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研究生:陳幸儀
研究生(外文):CHEN, HSING-YI
論文名稱:探討轉錄因子p53於人類LRWD1基因啟動子之調控作用
論文名稱(外文):Transcription factor p53 regulates transcription activity of human LRWD1 genes
指導教授:鄧燕妮
指導教授(外文):Teng, YEN-NI
口試委員:邱建智王家義陳品晟洪瑞祥
口試委員(外文):CHIU,CHIEN-CHIHWANG,CHIA-YIHCHEN , PIN-SHERNHUNG, JUI-HSIANG
口試日期:2018-07-26
學位類別:碩士
校院名稱:國立臺南大學
系所名稱:生物科技學系碩士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:中文
論文頁數:117
中文關鍵詞:LRWD1腫瘤抑制蛋白喜樹鹼p53抑制劑1.4活性氧化物
外文關鍵詞:LRWD1p53CamptothecinPifithrin-αROS
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Leucine-rich repeats and WD repeat domain containing 1 (LRWD1)位於人類第七號染色體長臂22.1,由一個LRR和三個WD40 domain所組成的,主要在睪丸組織中具有高度表現量,在造精過程中,發現在精原細胞(spermatid)與精母細胞(spermatocyte)具有特別明顯,因此LRWD1可能是參與造精過程(spermatogenesis)的重要因素,利用生物軟體資訊promo3.0來預測是否也有其他的轉錄因子,預測結果顯示LRWD1 啟動子上有三個p53轉錄因子結合位點, p53不只是調控細胞週期、細胞凋亡、抑制血管新生等其他功能之外,p53在生殖方面上,對生殖細胞發育期與減數分裂期間皆是扮演重要的角色,穩定生殖細胞的生長,如p53過量表現或降低表現時,會導致精子發生缺陷,p53也是氧化還原活性轉錄因子,維持體內的ROS平衡,避免細胞受到傷害而誘發死亡,將進一步去探討p53轉錄因子對LRWD1的調控,在PROMO3.0軟體分析LRWD1啟動子區域,結果發現在LRWD1 的-165/-159、-66/-60、-39/-28位置有p53的結合位點,以Chromatin Immunoprecipitation assay (ChIP)與DNA affinity purification assay (DAPA)實驗證實p53轉錄因子會與LRWD1啟動子有穩定的結合。以p53 抑制劑 (Pifithrin-α)處理生殖細胞抑制p53活化,發現LRWD1轉錄活性在處理時有明顯下降的趨勢,因此當p53被抑制時,會造成LRWD1啟動子活性下降,而無法進行轉錄的調控,以p53 activator 喜樹鹼(Camptothecin)處理生殖細胞可促進p53活化進入核內與LRWD1啟動子上的p53區域結合,發現LRWD1轉錄活性在處理時有明顯上升的趨勢,因此當p53被活化時,會造成LRWD1啟動子活性上升,而進行轉錄的調控;接著探討p53對細胞週期關係,結果顯示當缺乏LRWD1受到p53刺激下或抑制時,細胞停留在G1期,因此p53表現決定生殖細胞生長;了解p53是否對LRWD1 造成DNA損傷,利用彗星試驗,結果顯示當缺乏LRWD1會p53過度表現時,會造成DNA 損傷,反而p53被抑制時,加劇對LRWD1 的DNA 損傷影響更嚴重,認為當有LRWD1存在時,可避免細胞走向細胞凋亡;為了進一步了解p53受ROS誘導活化後對LRWD1基因調控作用,利用轉染LRWD1 啟動子至NT2/D1細胞,藉由H2O2來產生ROS及p53 activator 喜樹鹼(Camptothecin, CPT) 和p53 抑制劑 (Pifithrin-α)共同處理後,進行啟動子的活性分析,發現當環境中的ROS濃度提升時,p53的表現增加與減少會影響LRWD1 啟動子活性,總結p53對於LRWD1在生殖細胞中可以維持細胞避免外來環境影響,造成DNA損傷進而影響生殖及p53對於生殖細胞內ROS的調控,保護生殖細胞清除過多的ROS,來維持生殖發育,因此p53對於LRWD1可能扮演重要的角色。
The human leucine‐rich repeats and WD repeat domain containing 1 (LRWD1) gene is located on chromosome 7q22.1, it encodes a protein with a leucine-rich repeat (LRR) domain in the N-terminus and three tryptophan-aspartic acid (WD40) motifs in the C-terminus, is highly expressed in normal testicular cells. In the process of spermatogenesis, it is found that spermatogonial cells and spermatocytes are particularly obvious, so LRWD1 may be an important factor involved in spermatogenesis, then Oxidative stress