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系統識別號 U0026-0812200914242514
論文名稱(中文) 三氧化二砷誘導人類子宮頸上皮癌 A431 細胞 p21WAF1/CIP1 基因表現轉錄機制之探討
論文名稱(英文) Transcriptional regulation of p21WAF1/CIP1 gene expression by arsenic trioxide in A431 cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 劉姿妙
研究生(英文) Zi-Miao Liu
電子信箱 p21actin@yahoo.com.tw
學號 S5891108
學位類別 博士
語文別 中文
論文頁數 169頁
口試委員 指導教授-黃暉升
召集委員-劉校生
口試委員-張文昌
口試委員-陳麗玉
口試委員-李德章
口試委員-黃奇英
中文關鍵字 三氧化二砷 
英文關鍵字 arsenic trioxide 
學科別分類
中文摘要 砷化物是已知的致癌物,長期暴露可能增加罹患皮膚癌、膀胱癌及肺癌
的機率;然而砷化物過去也被有效使用於治療急性骨髓前白血病及引發數種
人類癌細胞株生長週期停止或細胞凋亡,然而砷化物致癌或治療癌症的機轉
並不清楚。先前的研究顯示三氧化二砷誘導人類子宮子上皮癌A431 細胞
p21 的表現並導致細胞毒性,使用 Reporter assay、RT-PCR、及西方墨點法,
我們發現c-Src 是三氧化二砷活化 EGFR/ Ras/ Raf/ ERK 路徑的前驅物,進
一步分析不同段落及單點突變的p21 啟動子,顯示三氧化二砷及上皮生長因
子透過p21 啟動子上的Sp1 結合位 (位於 –64~-84 bp)誘導其表現。三氧化
二砷及上皮生長因子誘導 p21 表現除透過基因啟動外,與蛋白質的穩定性
增加也有關。因此,我們推論 p21 啟動子上Sp1 結合位置是三氧化二砷透
過 c-Src/EGFR/Ras/Raf/ERK 路徑誘導 A431 細胞p21 表現之所需;且轉錄
後修飾及轉譯後修飾也會影響三氧化二砷誘發p21 表現。相反的,由
MEKK/JNK 路徑會經由p21 啟動子上的Sp1 結合位置抑制p21 的表現。透
過EMSA、DNA affinity precipitation assay 及ChIP assay 發現三氧化二砷刺
激轉錄因子c-Jun 及c-Fos 結合在 p21 啟動子Sp1 結合位置上(–64~-84
bp),並且有功能的促使p21 啟動子活化。除此,c-Jun 蛋白質ser63/73 磷酸
化的增加會誘導TGIF/HDAC1 結合至p21 啟動子的Sp1 位置上,並抑制p21
基因轉錄;相對的,c-Jun 的C-端(TAM67)、c-Fos、及p300/CBP 會促進p21
基因轉錄。此外,三氧化二砷透過ERK 路徑調控c-Fos 的C-端 transactivation
domain 的磷酸化會影響 c-Fos 與p21 promoter 的結合,位於c-Fos C-端
transactivation domain 的 Thr232, Thr325, Thr331 及Ser374 以及c-FosN-端
transactivation domain 的Ser70 都會影響三氧化二砷對p21 誘導表現。我們
推測三氧化二砷初期經由活化JNK1 使c-Jun 的N-端磷酸化,誘使
TGIF/HDAC1 結合至Sp1 結合位置而抑制p21 表現;隨後經由ERK1/2 活化
促進c-Jun 生合成增加,而藉由c-Jun 的C-端與p300/CBP 及c-Fos 互相合作
促進p21 表現。意即三氧化二砷對p21 啟動子的作用包含兩種相對的訊息傳
遞路徑並需要數種轉錄因子參與在高度協調性及時間性的調控。從探討砷化
物的機轉中我們推測JNK 路徑活化降低了三氧化二砷的治療效果,在臨床
應用上如果降低JNK 的活化或去除TGIF 的表現,可能增加砷的抗癌作用
或減少砷的副作用,對砷在癌症的治療上提供一個新的治療方向。
英文摘要 Arsenic is a well known carcinogen, long term exposure may increase
risks of cancer in skin, bladder and lung. Arsenic has been effectively used to
treat acute promyelocytic leukemia, and can induce cell cycle arrest or
apoptosis in human solid tumors. However, the mechanistic basis for the
carcinogenic or therapeutic effects of arsenic is still poorly known. Previously,
we have demonstrated that As2O3 can induce p21WAF1/CIP1 (p21) expression in
A431 cells and then lead to cellular cytotoxicity. Using reporter assay,
RT-PCR and Western blotting, we show that c-Src activation might be a
prerequisite for As2O3-induced EGFR/Ras/Raf/ERK signaling. Furthermore,
with the aids of 5’-deletion and site-directed mutagenesis, we demonstrate
that Sp1 binding sites, ranging from -64 to -84 bp, are essential for As2O3- or
EGF-regulated p21 expression. Besides, our experiments utilizing
cycloheximide prompt the suggestion that the stability of mRNA or protein
also contributes to As2O3- or EGF-induced p21 expression. Taken together,
we conclude that the Sp1 binding sites are required for As2O3- induced p21
gene transcription through c-Src/EGFR/Ras/Raf/ERK pathway. Furthermore,
post-transcriptional or post-translational stabilization mechanism is also
essential for As2O3-induced p21 expression. EGF-induced p21 expression
may involve similar mechanisms as those that operate in the As2O3-mediated
reactions in A431 cells. In contrast, JNK / MEKK pathway inhibited the
As2O3-induced p21 activation. We prove that Sp1, c-Jun, and c-Fos
functionally cooperate to activate p21 promoter expression through Sp1
binding sites (-84/-64) by using EMSA, DNA affinity binding, chromatin
immunoprecipitation, and promoter assays. Surprisingly, As2O3-induced c-Jun
(Ser63/73) phosphorylation can recruit TGIF/HDAC1 to the Sp1 binding sites
