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系統識別號 U0026-0308201015563000
論文名稱(中文) Sp1的磷酸化在有絲分裂時所扮演的角色
論文名稱(英文) The role of phosphorylation of Sp1 during mitotic stage
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 98
學期 2
出版年 99
研究生(中文) 莊健盈
研究生(英文) Jian-Ying Chuang
學號 s5894150
學位類別 博士
語文別 英文
論文頁數 155頁
口試委員 指導教授-張文昌
共同指導教授-洪建中
召集委員-呂增宏
口試委員-賴明德
口試委員-呂佩融
口試委員-洪文俊
口試委員-黃奇英
口試委員-孟子青
中文關鍵字 none 
英文關鍵字 Sp1  mitosis  phosphorylation 
學科別分類
中文摘要 轉錄因子Sp1是普遍表現在各種細胞中,並且調控許多維持細胞正常功能的相關基因表現。在這個研究中發現在有絲分裂時期JNK1會被活化,進一步磷酸化Sp1在酥胺酸278/739位置以避免被蛋白酶體分解,幫助Sp1蛋白質的穩定性。此外我們也有結果顯示在腫瘤生成過程中會伴隨一些機制活化而穩定Sp1蛋白質,然後導致Sp1在癌細胞中量的增加,這些結果也已經被發表在2008年的Mol. Biol. Cell期刊中。然而我們也進一步發現當細胞開始進入有絲分裂期,Sp1的酥胺酸739位置也會被CDK1所磷酸化,而且這磷酸修飾後的位置會被蛋白質異構酶Pin1所辨識而結合,以保護這磷酸根不被PP2A所分解。然而被磷酸化的Sp1會失去它的DNA結合能力而分布在染色體的周圍,但是當有絲分裂結束時PP2A便可以分解Sp1的磷酸根而再次活化Sp1的DNA結合能力。因此癌細胞利用Pin1調控磷酸化的機制而有效的使用Sp1在不同細胞週期,當細胞分裂結束後,癌細胞便可以馬上再度利用Sp1的轉錄活性,去增加促進細胞增生因子的表現,而促進癌細胞的增生。在致癌因子MNU所誘導產生的大鼠乳腺腫瘤中,我們也發現Pin1、CDK1和JNK1的蛋白質量與活性皆與Sp1的表現量都有相對應的累積增加。然而我們也發現當細胞進入有絲分裂期時,不能正常被磷酸修飾的Sp1會阻礙染色質的緊縮以及造成DNA壓力,而誘導細胞進行計劃性凋亡,而且這部分的結果也已經被發表在2009年的Int. J. Cancer期刊中。因此,簡單來說本研究指出癌細胞在有絲分裂期會藉由磷酸化修飾去調控Sp1的轉錄活性、DNA結合能力以及蛋白質穩定度,而能維持Sp1的高度表現和有效的利用Sp1以促進細胞的增生。
英文摘要 The transcription factor Sp1 is ubiquitously expressed in different cells and thereby regulates the expression of genes involved in many cellular processes. In this study, we found that JNK1 was activated during mitosis, and then caused Sp1 to be phosphorylated form. JNK1 phosphorylated Sp1 at Thr278 and Thr 739, thereby increasing the Sp1 stability by repressing the Sp1 degradation in the proteasome- dependent pathway. These results characterize the stability of Sp1 and suggest a tumorigenic action of Sp1. In addition, we also found that Sp1 is a new substrate of CDK1 and is phosphorylated at Thr739 before the entry of mitosis. Further, during mitosis, Pin1, a peptidyl-prolyl isomerase, shields phospho-Sp1-Thr739 from dephosphorylation by PP2A via an action involving the isomerase activity of Pin1. Phospho-Sp1 loses its affinity for DNA and appears to exist as a congregated ring in the periphery of chromosomes. At the end of mitosis and the beginning of interphase however, Sp1 becomes dephosphorylated by PP2A and returns to the chromatin. The results indicate that cancer cells utilize Pin1 to stabilize Sp1 in phosphorylated form and recycle the latter between mitosis and interphase. Pin1 thus, by stabilizing phospho-Sp1, serves to facilitate the quick initiation and execution of interphase in order to maintain the favorable proliferative nature of cancer cells. In MNU-induced mammary tumors, we also found the high Pin 1, CDK1, and JNK1 activation and a high Sp1 accumulation. However, we also found that incompletely phosphorylated Sp1 could block global chromatin condensation and led to a type of DNA-packaging stress. Finaly, the incompletely phosphorylated Sp1 induced cell apoptosis when cells entered the mitotic stage. In conclusion, phosphorylation could play some important roles to regulate the DNA binding ability, transcription activity, and protein stability of Sp1 during mitosis.
論文目次 Abstract..........................................................................................................................i
Abstract in Chinese......................................................................................................ii
Acknowledgments.......................................................................................................iii
Contents........................................................................................................................v
Abbreviation list..........................................................................................................xi