increased LRWD1 expression through a Nrf2- and NF-κB transcription factor dependent mechanism, which plays an important role in cellular adaptation to oxidative stress. Bioinformatics prediction showed that LRWD1 core promoter region contains binding sites three of p53. p53 can plays a role in cell cycle, apoptosis, and inhibition of angiogenesis. p53 is important in the regulation of cell production during normal spermatogenesis either by regulation of cell proliferation and Normal of p53 expression is necessary for cell selection during germ cell development and for meiotic division, either an excessive or a deficient amount of p53 can lead defects in spermatogenesis. We used the PROMO 3.0 software to analyze the 200 bp segment immediately upstream to the LRWD1 transcription start site and revealed the p53 (Tumor protein p53) binding site at -168 to -159, -66 to -60 and -39to -28 bp, respectively. We used Chromatin Immunoprecipitation (ChIP) and DNA affinity purification assay (DAPA) to confirm p53 binding element within the LRWD1 core promoter. Our results suggest that p53 regulates the expression of LRWD1. The transcription activity and expression of LRWD1 was assayed by reporter assay, the results showed LRWD1 promoter activity was positively regulated by Camptothecin treatment. But treatment Pifithrin-α promoter activities of these were decrease. In the cell cycle, our results when p53-regulated activity or inhibitor knockdown LRWD1 cell in G1 phase, , we think the p53 expression cause to regulation of cell cycle and cannot successfully perform cell growth and cell division, the p53 response during DNA damage and expression of LRWD1 was assayed by Comet assay, our results knockdown LRWD1 in NT2/D1 cell can induces p53 dependent apoptosis. In the previous studies, oxidative stress increased LRWD1 expression. Therefore, we co-treated with hydrogen peroxide (release reactive oxygen species) and Camptothecin or hydrogen peroxide and Pifithrin-α) treatment NT2/D1 cell to stimulate p53 activity, we found the Camptothecin to promote LRWD1 promoter expression in the cell, but Pifithrin-α 抑制劑 LRWD1 expression. In conclusion, p53 can avoid the external environment, causing LRWD1 DNA damage and p53 is involved in the regulation of LRWD1 expression. and remove excessive stress to maintain reproductive development, so we suggest that p53 regulates the transcription of expression of LRWD1.
