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系統識別號 U0026-0509201221234100
論文名稱(中文) 含雙色胺酸功能區氧化還原酶在MAPK訊息傳遞的角色
論文名稱(英文) Role of WW domain-containing oxidoreductase in MAPK signaling
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 100
學期 2
出版年 101
研究生(中文) 許博智
研究生(英文) Po-Chih Hsu
學號 T36991082
學位類別 碩士
語文別 英文
論文頁數 70頁
口試委員 指導教授-徐麗君
口試委員-林以行
口試委員-張南山
口試委員-詹明修
中文關鍵字 含雙色胺酸功能區氧化還原酶 
英文關鍵字 WWOX 
學科別分類
中文摘要 人類WWOX基因位在染色體上易斷裂 (fragile) 的位置上,可轉錄出含雙色胺酸功能區氧化還原酶 (WW domain-containing oxidoreductase,也稱作WWOX、FOR或WOX1)。在許多人類癌症組織中發現,WOX1蛋白質表現量有明顯下降的情形,顯示WOX1蛋白質表現量的下降與癌症發生有關。有趣的是,我們先前發現到當細胞中大量表現WOX1蛋白質時,可以調控和細胞存活有關的PI3K/AKT訊息傳遞路徑。我們最近的研究顯示,當SCC-15細胞大量表現WOX1時,可以調控參與細胞許多重要生理功能的ERK蛋白質磷酸化 (phosphorylation)。許多臨床研究也指出在癌症細胞中,ERK訊息傳遞途徑有異常活化的情形。因此,本研究想瞭解WOX1蛋白質調控ERK訊息傳遞的分子機制為何。在SCC-15細胞中,大量表現WOX1蛋白質也促進ERK上游分子MEK蛋白質磷酸化的情形。同樣地,利用HeLa Tet-on的系統,誘導出WOX1的表現後也可以增加MEK以及ERK蛋白質磷酸化的現象。MEK/ERK訊息傳遞途徑為mitogen-activating protein kinase (MAPK) 途徑的主要路徑之一,它負責調控細胞的增生、分化與存活。MEK抑制劑U0126可以明顯抑制WOX1提升ERK蛋白質磷酸化的情形。總結而言,WOX1蛋白質能活化MEK/ERK訊息傳遞。釐清WOX1蛋白質在MAPK訊息傳遞過程中所扮演的角色,將能提供一個全新的分子觀點來瞭解WOX1蛋白質在癌症進程中的影響。
英文摘要 WW domain-containing oxidoreductase (known as WWOX, FOR or WOX1) is encoded by a fragile gene WWOX. Loss of WOX1 protein expression has been shown in many human cancers. It has been suggested that downregulation of WOX1 protein expression is associated with tumorigenesis. Interestingly, we previously found that ectopic expression of WOX1 regulated the prosurvival PI3K/AKT signaling pathway. Our recent data showed that overexpression of WOX1 in SCC-15 cells regulated protein phosphorylation of ERK, a key kinase involved in many cellular functions. Substantial clinical evidences indicated that aberrant ERK signaling is frequently found in cancer cells. Thus, the aim of this study is to investigate the molecular mechanism by which WOX1 regulates ERK signaling pathway. In SCC-15 cells overexpressing WOX1, protein phosphorylation of ERK upstream kinase, MEK was also increased. Consistently, using HeLa tet-on system, our results demonstrated that inducible expression of WOX1 upregulated protein phosphorylation of MEK and ERK. MEK/ERK cascade is the main route of mitogen-activating protein kinase (MAPK) pathway that regulates cell proliferation, differentiation, and survival. MEK inhibitor U0126 significantly blocked WOX1-induced upregulation of ERK phosphorylation. In conclusion, our results suggest that WOX1 activates MEK/ERK pathway. Delineating the functional role of WOX1 in MAPK signaling pathway will provide a novel molecular insight into the influence of WOX1 on cancer progression.