and then suppress p21 promoter activation. Conversely, TAM67, c-Fos, and
p300/CBP are involved in As2O3-induced p21 activation. In addition, arsenic
trioxide treatment up-regulated the c-Fos carboxyl terminal TAD
phosphorylation dependent its recruitment to the promoter region through
ERK signaling and regulating p21 transcriptional activity. We suggest that, in
the early stage of As2O3 treatment, the N-terminal domain of c-Jun
phosphorylated by As2O3-induced JNK activation recruits TGIF/HDAC to the
Sp1 sites and then suppresses p21 expression. In the latter stage, c-Fos and
p300/CBP cooperate with the C-terminal domain of c-Jun to activate p21
expression via As2O3-induced ERK1/2 activation. Thr232, Thr325, Thr331
and Ser374 on the c-Fos carboxyl terminal transactivation domain and Ser70
on the NH2-terminal domain played a pivotal role in arsenic trioxide-induced
expression of p21. That is, p21 promoter regulation by As2O3 involves two
opposing signals and requires several transcription factors acting in a highly
coordinated, temporal-spatial manner. We suggest the JNK activation by
arsenic trioxide may decrease the theraputic effect, to unravel the mechanism
of As2O3 stimulation, simultaneous inhibition the JNK or knock down the
TGIF expression with other anti-tumor drugs could be used to decrease the
side effect of arsenic trioxide or facilitates cancer cell cytotoxicity. To help
developing new strategies for the cancer therapy.
論文目次 目錄
考試合格證明…………………………………………………………II
目錄 ………………………………………………………………… III
圖目錄 ………………………………………………………………VI
誌謝 …………………………………………………………………IV
中文摘要 ………………………………………………………………1
英文摘要 ………………………………………………………………2
縮寫檢索表 ……………………………………………………………4
第一章 緒論 ……………………………………………………………7
第一節 引言 ………………………………………………………7
第二節 研究動機 …………………………………………………24
第二章 實驗材料及方法 ………………………………………………25
第一節 實驗材料 …………………………………………………25
第二節 實驗方法 …………………………………………………30
一、細胞培養 …………………………………………………… 30
二、細胞溶解液 (Cell lysates) 的製備 ……………………………… 30
三、細胞核的萃取 ……………………………………………… 31
四、蛋白質濃度的測定 ……………………………………………32
五、西方墨點法 (Western blot) ……………………………………33
六、凝膠電泳位移測定 (Electrophoretic mobility shift assay, EMSA) …35
七、DNA 親和免疫沈澱分析 (DNA affinity precipitation assay, DAPA) …37
八、染色質體免疫沈澱分析 (Chromatin immunoprecipitation, ChIP assay) ..40
九、轉移感染(transfection) 以及報告基因(luciferase)之分析 …………45
十、質體 (plasmids) 的製備 ……………………………………… 46
十一、質體 (plasmids) 的建構 ……………………………………48
第三章 實驗結果 ……………………………………………………54
第一節 三氧化二砷 (As2O3, ATO) 及表皮生長因子 (EGF) 誘導 p21 表現 …………………………………………………… 54
第二節 三氧化二砷誘導 c-Jun 生合成以及磷酸化,在三氧化二砷調控 p21 表現扮演不同的角色 ………………………… 59
第三節 三氧化二砷誘導 c-Jun N 端 Ser63/73 磷酸化進而使 TGIF 抑制 p21 轉錄 ……………………………………… 62
第四節 三氧化二砷促進 c-Fos 的生合成及磷酸化並參與三氧化二砷調控 p21 表現 …………………………………………… 65
第五節 coaivator p300 參與在三氧化二砷誘導 p21 表現的機制中 ……………………………………………………………72
第四章 討論 …………………………………………………………73
結論 …………………………………………………………82
參考文獻 ……………………………………………………………83
附錄 …………………………………………………………………142
附錄一.自然界中的砷化物 …………………………………………142
附錄二. Metalloid transporters in eukaryotes ……………………………143
附錄三. Biotransformation of inorganic arsenic in mammalian systems …… 144
附錄四.砷化物在醫療上的使用記錄 …………………………………145
附錄五.Arsenic trioxide: potential mechanisms of action …………………146
附錄六. Map of p21WAF1/Cip1 and of its direct protein-protein interactions ……147
附錄七. Positive and negative regulation of G1 progression by p21WAF1 ………148
附錄八. Involvement of p21WAF1/Cip1 and p53 proteins in response of human tumor cells to therapy …………………………………………………149
附錄九.A variety of extracellular signals activate transcription of the p21 gene …150
附錄十.p21 的轉錄調控 …………………………………………………151
