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系統識別號 U0026-0812200914083386
論文名稱(中文) 鈣調去磷酸酶calcineurin去磷酸化c-Jun C端對c-Jun蛋白功能的調控
論文名稱(英文) The role of calcineurin-mediated c-Jun C-terminus dephosphorylation in the functional regulation of c-Jun protein
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) 黃祺真
研究生(英文) Chi-Chen Huang
學號 s5892119
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 口試委員-孟子青
口試委員-陳瑞華
口試委員-湯銘哲
口試委員-楊性芳
召集委員-蔣輯武
口試委員-呂增宏
指導教授-張文昌
中文關鍵字 鈣調去磷酸酶  致癌因子  去磷酸化 
英文關鍵字 oncogene  calcineurin  c-Jun  dephosphorylation 
學科別分類
中文摘要 致癌因子 c-Jun 在調控細胞癌化過程中扮演重要的角色,其 C 端靠近DNA binding domain 位置的磷酸化不但會影響與 DNA 結合的親和力還會影響此蛋白因子本身的穩定度。在我們的研究發現 c-Jun C 端的 Ser-243 位置會受到鈣調去磷酸酶 calcineurin (CaN,又稱為 PP2B ) 去磷酸化,增加 c-Jun 與另一個轉錄因子 Sp1 結合的能力,進而促進 c-Jun 調控下遊基因的表現。進一步利用 FRET (fluorescence resonance energy transfer) 的技術來確認CaN 和 c-Jun 會在細胞核內結合,且此結合主要是透過 CaN 的 calmodulin-binding domain。當檢測 c-Jun Ser-243 磷酸化對於 c-Jun 蛋白半衰期的影響發現,c-Jun-S243A 突變蛋白的半衰期比 wild-type 的 c-Jun 來的長;而以 siRNA oligo 將細胞內的CaN 蛋白生成量抑制時,則會增加 c-Jun ubiquitination 的現象,進而減少 c-Jun 蛋白的半衰期。分析臨床子宮頸癌病人組織,在與正常組織比較之下,發現在 46.6 % 惡性腫瘤組織裡的 CaN 的表現量會伴隨著 c-Jun 增高,而 c-Jun 蛋白的 Ser-243 磷酸化反而減少。這些研究結果顯示,CaN 會對 c-Jun Ser-243 進行去磷酸化,延長 c-Jun 蛋白的半衰期並增加在細胞內的細胞轉型能力。
英文摘要 The proto-oncogene c-Jun plays an important role in regulating tumor progression. The protein stability, DNA binding affinity and transcriptional activity of c-Jun are regulated by phosphorylation on c-Jun C terminus. In our study, we reported that Ser-243 of c-Jun is dephosphorylated by serine/threonine phosphatases, calcineurin (CaN, also called PP2B), and the CaN-mediated c-Jun Ser-243 dephosphorylation increases the interaction between c-Jun and Sp1, followed by the enhancement of c-Jun-induced gene expression. Here, we further confirmed that c-Jun/CaN interaction occurs in nucleus of living cells by fluorescence resonance energy transfer assay and the interaction is through the calmodulin-binding domain of CaN. Furthermore, c-Jun protein stability is altered by CaN-mediated Ser-243 dephosphorylation of c-Jun. The half-life of wild-type c-Jun in cells is shorter than that of c-Jun-S243A mutant and silencing of endogenous CaN expression results in enhanced ubiquitination and decreased stability of c-Jun protein. In 46.6 % of clinical cervical tissue samples obtained from patients with cervical cancer, enhanced c-Jun and CaN expression, as well as decreased phospho-Ser-243 expression levels were detected. It indicates that CaN potentially stabilizes c-Jun level in tumor. Taken together, these results suggest that CaN stabilizes c-Jun by dephosphorylating c-Jun at Ser-243 to enhance its tumorigenic ability.
論文目次 口試合格證明..............................................I
中文摘要.................................................II
Abstract................................................III
Acknowlegment............................................IV
Table of contents.........................................V
Figure index.............................................IX
Abbreviations...........................................XII
Introduction
I. The oncoprotein c-Jun..................................1
1. History and overview of c-Jun..........................1
2. Structural features of c-Jun...........................2
3. c-Jun oncogenic property...............................2
4. c-Jun phosphorylation..................................4
II. Ser/Thr phosphatase Calcineurin.......................8
1. Calcineurin structure..................................8
2. Substrates of CaN......................................9
3. The physiologic role of CaN...........................10
III. Cervical cancer.....................................11
1. Overview of cervical cancer...........................11
2. Pathologic types and stages of cervical cancer........12
3. Prognosis.............................................14
IV. Research aims........................................14
Materials and methods
I. Materials.............................................16
II. Methods
1. Cell culture and transfection.........................25
2. Cervical cancer samples...............................26
3. Immunoprecipitation...................................26
4. GST pull-down assay...................................26
5. In vitro phosphatase and GST pull-down assay..........27
6. Protein degradation and polyubiquitination assays.....27
7. Cell proliferation and soft agar assays...............28
8. CFP/YFP FRET microscopy and image analysis............28
9. Plasmid construction and siRNA oligonucleotides.......29
Results
I. Dephosphorylation of c-Jun by CaN in vitro and in cells....................................................33
1. CaN-mediated dephosphorylation of GST-c-Jun in vitro..33
2. Detection of the specificity of c-Jun Ser-243 antibody.................................................34
3. CaN dephosphorylates c-Jun at Ser-243 in cells........34
II. Interaction beween CaN and c-Jun in vitro and in cells....................................................35
1. CaN prefers to interact with GSK3-phosphorylated GST-c-Jun C-terminus region in vitro...........................35
2. PMA-enhanced the interaction between CaN and c-Jun in
cells....................................................36
3. Detection of the direct interaction between CaN and c-Jun in cell nucleus by FRET assay........................37
4. Analysis of the interaction domain of CaN that mediate
c-Jun/CaN interaction....................................38
5. Calmodulin competes the interaction between CaN and
c-Jun....................................................39
III. Effect of CaN-mediated c-Jun C-terminus dephosphorylation on the signal pathway of PMA-regulated gene expression..........................................39
1. CaN reveres the GSK-3-reduced interaction between c-Jun and Sp1..................................................39
2. CaN enhanced c-Jun/Sp1-mediated gene expression.......40
IV. CaN regulates the protein stability of c-Jun.........40
1. Effect of CaN on the protein stability of c-Jun.......40
2. CaN regulates the ubiquitin-dependant protein degradation of c-Jun ....................................42
3. Comparison of the protein stability between the point-mutant c-Jun proteins....................................43
V. The roles of c-Jun and CaN in cervical cancer.........44
VI. CaN-mediated dephosphorylation of c-Jun alters its transformation ability...................................45
Discussion
I. Interaction between CaN and c-Jun.....................47
II. CaN-regulated c-Jun protein stability................49
III. Effect of CaN on c-Jun-induced cell transformation..51
Conclusion...............................................56
References...............................................90
Publications............................................103
Curriculum vitae........................................104
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