Chapter 1--Introduction..............................................................................................1
I. The Sp1 transcription factor....................................................................................1
1. History and overview of Sp1............................................................................1
2. Structural features of Sp1.................................................................................2
3. The posttranslational modifications of Sp1......................................................2
4. The phosphorylation of Sp1.............................................................................4
5. The role of Sp1 in tumorigenesis.....................................................................5
II. c-Jun N-terminal Kinases (JNKs) ..........................................................................7
1. Mitogen-activated protein kinases (MAPKs)..................................................7
2. The overview of JNKs.....................................................................................8
III. The cell cycle..........................................................................................................9
1. Cell cycle fundamentals...................................................................................9
2. The regulation of cell cycle............................................................................11
3. The role of cyclin/CDK complexes in transcription......................................13
IV. The peptidyl-prolyl cis/trans isomerase (Pin1).....................................................14
V. Research aims........................................................................................................15

Chapter 2--Materials and methods...........................................................................16
I. Materials...............................................................................................................16
II. Expression of plasmids.........................................................................................17
III. Methods................................................................................................................18
1. Cell culture and transfection..........................................................................18
2. Cell synchronization and kinase inhibitor treatment......................................18
3. Immunofluorescence and confocal microscopy.............................................19
4. Time-lapse study............................................................................................20
5. Western blot analysis......................................................................................20
6. In vitro CIP phosphatase assay......................................................................21
7. Fluorescene-activated cell sorting (FACS) analysis......................................21
8. Immunoprecipitation assay............................................................................21
9. Purification of GST fusion proteins...............................................................21
10. GST-pull-down assay.....................................................................................22
11. In vitro JNK1 and CDK1/cyclin B1 kinase assay..........................................22
12. In vitro phosphatase assay..............................................................................23
13. Electrophoretic mobility shift assay (EMSA)................................................23
14. DNA affinity precipitation assay (DAPA).....................................................23
15. Chromatin immunoprecipitation (ChIP) assay...............................................24
16. Reverse transcription-PCR (RT-PCR)............................................................25
17. Generation of adenoviral stocks.....................................................................25
18. MTS assay......................................................................................................26
19. Apoptosis analysis..........................................................................................26
20. Labeling of proteins.......................................................................................27
21. Immunohistochemistry (IHC) assay..............................................................27
22. Experimental animals....................................................................................28
23. Cultured rat primary glial cells......................................................................29

Chapter 3--Results......................................................................................................30
I. The localization of Sp1 during cell cycle period..................................................30
II. The phosphorylated modification regulates the stability of Sp1 during mitosis..30
1. Sp1 is highly phosphorylated in the mitotic stage.........................................30
2. JNK1 activity attributes to the high phosphorylation of Sp1 in mitotic stage................................................................................................................31
3. JNK1 phosphorylates Sp1..............................................................................33
4. JNK1 phosphorylates Sp1 at Thr278 and Thr739..........................................34
5. JNK-induced phosphorylation of Sp1 confers the Sp1 stability necessary for the transcriptional activity of 12(S)-lipoxygenase and cell growth...............35
6. Sp1 accumulation and JNK1 activation occurred in MNU-induced mammalian cancer tumor...............................................................................37
III. The phosphorylated modification regulates the DNA binding affinity and the transcriptional activity of Sp1 during mitosis......................................................38
1. Phosphorylation of Sp1 in mitotic stage reduces its DNA binding affinity...38
2. CDK1 phosphorylates Sp1 at Thr739 in mitotic stage to repress its DNA binding affinity...............................................................................................39
3. PP2A dephosphorylates Sp1 after mitosis.....................................................41
4. Pin1 is recruited to phospho-Sp1 to prevent the latter from dephosphorylation by PP2A during mitosis.................................................................................42
IV. The increased level of unphosphorylated Sp1 leads to p53-dependent apoptosis in cancer cells.......................................................................................................44
1. Overexpression of Sp1 induces global chromatin relaxation and apoptosis-related gene expression..................................................................44
2. Sp1 overexpression reduces the viability of cancer cells.............................46
3. Sp1 overexpression induces cell apoptosis..................................................47
4. Overexpression of Sp1 induces cell apoptosis in a p53-dependent manner..........................................................................................................49
5. Underphosphorylation of Sp1 in mitosis is lethal to cancer cells................51
V. Sp1, CDK1, JNK1, and Pin1 accumulation in MNU-induced mammalian tumor tissue and cancer cells..........................................................................................52