附錄十一. Multiple factors employ distinct mechanisms to repress the p21 promoter ………………………………………………………152
附錄十二. Arsenic-induced signal transduction pathways ………………………153
附錄十三. Schematic representation showing the role of c-Src in arsenic-induced signaling pathways ………………………………………………154
附錄十四. The AP-1 transcription factor ……………………………………155
附錄十五. Comparison between mouse c-Jun and c-Fos and their viral counterparts v-Jun and v-Fos ………………………………………………………156
附錄十六. Transcriptional and post-translational activation of AP-1 ……………158
附錄十七. Proteins that can interact with Fos-Jun family members ……………159
附錄十八. The HOB1 and HOB2 motifs of Fos lie within a trans-activating domain ………………………………………………………160
附錄十九. Comparison the N-TM between c-Jun and c-Fos family ……………161
附錄二十. Domain structure and cooperations in Fos ………………………… 162
附錄二十一. Mammalian MAP kinase-transcription factor interactions ………… 163
附錄二十二. Mechanisms of transcriptional activation by p300/CBP ………… 164

附錄二十三. A biologically based dose–response model of arsenic carcinogenesis…165
附錄二十四.The paradox of arsenic………………………………………… 166
附錄二十五.Arsenic-modulated cellular target……………………………… 167
已發表之文獻著作 ……………………………………………………… 168
自述 ………………………………………………………………………169


Fig. 1.
Analysis of activation of EGFR and MAP kinases in A431 cells treated with As2O3 or EGF ……………………………………………105
Fig. 2.
Effect of PP-1 or DN Src on As2O3- or EGF-induced ERK activation and p21 expression ………………………………………………106
Fig. 3.
EGFR/Ras/Raf signaling pathway is involved in As2O3- or EGF induced ERK activation or p21 expression ……………………………109
Fig. 4.
ERK1/2 activation is involved in EGF-induced p21 expression …112
Fig. 5.
ERK1/2 activation is involved in As2O3-induced p21 expression …114
Fig. 6.
Suppression of JNK activation enhances As2O3- or EGF-induced
p21 expression ………………………………………………116
Fig. 7.
The Sp1 binding sites are required for As2O3- or EGF-induced p21 promoter activation …………………………………………118
Fig. 8.
Binding of Sp1 proteinsat Sp1-3 and Sp1-4 binding sitesby EMSA …121
Fig. 9.
Identification of Sp1 and c-Jun binding to the Sp1 sites …………122
Fig. 10.
Effect of c-Jun and its mutants on As2O3-induced p21 activation …124
Fig. 11.
Effects of c-Jun and its mutant on As2O3-induced p21 activation …126
Fig. 12.
Requirement of phosphorylated c-Jun(63/73) in the inhibitory effects
of TGIF on the p21 expression……………………………………127
Fig. 13.
Effects of TGIF on As2O3-induced p21 activation …………………128
Fig. 14.
The interaction region of TGIF with c-Jun ………………………129
Fig. 15.
The repression domain of TGIF interact with the histone deacetylases (HDACs) is required for suppressing arsenic –induced p21 activation 130
Fig. 16.
Involvement of HDAC1 in the TGIF-inhibited p21 promoter expression ………………131
Fig. 17.
ATO Induces c-Fos biosynthesis and protein phosphorylation in A431 cells
…………………………132
Fig. 18.
Involvement of ERK activation in ATO-induced c-Fos biosynthesis and protein phosphorylation ……………………………………133
Fig. 19.
ATO induced c-Fos binding to the Sp1 on p21 promoter …………134
Fig. 20.
Involvement of ERK in ATO-stimulated c-Fos and Sp1 interaction on p21 promoter ……………………………………………………136
Fig. 21.
C-terminus TAD of Fos phosphorylation was required for the ATO - induced p21 expression …………………………………………138
Fig. 22.
N-terminal Phosphorylated c-fos was required for ATO-induced
p21 activation ……………………………………………………139
Fig. 23.
Involvement of p300/CBP in the As2O3-induced p21 promoter activation …………………………140
Fig. 24.
The propouse signaling model of ATO-induced gene expression of p21
in A431 cells ………………………………………………………141
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