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研究生:廖建皇
研究生(外文):Chien-Huang Liao
論文名稱:在人類非小細胞肺癌細胞株中1-Nitropyrene,Benezo[a]pyrene,p14ARF和Taxol對染色體終端酶的分子調控機轉之研究
論文名稱(外文):Molecular Mechanisms of 1-Nitropyrene, Benezo [a] pyrene, p14ARF and Taxol mediated Telomerase Regulation in H1299 NSCLC Cell Line
指導教授:柯俊良柯俊良引用關係
指導教授(外文):Jiunn-Liang Ko, Ph.D
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:98
中文關鍵詞:終端酶人類終端酶反轉錄酶染色體終端酶的再活化基因選殖
外文關鍵詞:TelomeraseHuman telomerase reverse transcriptasetelomerase reactivationgene cloneBenzo(a)pyrene1-nitropyrenep14ARFtaxol
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壹、中文摘要
染色體終端酶通常在人類正常體組織內偵測不到活性,但是在所有腫瘤組織中85~90%會表現出活性,因此染色體終端酶的再活化被認為在細胞癌化過程中,扮演一個關鍵的角色。終端酶中的反轉錄催化單元是終端酶活性表現的速率決定步驟,其啟動子區域被活化與終端酶活性的再活化有關,因此利用基因選殖方式,選殖出反轉錄催化單元啟動子區域h.TERT-p-548~+50,另外,我們也構築一系列逐漸縮短的啟動子序列包括:h.TERT-p-212~+50 (core promoter)、h.TERT-p -196~+50 (deleted SP1 binding site)、h.TERT-p-177~+50 (deleted SP1 and c-MYC binding site)、h.TERT-p-155~+50 (deleted SP1、c-MYC and AP-2 binding site)來分析多環芳香烴類B[a]P和1-NP、抑癌基因p14ARF 及抗癌藥物taxol對終端酶活性的再活化調控機轉。因此,本研究先以TRAP assay方式偵測到人類非小細胞肺癌細胞(NSCLC cell)受到B[a]P、1-NP和p14ARF刺激後終端酶活性表現毫無影響,而以RT-PCR方式偵測人類非小細胞肺癌細胞反轉錄酵素次單元h.TERT mRNA表現情形發現B[a]P和1-NP低濃度處理後細胞內h.TERT mRNA level表現增加約1~2倍,而在p14ARF方面,隨著處理劑量增加,h.TERT mRNA level表現反而增加約1~1.5倍。接著再用短暫轉染實驗和螢光報告基因分析方式顯示B[a]P對h.TERT-p548轉錄活性影響不大,而1-NP、p14ARF 及taxol則會降低其轉錄活性。另外也顯示出1-NP、p14ARF 和taxol並不是透過這些轉錄因子來調控h.TERT-p轉錄活性,然而重要發現是單獨轉染一系列逐漸縮短h.TERT promoter載體於H1299細胞內,即使縮短至h.TERT-p177和h.TERT-p155仍有一半以上的轉錄活性,表示除了c-Myc外,尚有其它轉錄因子如AP-2及NF-E2仍參與h.TERT轉錄調控。最後我們利用流式細胞儀顯示B[a]P、1-NP和p14ARF 會造成Go/G1期些微增加,taxol則明顯使細胞停滯在G2/M期造成細胞凋亡,而MTT和細胞群落試驗顯示B[a]P、1-NP和taxol均對細胞有毒殺作用。因此本研究主要發現到B[a]P並不會影響h.TERT轉錄活性,而1-NP、p14ARF 和taxol皆會調控h.TERT轉錄活性且可能是藉由其他轉錄因子而不是透過c-Myc作用來調控終端酶活性表現。

貳、英文摘要
Telomerase activity is not detectable in most somatic cell but is upregulated in 85~95% of human canner, which suggests important role of telomerase in neoplastic transformation. Telomerase revese transcriptase was the determinant rate-limiting step in telomerase regulation, and its active promoter activity was involved in telomerase reactivation. Therefore we have cloned the telomerase revese transcriptase promoter (h.TERT-p548). In addition , we co-transfected a series of constructs containing unidirectionally delected fragments: h.TERT-p-212~+50 (core promoter)、h.TERT-p -196~+50 (deleted SP1 site)、h.TERT-p-177~+50 (deleted SP1 and c-MYC site)、h.TERT-p-155~+50 (deleted SP1、c-MYC and AP-2 site), respectively, to examine whether B[a]P、1-NP、p14ARF and taxol regulated telomerase activation through those transcription factors. In the present study, we first employed TRAP and RT-PCR to elucidate whether the regulation of telomerase activity and h.TERT mRNA expression in human NSCLC cell by treatment with B[a]P、1-NP and p14ARF . The telomerase activation was not influence by treament with B[a]P、1-NP and p14ARF ;h.TERT mRNA level was increased 1~2 fold by low concentration of B[a]P and 1-NP , and that was increased 1~1.5 fold by treatment with p14ARF .h.TERT-p548 was activated by low concentration of B[a]P, and repressed by 1-NP、p14ARF and taxol when experiment with transient transfection and luciferase reporter assay . In addition , they did not modulate these transcription factor to regulate h.TERT transcription activation. Significantly, after we alone transfecting h.TERT-p-177 or h.TERT-p-155 plasmid DNA , each still expressed 50~60% transcription activation.It indicated that except for c-Myc, AP-2 and NF-E2 have the ability to regulate telomerase reactivation. Finally our flow cytometric studed show that B[a]P、1-NP and p14ARF slightly increase G0/G1 percentage , and taxol cause cell cycle arrest in G2/M phase leading apoptosis . Furthermore, B[a]P、1-NP、p14ARF and taxol can induce cytotoxicity in H1299 and casue cell death using MTT and colony formation assay .
In summary, this study provides data showing that B[a]P、1-NP、p14ARF and taxol all were able to regulate h.TERT transcriptionactivation , but independently of c-Myc . Maybe they dependent on other transcription factors to regulate telomerase reactivation.

