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研究生:唐丕蓓
研究生(外文):Pi-Pei Tang
論文名稱:p53誘發IW32血癌細胞死亡與分化機轉的探討
論文名稱(外文):Studies of the Mechanisms Underlying p53-Induced Apoptosis and Differentiation in IW32 Erythroleukemia Cells
指導教授:陳芬芳陳芬芳引用關係
指導教授(外文):Fung-Fang Wang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:150
中文關鍵詞:分化酪氨酸磷酸水解脢血癌細胞細胞凋亡p53
外文關鍵詞:p53differentiationapotosisErythroleukemia cellprotein tyrosine phosphatase
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抑癌蛋白p53為一轉錄因子,參與調控細胞生長、DNA修補、分化與死亡,其生物功能主要為保護基因體防止細胞癌化。 吾人以IW32紅血球血癌細胞為模式,探討p53的作用機制。 IW32並不表現p53 mRNA及蛋白。 吾人建立數株可表現tsp53val135的穩定IW32細胞轉殖株。 將轉殖株培養於32.5oC,野生型(wild-type)p53表現時,細胞會先停滯於G1期,之後有的轉殖株會走向apoptosis,而有些細胞則會進行紅血球分化。 挑選傾向分化的1-5轉殖株與傾向apoptosis的3-2轉殖株,以探討p53引起apoptosis的作用機轉。 發現p53促使3-2細胞的apoptosis,伴隨著cytochrome c釋放至細胞質以及caspase-9與caspase-3的活化。 這兩個轉殖株在p53活化後p21與p27蛋白表現均增加,在傾向分化的1-5細胞其表現量明顯較3-2為多。 前處理廣效性caspase抑制劑z-VAD-fmk可抑制caspases的活化及p53所引發的apoptosis,並可促進3-2細胞p27蛋白表現量增加至與1-5細胞相當,而p21蛋白量則不受z-VAD-fmk影響。 因此,p53引發的IW32細胞apoptosis途徑包括了cytochrome c的釋放、caspases的活化與p27的分解。 在32.5℃p53表現時,可被benzidine染色的細胞增加,並且 b-globin與血質基(heme)合成酵素 d-aminolevulinic acid synthase(ALAS-E)mRNA表現明顯上升,證實p53可誘導IW32細胞分化。 Protein tyrosine phosphatase(PTPase)抑制劑sodium vanadate與phenylarsine oxide(PAO)可抑制p53誘導的細胞分化,但不影響p53所引發的生長停滯與死亡。 Sodium vanadate也會抑制p53刺激的b-globin與ALAS-E mRNA表現。 當p53活化後可偵測到細胞內PTPase活性上升,並在早期即可偵測到PTPb2與PTPe mRNA的表現,這些結果推測,PTPase似乎為p53誘發IW32細胞分化的重要因子。
綜上所述,活化的p53可抑制IW32細胞生長,並走向死亡或分化。 而p53可促使細胞釋放cytochrome c與活化caspases來引發apoptosis。 另一方面,p53所誘導的分化與 PTPase的活化有關。
The p53 tumor suppressor is a transcription factor involved in the regulation of cell cycle progression, DNA repair, differentiation and apoptosis. To dissect the p53-dependent signaling pathways, events following induction of p53 in IW32 erythroleukemia cell line were studied. IW32 cells had no detectable levels of p53 mRNA and protein expression. By transfecting a temperature-sensitive mutant p53 cDNA, tsp53val135, into the cells, several clones stably expressing the mutant p53 allele were established. At permissive temperature, these cells were growth arrested and underwent either apoptosis or differentiation. Two clones were selected for further characterization, clone 1-5 cells differentiated along the erythroid pathway and clone 3-2 cells underwent apoptosis upon wild-type p53 expression. The apoptotic response of 3-2 cells was accompanied by cytochrome c release, caspase activation as well as cleavage of caspase substrates. Levels of p21 and p27 proteins increased in both clones expressing wild type p53, with significantly greater levels of accumulation for the two proteins in clone 1-5 cells. Pretreatment of the broad spectrum caspase inhibitor z-VAD-fmk protected 3-2 cells from caspase activation and p53 induced apoptosis; and paralled with significantly elevated expression of p27 protein. p53 activation also triggered IW32 erythroleukemia cells to differentiate along the erythroid pathway, as evidenced by increased population of benzidine positive cells and elevated mRNA expression of β-globin and δ-aminolevulinic acid synthase (ALAS-E). Treatment of cells with sodium vanadate, a protein tyrosine phosphatase inhibitor, blocked the p53-induced differentiation, but not that of cell death or growth arrest. The p53 induced activation of β-globin and ALAS-E mRNA was also blocked by vanadate. Increased protein tyrosine phosphatase activity and enhanced mRNA expression of PTPβ2 and PTPε could be detected during the p53 induced IW32 cell differentiation. Together these results indicate that p53 induced multiple effects on IW32 erythroleukemia cells; the differentiation is dependent on PTPase activation whereas pathway leading to apoptosis is associated with cytochrome c release, caspase activation and p27 degradation.