Chapter 4--Discussion................................................................................................54

Conclusion..................................................................................................................62

References...................................................................................................................63

Figures.........................................................................................................................75
Figure 1. The distribution of Sp1 during the cell cycle.........................................75
Figure 2. Sp1 is highly phosphorylated during the mitotic stage..........................76
Figure 3. JNK1 activation in mitosis is important for Sp1 stabilization...............78
Figure 4. JNK1 phosphorylates Sp1 during mitosis..............................................80
Figure 5. Elevated JNK activation increases the phosphorylation of Sp1............81
Figure 6. JNK phosphorylates the Thr278/739 sites of Sp1.................................82
Figure 7. The Sp1 mutated at 278/739 is more unstable than wild-type Sp1 in cells.......................................................................................................84
Figure 8. Sp1 accumulation and JNK activation in glioma cells and MNU-induced tumor............................................................................86
Figure 9. JNK1 phosphorylates Sp1 to stabilize Sp1 during mitosis....................88
Figure 10. The DNA binding ability and transcriptional activity of Sp1 during mitosis...................................................................................................89
Figure 11. In mitotic stage, the phosphorylated modification mediates Sp1 DNA binding affinity.....................................................................................90
Figure 12. CDK1/cyclin B1 interacts with Sp1 during mitosis.............................91
Figure 13. CDK1 and JNK1 phosphorylates Sp1 at Thr739 during mitosis.........93
Figure 14. The Phosphorylation at Thr739 mediates Sp1 DNA binding affinity and transcriptional activity...................................................................94
Figure 15. PP2A dephosphorylates phospho-Sp1 at the end of mitosis to restore Sp1 DNA binding activity....................................................................95
Figure 16. The interaction between phosphor-Sp1 and Pin1................................96
Figure 17. Pin1 confers the stability of phospho-Sp1 against PP2A during mitosis..................................................................................................97
Figure 18. Pin1, CDK1, JNK1, and PP2A regulate the phosphorylation of Sp1 during the cell cycle..............................................................................98
Figure 19. Sp1 cannot interact with p300, Brg1 and RNA pol II during mitosis; and the acetylation of H3 is decreased in mitosis............................ ....99
Figure 20. Overexpression of Sp1.......................................................................100
Figure 21. Sp1 overespression impedes global chromatin condensation and increases the transcriptional activities of the p21 and p16.................101
Figure 22. Sp1 overexpression causes cell death when cells entered the mitotic stage....................................................................................................103
Figure 23. Overexpression of Sp1 induces cell death and inhibition of tumor growth.................................................................................................101
Figure 24. Overexpression of Sp1 induces cell apoptosis...................................104
Figure 25. Both adeno-GFP and adeno-GFP-Sp1 viral infection do not induce cellular ER stress................................................................................105
Figure 26. Sp1 overexpression increases p53 protein level and activates p53-dependent apoptotic pathway......................................................108
Figure 27. p53 is an essential factor for Sp1 overexpression-induced apoptotic cell death.............................................................................................109
Figure 28. Pin1 is required for protection of phosphor-Sp1 during mitosis........111
Figure 29. Unphosphorylated Sp1 (T739A) mutant interfered with mitosis cell cycle progression and induced cell apoptosis.....................................112
Figure 30. The level of Sp1, Pin1, and CDK1 is accumulated in MNU-induced tumor and glioma cells........................................................................114
Figure 31. Schematic diagram illustrates Pin1, CDK1, JNK1, and PP2A regulate the phosphorylation of Sp1 to recycle Sp1 back to the daughter cells of cancer..................................................................................................115

Appendixes................................................................................................................116

Curriculum vitae......................................................................................................129
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