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系統識別號 U0026-0108201201255300
論文名稱(中文) CDC2和CK2α藉由磷酸化作用調控hRAD9介導的細胞老化作用
論文名稱(英文) Modulation of Senescence Triggered by hRad9 via CDC2 and CK2α-dependent Phosphorylation
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 100
學期 2
出版年 101
研究生(中文) 黃旻杰
研究生(英文) Min-Jai Huang
學號 s16994093
學位類別 碩士
語文別 中文
論文頁數 97頁
口試委員 指導教授-張敏政
口試委員-張明熙
口試委員-張文粲
口試委員-鄭宏祺
中文關鍵字 hRAD9  大腸癌  CDC2  CK2α  細胞老化 
英文關鍵字 hRAD9  colon cancer  CDC2  CK2α  senescence 
學科別分類
中文摘要 人類的Rad9 (hRad9)是一個在結構上與S.pombe rad9極度相似的基因,目前已知hRAD9會參與調控DNA修復、細胞週期調控和細胞凋亡等。然而在hRAD9的C-terminal區域具有十個磷酸化位點,這些磷酸化位點一般認為可能調控著hRAD9的功能。本研究中發現hRAD9在大腸癌腫瘤中有被高度磷酸化的現象,因此我們想了解hRAD9的功能是否受到磷酸化作用的調控。先前我們實驗室的研究發現在乳癌、肺癌和大腸癌細胞當中hRAD9具有促進非p53依賴性的細胞老化作用。在藉由從癌細胞中過度表現模擬磷酸化的hRAD9 (hRad9-10D)與模擬非磷酸化的hRAD9 (hRad9-10A)後,我們發現hRad9-10A具有誘導細胞老化作用的能力,此外藉由hRad9-10A所誘導的細胞老化現象甚至比hRAD9強烈,但過度表現hRad9-10D卻失去誘導老化現象的能力。CDC2 和 CK2α這兩個hRad9的激酶被認為在癌症的進程中扮演著致癌基因的角色。而當我們抑制CDC2 或 CK2α時,我們發現去磷酸化型式的hRAD9具有增加的現象,同時也會誘導細胞老化作用並伴隨細胞p21表現量的增加。我們更進一步發現藉由抑制CDC2 或 CK2α所產生的細胞老化作用可以經由抑制hRAD9而得到回復的現象。另外,我們也發現CDC2 和 CK2α在大腸癌腫瘤檢體當中具有高度的表現量,而在CDC2 和 CK2α同時高度表現的腫瘤組織中hRAD9也具有高度的磷酸化現象。綜合我們的研究發現藉由CDC2 和 CK2α介導的hRAD9磷酸化作用對於hRAD9促進細胞老化作用具有負向的調控作用。
英文摘要 Human Rad9 (hRad9), a structural homologue of S.pombe rad9, is a multifunction protein which participates in DNA repair, cell cycle regulation, apoptosis. The ten phosphorylation sites located in the C-terminal domain of hRAD9 were suggested to be critical for modulating its functions. In this study, we found hRAD9 was aberrantly hypre-phosphorylated in cancerous colon tissues, thus we investigated whether its functions were modulated by protein phosphorylation. In our previous findings, hRad9 could promote p53- independent senescence in breast, lung, and colon cancers. By ectopic expression of phosphorylated or de-phosphorylated mimicking hRAD9 (hRad9-10D and -10A), we found hRad9-10A could induce senescence, even was stronger than hRad9, but overexpression of hRad9-10D made it lose the ability of inducing senescence. Two protein kinases, CDC2 and CK2α, which contributed to phosphorylation of hRAD9, were suggested to be oncogenic in tumorigenesis. By silencing CDC2 or CK2α, it caused the accumulation of de-phosphorylated hRAD9, and caused senescence accompanying with upregulation of p21. Furthermore, the effects caused by loss of CDC2 or CK2α were reversed by hRad9 knockdown. Otherwise, we accessed the levels of CDC2 and CK2α in colon cancer specimens, expressions of CDC2 and CK2α were consistent with the patterns of hyper-phophorylated hRAD9. In conclusion, our findings reveal that protein phosphorylation of hRad9, which is caused by CDC2 and CK2α result in a negative effect on hRAD9-triggered senescence.
