………17
B 抗體………………………19
C 儀器………………………21
實驗方法………………………24
A 上皮細胞株繼代培養………………………24
A-1 繼代培養………………………24
A-2 細胞保存………………………24
A-3 細胞解凍………………………25
A-4 細胞計數………………………25
B SPE B重組蛋白及其突變株蛋白之構築………………………26
B-1 ProSPE B及突變株蛋白C192S及G308S之構築………………………26
B-2 Glutathione S-transferase (GST)-SPE B片段重組蛋白之構築………………………26
B-3 Y224R重組蛋白之構築………………………27
C ProSPE B及其突變株蛋白之純化………………………27
C-1 ProSPE B及其突變株重組蛋白的表現………………………27
C-2 可溶性重組蛋白質純化………………………28
C-3 不可溶性重組蛋白質純化………………………29
C-4 重組蛋白質濃縮………………………29
C-5 重組蛋白質LPS污染之移除………………………29
C-6 28 kDa-C192S之製備………………………30
D 蛋白質分析………………………30
D-1 SDS-PAGE蛋白質電泳………………………30
D-1a SDS-PAGE膠體電泳製作………………………30
D-1b SDS-PAGE膠體電泳分析………………………31
D-1c Coomassie blue染色………………………32
D-1d 銀染法 (Silver stain)………………………32
D-2 西方點墨法………………………34
D-3 蛋白質定量………………………35
D-4 蛋白酶活性分析………………………35
E 細胞凋亡及其訊息傳導測定………………………36
E-1 細胞凋亡分析………………………36
E-2 細胞凋亡相關因子之觀察………………………36
E-2a 細胞內蛋白質(Total cell lysates)萃取………………………36
E-2b 粒線體及細胞質之蛋白質萃取………………………37
E-3 細胞膜電位測定………………………37
E-4 穩定表現Bcl-2細胞株之建立………………………38
E-4a 細胞轉染(transfection)………………………38
E-4b 穩定表現Bcl-2細胞株之篩選………………………38
E-5 短暫表現Caspase-8短片段雙股核糖核酸細胞株之建立………………………39
F SPE B與細胞之交互作用………………………39
F-1 細胞結合實驗(一)………………………40
F-1a 綠色螢光(FITC)接合蛋白………………………40
F-1b 細胞結合分析………………………40
F-2 細胞結合實驗(二)…………………………41
F-3 免疫沉澱法………………………41
F-4 SPE B親和性管柱尋找結合之膜蛋白………………………42
F-4a 28 kDa-C129S親和性膠體製備………………………42
F-4b 細胞膜蛋白萃取………………………43
F-4c 以親和性膠體找尋結合之膜蛋白………………………44
F-5 細胞表面接受器偵測………………………44
F-6 酵素結合免疫吸附法………………………45
G 細胞內鈣離子測定………………………45
G-1 細胞內鈣離子測定………………………45
G-2 粒線體內鈣離子測定(一)………………………46
G-3 粒線體內鈣離子測定(二)………………………46
G-4 內質網鈣離子測定………………………47
G-5 Casein zymography………………………47
H 統計方法………………………49
結果………………………50
一、SPE B及其突變蛋白C192S引起之A549細胞凋亡………………………50
二、SPE B引起A549細胞凋亡之訊息傳遞路徑………………………51
三、鈣離子在SPE B引起A549細胞凋亡之角色………………………53
四、SPE B經由integrin αvβ3引起之A549細胞凋亡………………………56
五、SPE B經由Fas引起之A549細胞凋亡………………………57
六、SPE B對於integrin αvβ3及Fas之調控………………………59
討論………………………61
一、SPE B在GAS感染扮演的角色………………………61
二、SPE B引發A549細胞凋亡在GAS感染扮演的角色………………………62
三、SPE B的蛋白酶活性及其大小為引發A549細胞凋亡所必須………………………63
四、SPE B可經由caspase及粒線體死亡路徑引起A549細胞凋亡………………………64
五、SPE B可經由細胞內鈣離子增加造成A549細胞凋亡………………………66
六、SPE B會經由integrin αvβ3引起A549細胞凋亡………………………68
七、SPE B可以經由Fas引起A549細胞凋亡………………………69
八、SPE B對細胞表面integrin αvβ3及Fas之調控機制………………………71
結論………………………73
參考文獻………………………74
圖………………………97
附錄………………………125
論文發表………………………132
作者簡歷………………………133
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陳秋月 熱原性鏈球菌外毒素 B的表現和特性之研究。國立成功大學生物化學研究所碩士班論文,民國八十八年。
蔡宛樺 熱原性外毒素B引發A549細胞凋亡之探討。國立成功大學生物化學研究所碩士班論文,民國八十九年。
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