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研究生:張家綾
研究生(外文):Chia-Ling Chang
論文名稱:ATAD3A於肺癌之高度表現
論文名稱(外文):Overexpression of ATAD3A in lung cancer
指導教授:周寬基周寬基引用關係
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:97
語文別:中文
論文頁數:62
中文關鍵詞:肺癌
外文關鍵詞:ATAD3A
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ATAD3A (ATPase family, AAA domain containing 3A)為一粒線體蛋白,隸屬於AAA+ (ATPases associated with various cellular activities)超級家族。AAA家族蛋白為Walker-type ATPases之子族群(subfamily),其序列中具有200至250個胺基酸的高度保留區,稱為AAA modules或者AAA cassettes,為AAA家族蛋白最顯著的特徵。ATAD3A為一癌症相關抗原(tumor associated antigen, TAA),但與癌症的關聯並不清楚。我們自製ATAD3A的單株抗體並檢測多種癌症細胞株,發現ATAD3A的確在癌細胞中有高度表現的情形;在50對肺癌病人檢體當中,更有高達九成以上的病患其腫瘤組織中ATAD3A表現量明顯高於非腫瘤組織,顯示ATAD3A的表現與腫瘤密切相關。免疫沉澱以及西方墨漬法的結果指出ATAD3A蛋白序列上可能具有絲胺酸 (serine) 位置的磷酸化;以protein kinase C (PKC) 抑制劑處理能夠大量降低ATAD3A的蛋白量,顯示ATAD3A受到PKC的嚴格調控,其中又以PKCγ(gamma)及PKCζ(zeta)具有較高的相關性。此外,雙胸腺嘧啶阻斷法(double thymidine block)及血清飢餓(serum starvation)處理的結果,顯示ATAD3A的表現與細胞週期(cell cycle)的進程息息相關,ATAD3A在S phase時具有最大的表現量,進入M phase後則降至最低。而ATAD3A的缺乏會導致粒線體的型態發生改變,在共軛焦顯微鏡下可以觀察到粒線體片段化的現象,也顯示此蛋白在粒線體內扮演相當重要的角色。在抗藥性的研究方面,我們發現ATAD3A的表現量並不會影響肺癌細胞株對於cisplatine的敏感程度,顯示其表現與肺癌細胞的抗藥性沒有顯著的相關性。ATAD3A的研究尚在起步階段,其確切的功能及參與的調控仍有待後續的研究,期待能為癌症的治療或者預防提供新的線索。
ATAD3A (ATPase family, AAA domain containing 3A) is a novel protein that belongs to the AAA+ (ATPases associated with various cellular activities) protein family. Members of this family have common structure but diverse functions. Here we show that ATAD3A are widely expressed in multiple cancer cell lines, and are highly expressed in tumor sections of almost all the lung cancer patients, suggesting the role of ATAD3A in lung carcinogenesis and disease progression. Western blot and immunoprecipitation show that ATAD3A is phosphorylated at a serine residue. Sensitivity of ATAD3A to Calphostin C, a PKC inhibitor, indicates that it is tightly regulated by PKC, especially by PKCγand PKC ζ. Moreover, ATAD3A protein expression is increased during serum starvation. Four hour after release of double thymidine block, expression of ATAD3A increases the most, which indicates the S phase of cell cycle. These phenomena imply that ATAD3A expression is, in a sense, cell cycle dependent. Confocal microscopy reveals that ATAD3A is localized in mitochondria, and ATAD3A knockdown alters mitochondrial morphology from filamentous to fragmented. However, there is no significant relation between ATAD3A expression and chemosensitivity to cisplatin in lung cancer cells. Our data show that ATAD3A plays a crucial role in mitochondria integrity, and through this, affecting tumorogenesis.
摘要 I
Abstract II
目次 III
圖表目次 VI
第一章、緒論
一、前言
(一) 肺癌 1
(二) 粒線體與癌症 3
(三) AAA與AAA+家族蛋白 4
(四) ATAD3A 6
二、研究動機 7
第二章、材料與方法
ㄧ、材料
(一)細胞株 (Cell line) 8
(二)肺癌病人組織檢體 8
(三)干擾性RNA (shRNA)之設計 8
(四)質體 (Plasmid) 8
(五)勝任細胞 (Competent cell) 8
(六)藥品 8
(七)緩衝溶液 8
(八)抗體 (Antibody) 9
(九)儀器 9
二、方法
(一) 細胞培養(cell culture)
1. 細胞解凍與冷凍保存 10
2. 細胞繼代(cell passage) 10
3. 細胞計數 10
4. 雙胸腺嘧啶阻斷法(Double thymidine block) 10
5. 激酶抑制劑之處理(kinase inhibitors treatment) 11
6. 蛋白質激酶C異構物大量表現(PKC isoforms overexpression) 11
7. 血清飢餓(serum starvation) 11
8. Cisplatin處理及WST-1細胞活性檢測 11
(二) 干擾性RNA之質體構築( shRNA plasmid construction)
1. 干擾性寡核酸片段之黏合 12
2. 瓊脂凝膠電泳(agarose gel electrophoresis) 12
3. 酵素切割(enzyme digestion) 12
4. 接合作用(ligation) 12
5. 轉型作用(transformation) 12
(三) ATAD3A knockdown stable clone製備
1. 暫時轉染(transient tansfection)與病毒液之收取 13
2. 病毒感染 13
(四) 蛋白質萃取(protein extration)及定量分析(protein quantification)
1. 由細胞中萃取蛋白 14
2. 由病人組織中萃取蛋白 14
3. 蛋白定量 14
(五) 西方墨漬法(Western blot)
1. SDS聚丙烯醯鹽胺凝膠電泳 15
2. 轉印(transfer) 15
3. 免疫反應與顯色 16
(六) 免疫沉澱法(Immunoprecipitation) 16
(七) 細胞與組織切片染色
1. 免疫組織化學染色法(Immunohistochemistry, IHC) 16
2. 免疫螢光染色(Immunofluorescence) 17
3. 粒線體螢光標定(mitotracker stain) 18
第三章、結果
一、ATAD3A於癌症細胞株之表現情形 19
二、ATAD3A於肺癌病人檢體中表現之情形 19
三、ATAD3A磷酸化之檢測 19
四、尋找ATAD3A上游之激酶 (kinase) 20
五、ATAD3A與細胞週期之關聯 20
六、ATAD3A knockdown stable clone之製備 21
七、ATAD3A對粒線體型態之影響 21
八、ATAD3A與肺癌細胞抗藥性之相關性 22
第四章、結語
一、討論 23
二、結論與展望 26
第五章、表 27
第六章、圖 30
參考文獻 39
附錄 52
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