論文目次 中文摘要 I
Abstract II
誌謝 III
目錄 V
圖表目錄 VIII
縮寫表 IX
第1章 緒論 1
前言 2
1-1 hRAD9的結構 2
1-2 hRAD9的生理功能 4
1-3 hRAD9的磷酸化修飾作用 5
1-4 hRAD9與癌症之關聯 7
1-5 腫瘤的生成 8
1-6 細胞老化 9
1-7 Casein kinase-2 (CK2) 9
1-8 CDC2/CDK1 11
1-9 研究動機 13
第2章 材料與方法 15
2-1 實驗菌株與培養基配方 16
2-1-1 實驗菌株 16
2-1-2 培養基配方 16
2-2 細胞培養方法 17
2-2-1 實驗細胞株 17
2-2-2 細胞解凍 17
2-2-3 細胞繼代培養 18
2-2-4 細胞計數 18
2-2-5 細胞保存 19
2-3 質體製備 20
2-3-1 聚合酶連鎖反應 20
2-3-2 構築PCR片段於質體DNA 21
2-3-3 E. coli 形質轉型 22
2-3-4 小量質體製備 23
2-4 蛋白質分析 24
2-4-1 蛋白質萃取 24
2-4-2 蛋白質定量 24
2-4-3 SDS-PAGE 蛋白質電泳 25
2-4-4 西方墨點法 26
2-5 在人類癌細胞SW620、H1299建立hRAD9過度表現的穩定細胞 28
2-5-1 hRad9之來源 28
2-5-2 細胞轉染 28
2-5-3 利用抗生素篩選穩定細胞株 29
2-6 hRAD9過度表現的穩定細胞株對於影響腫瘤生長能力的分析 30
2-6-1 利用細胞計數法檢測穩定細胞株生長速率 30
2-6-2 利用Colony Formation Assay觀察穩定細胞株形成細胞群落的能力 30
2-7 hRAD9過度表現的穩定細胞株對於影響細胞老化的分析 31
2-7-1 檢測穩定細胞株內senescence-associated β-galactosidase的活性 31
2-7-2 利用Rhodamine phalloidin螢光染色觀察肌動蛋白應力性纖維的分布 32
2-8 siRNA的暫時轉染 32
2-9 統計方法 33
第3章 實驗結果 34
3-1 在人類大腸癌檢體中hRAD9呈現磷酸化與去磷酸化兩種型態 35
3-2 構築模擬磷酸化hRAD9與非磷酸化hRAD9質體 36
3-3 人類大腸癌細胞株中hRAD9以磷酸化形式存在 37
3-4 在SW620人類癌細胞建立hRAD9過度表現的穩定細胞株 38
3-5 在H1299人類癌細胞建立hRAD9過度表現的穩定細胞株 38
3-6 在SW620與H1299細胞株中過度表現hRad9-WT、hRad9-10A、hRad9-10D會改變細胞型態 39
3-7 在SW620與H1299細胞株中過度表現hRad9-WT、hRad9-10A會降低細胞生長速率 39
3-7-1 利用細胞計數法檢測穩定細胞株生長速率 40
3-7-2 利用Colony Formation Assay觀察穩定細胞株形成細胞群落的能力 41
3-8 在SW620與H1299細胞株中過度表現hRad9-WT或hRad9-10A會促使細胞老化發生 42
3-9 抑制CK2α與CDC2會影響hRAD9的磷酸化狀態 43
3-10抑制CK2α與CDC2會促使細胞老化發生 44
3-11抑制CK2α與CDC2會藉由增加p21而促使細胞老化發生 45
3-12抑制CK2α與CDC2藉由hRAD9介導產生細胞老化現象 45
3-13在人類大腸癌檢體中CDC2與CK2α具有過度表現的情形 47
第4章 實驗討論 49
4-1 hRAD9在癌症之中扮演之角色 50
4-2 hRAD9的磷酸化狀態與表現量在癌細胞中扮演的角色 51
4-3 CK2α與CDC2對於hRAD9介導的細胞老化作用調控角色 53
4-4 細胞中CK2α與CDC2磷酸化hRAD9的作用地點 55
4-5 磷酸化作用對於hRAD9活化p21的影響 56
4-6 調控hRAD9促進細胞老化功能的磷酸化位點 57
4-7 hRAD9的治療潛力 58
參考文獻 59
實驗圖表 67
附錄 92
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