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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許金玉 | |
| dc.contributor.author | Liang-Jie Wang | en |
| dc.contributor.author | 王亮傑 | zh_TW |
| dc.date.accessioned | 2021-06-13T07:48:03Z | - |
| dc.date.available | 2007-08-02 | |
| dc.date.copyright | 2005-08-02 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/35905 | - |
| dc.description.abstract | GL331是一個半合成podophyllotoxin的衍生物。和其類似物VP-16 (etoposiside)一樣，被視為topoisomerase II (Topo II) poison，具有引發DNA damage的潛在能力。在我們的研究當中，我們深入探討GL331的處理抑制子宮頸癌細胞HeLa S3生長的作用與機轉，GL331透過活化癌症細胞G1/S細胞週期的停滯和細胞凋亡的機轉達到有效抑制癌症細胞。GL331藉由p53的活化促進p21的表現，使得細胞停留在G1/S phase，磷酸化p34cdc2量的增加也表示細胞並未進入M phase。另一方面，GL331的處理啟動細胞中粒線體調控的細胞凋亡途徑(mitochondrial-mediated apoptosis)和接收器調控的細胞凋亡途徑(receptor- mediated apoptosis)，對於GL331所活化的細胞凋亡扮演必要和同等重要的角色。由實驗結果得知，BCL-2在粒線體膜上的表現減少導致細胞中cytochrome c從粒線體釋放到細胞質，隨之caspase 9的活化啟動了粒線體調控的細胞凋亡途徑。GL331也透過增加細胞中FADD的表現和caspase 8的活化啟動了接收器調控的細胞凋亡途徑。因此GL331促進caspase 8和caspase 9的活化進而導致caspase 3的活化和PARP (Poly(ADP-ribose)polymerase)的切割，使得細胞走向死亡。
另外，我們發現mitogen-activated protein kinases (MAPKs)中的extracellular signal-regulated kinase (ERK1/2)明顯的活化，且ERK的活化參與了部份GL331引發的細胞凋亡機轉。為了驗證ERK在GL331處理的細胞中所扮演的角色，我們使用MEK的抑制劑 (U0126)結合GL331的處理，實驗發現U0126具有部分抑制caspase 8和caspase 9活性的能力。我們也首次發現ERK的活化在於FADD protein和mRNA的表現扮演重要的角色，ERK透過活化FADD mRNA的表現促進caspase 8的活化，讓我們重新思考ERK在細胞中的定位，至於ERK是如何促進FADD mRNA的表現將是我們接下研究的主要方向。 | zh_TW |
| dc.description.abstract | GL331 is a semi-synthetic podophyllotoxin-derived compound. Like its congener VP-16 (etoposide), it was originally identified as a potent topoisomerase II (Topo II) poison. In this study, we investigate the anticancer effect of GL331 in human cervical cancer cell line HeLa-S3. GL331 exhibited effective cell growth inhibition by inducing cancer cells to undergo G1/S phase arrest and apoptosis. GL331 induced G1/S arrest by up-regulation of p53-dependant p21CIP1/WAF1 expression. On the other hand, GL331 treatment triggered the mitochondrial - mediated and receptor-mediated apoptotic pathway. Both are essential and equally contributed to GL331-induced apoptosis. GL331 treatment triggered the mitochondrial apoptotic pathway indicated by loss of BCL-2 on the mitochondria membrane , cytochrome c release, and caspase-9 activation. GL331 also induced receptor-mediated apoptosis by increasing the amount of FADD and caspase 8 activation. Take together, activation of both caspase 8 and caspase 9 causes caspase 3 activation and cleavage of PARP (Poly(ADP-ribose)polymerase).The consequential result was the cell apoptosis.
Additionally, we found mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2), are significantly activated and partially participate in GL331-induced apoptosis. To demonstrate proapoptotic function of ERK, we combine GL331 treatment with MEK1/2 inhibitor,U0126. U0126 is able to block partially caspase 8 and caspase 9 activity. ERK is a critical mediator in GL331-induced caspase 8 and caspase 9 activation. Surprisingly, we firstly found that ERK activation promotes increasing the amount of FADD protein and mRNA. ERK alternatively induces the expression of FADD and triggers caspase 8 activation in GL331 treatment. And it will be interesting to explore how ERK stimulates the up-regulation of FADD mRNA. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T07:48:03Z (GMT). No. of bitstreams: 1 ntu-94-R92442011-1.pdf: 675144 bytes, checksum: 73e2d23869acd87efa317b6895681ac7 (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 頁次
中文摘要…………………………………………………………………………. 1 英文摘要…………………………………………………………………………. 2 緒論………………………………………………………………………………. 4 實驗材料與方法…………………………………………………………………. 9 材料: 細胞株(cell line) 培養液(medium) 試劑(reagent) 試劑(reagent) 流式細胞儀使用的染劑 FADD引子(primer) 實驗方法: 培養條件及繼代培養 藥物的處理 MTT試驗 利用流式細胞儀分析細胞週期 細胞凋亡生化特徵之偵測(萃取DNA的片斷) 蛋白質定量 正十二烷硫酸鈉-聚苯烯醯胺膠電泳分析 西方墨點分析法(Western blot analysis) caspase 8和caspase 9活性的偵測 RNA的製備 隨機引子反轉錄作用( Random primer reverse transcription ) DNA 聚合酶連鎖反應( DNA polymerase chain reaction ) 偵測細胞死亡的程度(Nucleosome ELISA Kit) 結果………………………………………………………………………………. 19 圖表與說明………………………………………………………………………. 26 討論………………………………………………………………………………. 38 參考文獻…………………………………………………………………………. 41 | |
| dc.language.iso | zh-TW | |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 拓蹼酶 | zh_TW |
| dc.subject | apoptosis | en |
| dc.subject | GL331 | en |
| dc.title | 拓蹼酶抑制劑(GL331)對子宮頸癌細胞株HeLa S3細胞毒性機轉之探討 | zh_TW |
| dc.title | The Mechanism of Topoisomerase Inhibitor, GL331, Causing Cell Cytotoxicity in HeLa S3 Cell | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃智興,羅?升 | |
| dc.subject.keyword | 拓蹼酶,細胞凋亡, | zh_TW |
| dc.subject.keyword | GL331,apoptosis, | en |
| dc.relation.page | 45 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-26 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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