摘要 i
ABSTRACT iii
誌謝 v
目 次 vi
表 次 xii
圖 次 xiii
附 錄 xiv
縮寫表 xvi
第一章 緒論 1
1.1 男性不孕症 (Male infertility) 1
1.2 哺乳類動物精子形成過程(Spermatogenesis) 1
1.3 Leucine-rich repeats and WD repeat domain containing 1 (LRWD1) 基因在生殖與胚胎相關研究 2
1.4 活性氧化物(Reactive oxygen species, ROS) 3
1.5 活性氧化物(ROS)在生殖上扮演角色 4
1.6 Nuclear factor-erythroid 2 related factor 2 (Nrf2)轉錄因子對LRWD1調控 5
1.7 腫瘤抑制蛋白 p53相關介紹 6
1.8 喜樹鹼(喜樹鹼, CPT) 對細胞影響 7
1.9 p53 促進劑 (喜樹鹼, CPT)作用機制 8
1.10 p53抑制劑 (Pifithrin-α) 對細胞影響 8
1.11 p53抑制劑 (Pifithrin-α)作用機制 9
1.12 p53促進劑 (喜樹鹼)與p53抑制劑 (Pifithrin-α) 在生殖細胞上的影響 9
1.13 在氧化壓力環境下p53對生殖細胞影響 10
1.14 研究動機 11
1.15 實驗架構 12
第二章 實驗材料與方法 13
2.1 生殖細胞培養與保存方式 13
2.1.1 細胞培養 13
2.1.2 病毒感染細胞與篩選及stable clone的製備 14
2.1.3 細胞凍存 15
2.1.4 細胞解凍 16
2.2 p53轉錄因子對LRWD1基因轉錄調控 16
2.2.2 染色質免疫沉澱 (Chromatin Immunoprecipitation assay, ChIP) 16
2.2.3 聚合酶連鎖反應 19
2.2.4 瓊脂糖凝膠電泳 21
2.2.5 核蛋白萃取 21
2.2.6 DNA親和性沉澱分析法 23
2.2.7 細胞蛋白質萃取 25
2.2.8 蛋白質濃度測定 26
2.2.9 西方墨點法 27
2.2.10 藥物處理細胞 30
2.2.11 MTT assay 31
2.2.12 細胞型態 32
2.2.13 質體萃取 33
2.2.14 pGL3-basic-LRWD1 啟動子質體轉染作用 35
2.2.15 喜樹鹼對LRWD1 啟動子活性分析 36
2.2.16 p53抑制劑對LRWD1 啟動子活性分析 38
2.3 p53對生殖細胞生長的關係 39
2.3.1 細胞週期分析 39
2.4 LRWD1蛋白與DNA損傷之關係 41
2.4.1 細胞DNA損傷 41
2.4.2 Coating Comet Slide 42
2.4.3 彗星分析 43
2.5 在活性氧環境下p53對LRWD1 啟動子的影響 46
2.5.1 分析細胞內活性氧 46
2.5.2 喜樹鹼與活性氧共同處理對LRWD1轉錄活性的影響 47
2.5.3 p53抑制劑與活性氧共同處理對LRWD1轉錄活性的影響 49
第三章 結果 51
3.1 p53轉錄因子與LRWD1基因的結合 51
3.1.1 生物軟體PROMO3.0預測LRWD1啟動子 51
3.1.2 染色質免疫沉澱(ChIP)探討轉錄因子與LRWD1的結合情況 51
3.1.3 DNA親和性沉澱分析法(DAPA)探討轉錄因子與LRWD1的結合情況 51
3.2 p53 促進劑 (喜樹鹼)與p53 抑制劑 (Pifithrin-α)對生殖細胞影響與轉錄因子p53對
LRWD1的關係 52
3.2.1 利用細胞存活率(MTT assay)分析p53 促進劑 (喜樹鹼)與p53 抑制劑 (Pifithrin-
α)對生殖細胞生長 52
3.2.2 觀察p53 促進劑(喜樹鹼)與p53 抑制劑 (Pifithrin-α)對睪丸癌細胞的細胞型態
(Cell morphology) 52
3.2.3 分析p53 促進劑(喜樹鹼)與p53 抑制劑 (Pifithrin-α)對LRWD1的活性 52
3.2.4 雙螢光素酶報告基因檢測系統( Dual-Luciferase Reporter Assay)探討p53 促進劑
與p53 抑制劑對LRWD1 啟動子的調控作用 53
3.3 探討p53對生殖細胞的細胞週期(Cell Cycle)之關係 53
3.4 探討LRWD1與DNA損傷(DNA damage)關係 54
3.4.1 利用Comet assay分析細胞knockdown LRWD1對DNA損傷 54
3.5 探討p53轉錄因子受ROS刺激後對下游基因LRWD1的影響 54
3.5.1 利用活性氧測定(DCFH-DA assay) 分析單獨處理喜樹鹼與Pifithrin-α對LRWD1的影響
54
3.5.2 利用活性氧測定(DCFH-DA assay) 分析單獨處理H2O2與共同處理喜樹鹼與Pifithrin-
α 對LRWD1的影響 55
3.5.3 利用雙螢光素酶報告基因檢測系統( Dual-Luciferase Reporter Assay)分析喜樹鹼
對LRWD1 啟動子的調控作用 55
3.5.4 利用雙螢光素酶報告基因檢測系統 (Dual-Luciferase Reporter Assay)分析p53抑
制劑對LRWD1 啟動子的調控作用55
第四章 討論 57
第五章 結論 60
第六章 參考文獻 62
附錄 105


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