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系統識別號 U0026-0812200915284332
論文名稱(中文) 細胞匯聚對含雙色胺酸功能區氧化還原酶之表現的調控
論文名稱(英文) Regulation of WW domain-containing oxidoreductase expression by cell confluence
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 97
學期 2
出版年 98
研究生(中文) 張筱琦
研究生(英文) Shiao-Chi Chang
學號 s4696410
學位類別 碩士
語文別 英文
論文頁數 71頁
口試委員 口試委員-林以行
口試委員-張南山
口試委員-詹明修
指導教授-徐麗君
中文關鍵字 接觸性細胞生長抑制 
英文關鍵字 contact inhibition  E-cadherin  GSK3β  β-catenin 
學科別分類
中文摘要 接觸性細胞生長抑制 (contact inhibition of cell growth) 是正常細胞維持組織恆定 (tissue homeostasis) 的基本特性。當細胞失去此種特性後,會導致細胞轉型(cellular transformation) 進而使細胞能夠無限制生長而形成腫瘤。E-cadherin是構成adherens junctions (AJs) 的主要分子,可能參與接觸性細胞生長抑制的調控。E-cadherin細胞質的部分連結β-catenin,因而將β-catenin限制在AJs的位置,使其無法入核去活化促進細胞週期的基因表現。另外,當β-catenin被casein kinase 1 和 glycogen synthase kinase 3β(GSK3β) 進行磷酸化之後,會走向ubiquitination及蛋白酶體降解。GSK3β已知參與在許多細胞功能當中,包括細胞分裂及細胞凋亡。然而,目前仍不清楚AJs是否會去調控GSK3β的活性。在我們的研究中發現,當人類初代皮膚纖維母細胞 (primary fibroblast) 和三種上皮細胞株A549、SCC-4和DOK生長在高密度 (confluence) 和低密度 (non-confluence) 的狀態下,低密度細胞進入S和G2/M phases的比例明顯高於高密度細胞,同時也觀察到GSK3β在Ser9位置的磷酸化情形增加,其下游的受質β-catenin的磷酸化則減少,表示在低密度細胞中,GSK3β較不活化。進一步發現,在低密度細胞中,GSK3β有入核的現象發生。總結以上的研究結果,我們首次發現細胞密度會去調控GSK3β的活性。
英文摘要 Contact inhibition of cell growth is a fundamental property of normal cells to maintain tissue homeostasis. Loss of contact inhibition is associated with cellular transformation and enables cancer cells to grow in an uncontrolled fashion. E-cadherin, a major component of the adherens junction, recruitsβ-catenin to the cell membrane and has been suggested to be responsible for the regulation of contact inhibition. E-cadherin binding prevents β-catenin nuclear translocation and transactivation of genes that promote the cell cycle. Phosphorylation of β-catenin by casein kinase 1 and glycogen synthase kinase 3β(GSK3β) leads to its ubiquitination and proteasomal degradation. GSK3βhas been implicated in diverse cellular functions including cell division and apoptosis. However, it is unclear whether cell-cell junctions regulate GSK3β activity. We show here that the percentages of cells in S and G2/M phases of the cell cycle were increased in non-confluent human primary fibroblasts and epithelial A549, SCC-4 and DOK cell lines, as compared with the fully confluent cells. Downregulation of GSK3β activity by phosphorylation at serine 9 and dephosphorylation of its downstream target β-catenin were detected in non-confluent cells, as compared to the cells in high density culture. Moreover, nuclear accumulation of GSK3β was observed in non-confluent cells. Taken together, our results suggest a role of cell-cell junctions in regulating GSK3β activity.
論文目次 Chinese Abstract I
English Abstract II
Acknowledgement III
Contents IV
Figure Index VI
Introduction 1
Materials and Methods
A.Materials 9
A-1 Celllines 9
A-2 Drugs 9
A-3 Antibodies 11
A-4 Consumables 12
A-5 Instruments 13
B.Methods 14
B-1 Cell culture 14
B-2 Plasmid DNA purification 15
B-3 Transfection by electroporation 17
B-4 Lentivirus preparation 18
B-5 Lentivirus infection 19
B-6 Protein extraction 19
B-7 Normalization of protein content 21
B-8 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting 21
B-9 RNA extraction 24
B-10 Reverse transcription-polymerase chain reaction (RT-PCR) 25
B-11 Real-time polymerase chain reaction (Real-time PCR) 26
B-12 Immunofluorescence staining 28
B-13 Cell cycle analysis by propidium iodide (PI) staining 29
B-14 T cell factor (TCF) promoter activity reporter assay 30
B-15 Tetracycline-inducible (Tet-On advanced) system in HeLa and U2-OS cells 31
B-16 Site-directed mutagenesis 31
B-17 Bacterial transformation 33
Results 34
Discussion 41
References 46
Figures 55
Appendix 67
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