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研究生:郭弘億
研究生(外文):Hong-Yi Kuo
論文名稱:類小泛素修飾CREB結合蛋白於基因轉錄調控之研究
論文名稱(外文):SUMO modification of CREB-binding protein in transcriptional regulation
指導教授:施修明
指導教授(外文):Hsiu-Ming Shih
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:85
中文關鍵詞:類小泛素CREB結合蛋白基因轉錄調控
外文關鍵詞:SUMOCREB-binding proteinTranscritional regulationDaxx
相關次數:
  • 被引用被引用:0
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摘要
CREB結合蛋白(CBP)是細胞中一個重要的轉錄輔活化因子。許多轉錄因子,如CREB、p53、STAT-1與p65等在的活化基因轉錄時都須要CBP的參與及協助。類小泛素化是一個新穎的蛋白質修飾機制,我們發現類小泛素可以針對CBP的lysine 999、1034及1057進行修飾。於培養的細胞中進行報導基因實驗時,將CBP中此三個lysine各別突變為arginine時會使CBP的轉錄活性提升,將此三個lysine同時突變時(CBP 3KR),CBP轉錄活性更加提升,這顯示類小泛素修飾CBP具有抑制其活化基因轉錄的能力。我們也發現,有一個轉錄輔抑制因子Daxx會與被類小泛素所修飾的CBP相結合,因而抑制CBP活化基因轉錄的能力。另方面Daxx會增進組蛋白去乙醯化酵素二號(HDAC2)與CBP於promoter附近的相合。綜合以上發現,我們認為類小泛素修飾CBP會促使Daxx及HDAC2與之相結合進而抑制CBP的轉錄活性。

接著我們嘗試探尋有何細胞內的訊習傳遞會調控類小泛素修飾CBP。在報導基因的實驗中,我們發掘表現CaMKIV會提升CBP WT而非3KR的轉錄活性,這暗示CaMK訊息傳遞可能會調控CBP的類小泛素化。進而我們發現,在細胞中表現CaMKIV或是以Ionomycin刺激細胞內CaMK訊息傳遞,會使CBP的類小泛素化程度下降,顯示CaMK訊息傳遞會抑制CBP的類小泛素化。另方面我們發現組蛋白去乙醯化酵素四號(HDAC4)會與CBP相結合並且擁有增進CBP類小泛素化的能力。我們也觀察到,活化細胞內CaMK訊息傳遞會阻斷CBP與HDAC4的相結合。綜合以上發現,我們認為細胞內CaMK訊息傳遞可能是透過影響CBP與HDAC4的相結合而調控類小泛素修飾CBP。
Abstract
Small ubiquitin-like modifier (SUMO) modification is emerging as an important posttranslational modification playing a variety of roles in the regulation of gene transcription. We found that CREB-binding protein (CBP), a versatile transcriptional coactivator for numerous transcription factors in response to diverse signaling events, can be modified by SUMO-1 at lysine 999, 1034, and 1057 both in vitro and in vivo. Mutation of the three lysine residues either individually or in combination enhanced CBP transcriptional activity, and expression of SENP2 which removes SUMO from CBP potentiated the transcriptional activity of CBP wild-type but not its SUMOylation mutant (3KR) indicating that SUMO modification negatively regulates CBP transcriptional activity. Furthermore, we demonstrated that the transcriptional corepressor Daxx can interact with the SUMO-1-modified CBP and an essential role of Daxx in mediating SUMO-dependent repression of CBP transcriptional activity through histone deacetylase 2 (HDAC2) recruitment. These findings indicate that SUMO modification of CBP and subsequent recruitment of Daxx and HDAC2 represents a previously undescribed mechanism in modulating CBP transcriptional potential.