封面
中文摘要
英文摘要
縮寫表
壹、緒論
1. 細胞週期(Cell cycle) 的調控
1.1 Cyclin-dependent kinases與cyclins
1.2 CDK的磷酸化與去磷酸化調控
1.3 Cyclin-deendent kinase inhibitors (CKIs)
1.4 Checkpoints與細包週期之調控
2. 程式化死亡(Apoptosis)
2.1 粒線體途徑(Mitochondrial pathway)
2.2 死亡受體之途徑(Death receptor pathway)
3. 血球分化
3.1 血紅素之生合成
3.1.1 血紅素蛋白之生合成
3.1.2 血質基之合成
4. p53腫瘤抑制蛋白
4.1 p53蛋白的結構與功能
4.1.1 Transactivation domain
4.1.2 Proline-rich domain
4.1.3 Central DNA-binding core domain
4.1.4 C端oligomerization domain
4.1.5 C端multi-functional basic domain
4.2 P53表現及活性的調控
4.2.1 轉譯
4.2.2 p53蛋白穩定性的調控
4.2.2 P53功能活性的調控
(1) 磷酸化(phosphorylation)與去磷酸化(dephosphorylation)
(2) 乙醯化(acetylation)
4.3 p53的下游效應
4.3.1 p53對細胞週期的調控
4.3.2 p53對apoptosis的調控
4.3.3 p53在DNA修補所扮演的角色
4.3.4 p53與分化的關聯
5. 細胞模式系統-IW32細胞
貳、研究動機
1. 材料
1.1 化學藥品和實驗材料
1.2 酵素和試劑
1.3 質體DNA
1.4 細胞株
1.5 探針質體
1.6 抗體
1.7 放射性物質
2. 方法
2.1 細胞培養
2.2 tsp53va1135穩定IW32細胞轉殖株的建立
2.3 Benzidine染色法
2.4 RNA的製備
2.5 北方墨點轉漬分析(Northern blot analysis)
2.6 放射免疫沉澱法(Radioimmunoprecipitation,RIP)
2.7 細胞全蛋白質的抽取
2.8 蛋白質定量法
2.9  西方墨點分析法(Western blot analysis)
2.10 質體製備
2.11 DNA片段的選殖(cloning)
2.12 Luciferase assay
2.13 流式細胞分析儀(flow cytometry analysis)
2.14 DNA梯狀踤片(DNA fragmentation)電泳的觀察
2.15 免疫螢光染色法(Immunofluorescence Assay)
2.16 Terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nickend labeling (TUNEL)測定法
2.17 PTPase活性測定
2.18 細胞內cytochrome c之分離
2.19 Caspase活性測定
肆、實驗結果
1. 建立表現p53的穩定IW32 hbt krru vfw bpru dhjd
1.1 p53基因表現的鑑定
1.2 tsp53va1135穩定轉殖株(stable transfectants)的建立
2. 確定溫度改變能表現具功能性之p53蛋白
2.1 p53活化後會由細胞質轉位至細胞核
2.2 細胞內之tsp53va1135於32.5C具有轉錄活性
3. 表現p53對IW32血癌細胞生物功能的鑑定
3.1 P53活化造成IW32血癌細胞生長停滯、死亡及分化
3.1.1 p53表現引發細胞apoptosis
3.1.2 p53所誘導之apoptosis伴隨著caspases的活化
3.1.3 Caspases抑制劑z-VAD-fink抑制p53所引發之apoptosis
3.1.4 p53所誘導之apoptosis伴隨著cytochrome c自粒線體釋出
3.1.5 p21、p27、Bax及Bc1-2於p53誘發apoptosis之變化
3.1.6 z-VAD-fmk對p21與p27表現之影響
3.2 細胞生長停滯與調控細胞週期有關基因或蛋白的變化
3.3 p53誘發IW32血癌細胞進行紅血球分化
3.3.1 Protein tyrosine phosphatase(PTPase) 抑制劑可抑制p53所誘發的分化及B-globin與ALAS-E基因的活化
3.3.2 PTPase抑制劑不影響細胞週期停滯及apoptosis
3.3.3 PTPase抑制劑不影響p21基因的活化
3.3.4 p53誘發IW32細胞分化過程中PTPase活性明顯上升
3.3.5 p53誘發IW32細胞分化時,PTPB2、PTPe mRNA被活化
伍、討論
1. P53促使IW32血癌細胞生長停滯、死亡及分化
2. P53引發IW32細胞休止於G1期的機制
3. P53引發cytochrome c釋放與活化caspases
4. Bax與apoptosis之關連
5. P21與p27在apoptosis可能扮演的角色
6. P53可誘導IW32血癌細胞分化
7. PTPase參與p53引發IW32細胞的分化
8. 結論
陸、參考文獻
柒、圖表
捌、附件一
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