目 錄
壹、中文摘要 1
貳、英文摘要 3
參、縮寫表 5
肆、前言
一、染色體終端酶與細胞腫瘤的關係 6
二、染色體終端酶與細胞衰老的關係 7
三、細胞衰老與細胞腫瘤的關係 8
四、染色體終端酶的結構 8
五、染色體終端酶的分子調控 11
六、環境污染物與肺癌相關性 13
七、p14ARF與癌症的關係 15
八、抗癌藥物taxol與癌症的關係 16
九、研究動機 18
伍、材料與方法
一、細胞株 21
二、細胞專用材料 21
三、質體(Plasmid)DNA 22
四、藥品: 22
五、常用儀器 24
六、方法
1.細胞培養 25
2.細胞分盤 25
3.冷凍細胞 26
4.解凍細胞 27
5.細胞DNA抽取 27
6.Telomerase Catalyic Subunit promtor
(tert-p)deletion的基因選殖 28
7.染色體終端酶重覆增幅步驟 38
8.反轉錄酶鏈聚合酶連鎖反應 41
9.MTT assay 43
10.流式細胞分析 44
11.細胞群落形成效率 46
陸、結果
一、多環芳香烴類B[a]P、1-NP與
抑癌基因p14ARF對染色體終端酶
活性的影響分析 48
二、多環芳香烴類B[a]P、1-NP與
抑癌基因p14ARF對染色體終端酶
反轉錄酶mRNA level的影響分析 49
三、染色體終端酶反轉錄酶啟動子
(h.TERT-promoter)及promotor
deletion的核酸序列之構築 51
四、染色體終端酶反轉錄酶啟動子
(h.TERT-promoter)及promotor
deletion的核酸序列分析 52
五、染色體終端酶反轉錄酶
的分子調控之探討 53
六、多環芳香烴類B[a]P、1-NP
、抑癌基因p14ARF與抗癌藥物
taxol影響H1299 NSCLC細胞毒
性能力之分析 56
七、多環芳香烴類B[a]P、1-NP
、抑癌基因p14ARF與抗癌藥物
taxol對H1299 NSCLC細胞週期
調控之分析 57
八、多環芳香烴類B[a]p、1-NP
、抑癌基因p14ARF與抗癌藥物
taxol對H1299 NSCLC細胞毒殺
作用之分析 58
柒、討論 59
捌、圖表目錄
圖一、多環芳香烴類B[a]P、1-NP
與抑癌基因p14ARF對染色體終端酶
活性的影響分析 70
圖二、多環芳香烴類B[a]P、1-NP
與抑癌基因p14ARF對染色體終端酶
反轉錄酶mRNA level的影響析 71
圖三、染色體終端酶反轉錄酶啟動子
(h.TERT-promoter)及promotor deletion
的核酸序列之構築 72
圖四、Telomerase revese transcriptase
promoter(tert-p)and promoter deletion
核酸序列分析 73
圖五、分析不同長度的啟動子區域在H1299
和BEAS 2B細胞內轉錄活性 74
圖六、分析B[a]P、1-NP、和taxol對h.TERT
啟動子轉錄活性的影響 75
圖七、分析B[a]P、1-NP、p14ARF和taxol
在h.TERT啟動子區域上的分子調控 76
圖八、分析B[a]P和1-NP是否只調控染色體
終端酶中h.TERT轉錄活性 77
圖九、多環芳香烴類B[a]P、1-NP、抑癌基因
p14ARF與抗癌藥物taxol影響H1299 NSCLC細胞
毒性能力之分析 78
圖十、多環芳香烴類B[a]P對H1299 NSCLC細胞
週期之分析 79
圖十一、多環芳香烴類1-NP對H1299 NSCLC
細胞週期之分析 80
圖十二、抑癌基因p14ARF對H1299 NSCLC細胞
週期之分析 81
圖十三、抗癌藥物taxol對H1299 NSCLC細胞
週期之分析 82
圖十四、多環芳香烴類B[a]P對H1299 NSCLC
細胞毒殺作用之分析 83
圖十五、多環芳香烴類1-NP對H1299 NSCLC
細胞毒殺作用之分析 84
圖十六、抑癌基因p14ARF對H1299 NSCLC
細胞毒殺作用之分析 85
圖十七、抗癌藥物taxol對H1299 NSCLC細胞
毒殺作用之分析 86
玖、附錄
附表一、設計h.TERT promoter deletion 87
附表二、引子序列 88
拾、參考文獻 89

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