論文目次 中文摘要…………..……………………………………………… Ⅰ
English Abstract……………………………………………………………… Ⅱ
Acknowledgement………………………………………………………………… Ⅲ
Abbreviations and Symbols……………………………………………………………Ⅳ
Contents………………………………………………………………………………… Ⅴ
Introduction……………………………………………………………………………… 1
Protein structure of WOX1………………………………………………………… 1
The fragile WWOX gene…………………………………………………………… 2
WOX1 functions as a tumor suppressor………………………………………… 2
The regulatory role of WOX1 in apoptotic signaling…………………………… 3
WOX1 acts more than a tumor suppressor…………………………………………3
ERK-MAPK signaling……………………………………………………………… 4
Protein kinase C (PKC) family…………………………………………………… 5
Regulation of PKC activity………………………………………………………… 5
Research Objective……………………………………………………………………… 7
Materials and Methods …………………………………………………………………8
A. Materials …………………………………………………………………………8
A-1 Cell lines……………………………………………………………………… 8
A-2 Reagents and kits……………………………………………………………… 8
A-3 Chemical drugs……………………………………………………………… 10
A-4 Antibodies…………………………………………………………………… 10
A-5 shRNA clones (bought from RNAi core)…………………………………… 11
A-6 Consumables…………………………………………………………………. 11
A-7 Instruments…………………………………………………………………… 12
B. Methods…………………………………………………………………………… 14
B-1 Cell culture…………………………………………………………………… 14
B-2 Plasmid DNA purification…………………………………………………… 14
B-3 Transfection of cells by electroporation………………………… 16
B-4 Transfection of cells by T-pro NTR non-liposomal reagent……………… 17
B-5 Preparation of the lentivial shRNA-knockdown cells………………………... 18
B-6 Doxycycline-induced specific protein expression in HeLa Tet-on cells……... 18
B-7 Protein extraction…………………………………………………………….. 19
B-8 Quantification and adjustment of protein content……………………………. 21
B-9 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting……………………………………………………………… 21
B-10 Immunofluorescence staining………………………………………………. 24
B-11 Extraction of glutathione S-transferase (GST) fusion protein from bacteria.. 25
B-12 Active Ras pull-down assay………………………………………………… 26
B-13 coimmunoprecipitation (coIP)……………………………………………… 28
Results……………………………………………………………………………………. 29
Ectopic overexpression of WOX1 upregulates protein phosphorylation of Raf, MEK and ERK……………………………………………………………………. 29
The role of WOX1 in other MAPK pathways……………………………………. 30
Ectopic expression of WOX1 increases protein phosphorylation of three Raf isoforms…………………………………………………………………………… 30
WOX1 upregulates ERK protein phosphorylation via Raf/MEK cascade……….. 30
WOX1-upregulated phosphorylation of Raf is independent of Ras……………… 31
C-Raf activation by WOX1 is not through dephosphorylation of the negatively regulatory sites on C-Raf…………………………………………………………. 31
Classical PKC family is involved in WOX1-upregulated ERK signaling………... 32
PLC is not involved in WOX1-upregulated ERK-MAPK signaling……………… 33
WOX1 interacts with PKC-α and activates PKC downstream signaling…………. 33
WOX1 mediates PMA-induced C-Raf and ERK activation……………………… 34
Discussion ……………………………………………………………………………….35
The dual role of WOX1 in cancers………………………………………………... 35
WOX1-induced activation of ERK signaling evokes several negative feedback mechanisms……………………………………………………………………….. 36
The role of WOX1 in activation of ERK signaling upon stimulation with diverse mitogens…………………………………………………………………………... 36
The role of WOX1 in the crosstalk between PKC and ERK-MAPK signaling…... 37
Conclusion ………………………………………………………………………………39
References ………………………………………………………………………………40
Figures …………………………………………………………………………………..48
Appendixes …………………………………………………………………………….67
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