In an attempt to identify cellular signaling that regulates SUMO modification of CBP, in the reporter assay system, we found that expression of CaMKIV upregulated CBP transcriptional activity in a SUMOylation-dependent manner. This result indicates that CaMK signaling might be involved in the regulation of CBP SUMOylation. Furthermore, expression of CaMKIV or treating cells with Ionomycin which triggers cellular CaMK signaling reduced SUMO modification of CBP suggesting that CaMK signaling can negatively regulate CBP SUMOylation. HDAC4 was a Class II HDAC protein function as a signal transducer for cellular signaling pathways including CaMK signaling. In addition, HDAC4 was found to possess SUMO E3-like activity and shown to enhance SUMO modification of transcription factors such as MEF2D. Intriguingly, we found that HDAC4 can interact with CBP and enhance SUMO modification of CBP. Consistently, HDAC4 can repress the transcriptional activity of CBP WT but not 3KR. More importantly, inducing CaMK signaling can dissociate the CBP-HDAC4 interaction. These results implicate that CaMK signaling might attenuate CBP SUMOylation through interfering with the CBP-HDAC4 interaction.
Content
Contents.....................................I
List of Tables..............................IV
List of Figures............................ V
English Abstract............................1
Chinese Abstract............................3
Chapter I : Introduction……………...........4
1. SUMO
1.1 Identification of SUMO-1…………….……….5
1.2 SUMOylation………………………..…………5
1.3 The consensus SUMOylation motif…….6
1.4 Regulation of transcription factors by SUMOylation.7
2. Daxx is an adaptor protein……………………………………….8
3. Histone deacetylase (HDAC) ………………………………………9
3.1 HDAC4 represses transcription through multiple mechanisms…………......................................….10
3.2 The nucleocytoplasmic distribution of HDAC4 is regulated by cell signaling………………………………………………………………….11
4. CREB-binding protein (CBP)
4.1 CBP is a general transcriptional coactivator……….….…12
4.2 CBP interacts with members of the general transcription machinery………13
4.3 CBP contains intrinsic histone acetyltransferase (HAT) activity…………...13
4.4 Regulation of CBP activity by other posttranslational modifications………15
5. Specific aims……………………..……………………………..15
Chapter II : Materials and Methods………………………………17
1. Plasmids and Antibodies………………………………………..18
2. Cell Culture, Transfection, Reporter Gene Assays……………………………..19
3. Immunoprecipitation and Western Analyses…………………………………...19
4. Yeast Two-Hybrid and β-Gal Assays…………………………………………...20
5. In vitro SUMOylation and Protein Interaction Assays…………………..……...20
6. Quantification of IRF1 Expression Level………………………………………21
7. Chromatin Immunoprecipitation (ChIP) Analysis……………………………...22
Chapter III : Results………………………………………………………………..23
1. CBP is modified by SUMO…………………………………………………….24
2. CBP contains three SUMOylation sites………………………………………...25
3. SUMOylation of CBP negatively regulates its transcriptional activity…………26
4. HDAC protein(s) might be involved in the repression of CBP transactivation potential by SUMOylation……………………………………………………...27
5. Daxx interacts with SUMOylated CBP………………………………………....28
6. Daxx is involved in the SUMOylation-mediated repression of CBP transcriptional activity……………………….………………………………….29
7. CBP SUMOylation is regulated by CaMK signaling……………………….......30
8. CBP serine301 is not essential for the regulation of CBP SUMOylation by CaMK…………………………………………………………………………...32
9. HDAC4 interacts with CBP………………………………………………….....32
10. HDAC4 is a positive regulator in CBP SUMOylation………………………...33
11. The CBP-HDAC4 interaction is interfered by CaMK signaling………………35
Chapter IV : Discussion.............................................................................................37
1. The SUMOylation sites of CBP conform to the NDSM…………………..…....38
2. Difference between SUMO modification of CBP and p300……………..…….39
3. SUMO could regulate transcription through modifying CBP ……………..…..39
4. Daxx is a SUMO reader……………………………………………………..….40
5. The role of HDAC in the SUMOylation-mediated repression of transcription...41
6. Dissociation of the CBP-HDAC4 interaction might be involved in the activation of CREB-dependent transcription by CaMK signaling…………………………42
7. SUMO modification of CBP is involved in the repression of MEF2D-dependent transcription by HDAC4………………………………………………………..42
Tables…………………….………………………………………………………..44
Figures…………………….…………………………………………………………47
References………………….……………………………………………………..77


















List of Tables
Table 1. Prediction of putative SUMO modification sites of CBP by SUMOplotTM.
……………………………………………………………………………………..44
Table 2. The CBP5 901-1100 interact with Daxx in the yeast two-hybrid assay.….…45





















List of Figures
Figure 1. CBP can be covalently modified by SUMO-1 in vitro and in vivo...……47 Figure 2. CBP 901-1100 is modified by SUMO in vitro and in vivo…………………48
Figure 3. Putative SUMOylation sites within CBP5…………………………..…..50
Figure 4. K999, K1034, and K1057 are the SUMO acceptor sites in CBP……….51
Figure 5. SUMOylation negatively modulates CBP transcriptional activity……...53
Figure 6. SUMO modification of CBP negatively regulates CBP coactivation of the IFN- stimulated Stat-1-dependent transcription activation…………….55
Figure 7. HDAC activity is involved in the SUMOylation-mediated repression of CBP transactivation potential…………………………………………...56
Figure 8. SUMO modification of CBP mediates Daxx interaction………………..57
Figure 9. Daxx suppresses the transcriptional activity of SUMOylated CBP via HDAC2 recruitment…………………………………………………….59
Figure 10. CaMKIV signaling might regulate the modification of CBP by SUMO
…………………………………………………………………………61
Figure 11. CaMK signaling regulates CBP SUMOylation………………….…….62
Figure 12. CBP Serine301 is not essential for the CaMKIV-mediated reduction of CBP SUMOylation…………………………………………………….64
Figure 13. CBP interacts with HDAC4……………………………………………65
Figure 14. HDAC4 plays positive role in CBP SUMOylation…………………….67
Figure 15. HDAC4 represses CBP-dependent transcriptional activity in a SUMOylation dependent manner…………………………………..…...69
Figure 16. The nuclear localization of CBP is not altered by CaMK signaling…...70
Figure 17. CaMK signaling dissociates the CBP-HDAC4 interaction……………71
Figure 18. Alignment of SUMO modification sites of mouse CBP and p300…….73
Figure 19. CBP SUMOylation is involved in the repression of MEF2D-dependent transcription by HDAC4………………………………………………..74
Figure 20. Daxx1–732 Fails to Suppress CBP-mediated Transactivation…………...76
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