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研究生:林螢美
研究生(外文):Ying-Mei, Lin
論文名稱:HIC1結合蛋白質與後轉譯修飾之分析
論文名稱(外文):Analysis of HIC1 interacting proteins and post-translational modifications
指導教授:施修明
指導教授(外文):Hsiu-Ming Shih
口試委員:施修明周玉山張久媛李芳仁馮濟敏
口試委員(外文):Hsiu-Ming, ShihYuh-Shan, JouJoanne Jeou-Yuan, ChenFang-Jen, LeeJim C., Fong
口試日期:2012-08-26
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:2013
畢業學年度:102
語文別:英文
論文頁數:97
外文關鍵詞:HIC1STAT3
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HIC1 (hypermethylated in cancer 1) 蛋白質是一種腫瘤抑制基因,在人類癌症當中,他的表現經常是被抑制的。然而目前關於HIC1的抗癌分子機制與後轉錄修飾如何調控HIC1蛋白的功能卻相當不清楚。我們首先發現HIC1會與Signal Transducers and Activators of Transcription 3 (STAT3)形成複合物,並且可抑制STAT3所調控的轉錄。藉由蛋白質的親和捕獲法和質譜法分析,STAT3被確定為一個HIC1的結合蛋白。過度表達或減少HIC1的表現量可導致減少或增加白細胞介素-6(IL-6)/制瘤素M(OSM)所誘導STAT3所調控報導基因的表達,如VEGF和c-Myc。此外,在MDA-MB 231細胞中,HIC1抑制VEGF和c-Myc的啟動子活性和細胞集落的形成是與STAT3的表現相關連的。進一步的研究顯示,HIC1 與STAT3的DNA結合結構區域結合,並抑制STAT3與其標靶基因啟動子的結合。Domain mapping研究結果顯示,HIC1的C端參與STAT3的結合。在MDA-MB 231細胞中,與STAT3結合有缺陷的HIC1突變會減少STAT3的DNA結合活性,並抑制報導基因活性和VEGF與c-Myc基因表達與細胞生長。總言之,此一研究發現HIC1所抑制STAT3誘導的VEGF和c-Myc轉錄可能與HIC1抑制細胞癌化的功能有關。另外關於HIC1的後轉錄修飾作用,我們也發現HIC1會在胺基酸K314的位置被小類泛素(SUMO)所修飾。氯化鋰(LiCl), 這是一個眾所周知的GSK3β抑製劑,可以調控HIC1小類泛素修飾的程度,然而此一調控是與GSK3β有相關性的。GSK3β可與HIC1結合並將之磷酸化。被GSK3β磷酸化的HIC1可減少HIC1的小類泛素修飾。進一步研究結果顯示,氯化鋰可增加HIC1小類泛素修飾程度是經由增加HIC1與SUMO E2 UBC9結合。此一結果顯示一個新的調控HIC1小類泛素修飾路徑。此外,我們也發現HIC1藉由BTB domain與Cullin-3/ROC1結合,此結果暗示HIC1可能為BCR(BTB-Cullin-3-ROC1) E3 ligase的adaptor並參與蛋白質的降解。有趣的是HIC1也可與Cullin-1和FBX7結合,並提高HIC1泛素化。由此結果我們推測HIC1可能為SCFFBX7 ubiquitin E3 ligase 的受值。整體而言,我們的研究不僅顯示了HIC1可藉由蛋白與蛋白的結合參與細胞反應的調控,同時也提供了小類泛素修飾和泛素化可能對HIC1的調控。
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene, expression of which is frequently suppressed in human cancers. To date, very little is known about how HIC1 antagonizes oncogenic pathways and how HIC1 protein is regulated by posttranslational modifications. We first show that HIC1 forms a complex with the Signal Transducers and Activators of Tanscription 3 (STAT3) and attenuates STAT3-mediated transcription. STAT3 was identified as a HIC1-interacting protein by mass spectrometry following affinity capture. Overexpression or depletion of HIC1 resulted in decreased or increased levels of interleukin-6 (IL-6)/oncostatin M (OSM)-induced STAT3-mediated reporter activity and expression of target genes such as VEGF and c-Myc, respectively. Furthermore, HIC1-mediated suppression of VEGF and c-Myc promoter activity and colony formation of MDA-MB 231 cells were STAT3-dependent. Domain mapping studies show that the C-terminal domain of HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, reporter activity, gene expression of VEGF and c-Myc, and cell growth in MDA-MB 231 cells. Altogether, these findings uncover a novel role of HIC1 in inhibiting STAT3-mediated transcription of VEGF and c-Myc, which may be associated with HIC1 function in antagonizing cell transformation. On the front of HIC1 protein posttranslational modifications, we found that HIC1 can be sumoylated on lysine 314 both in vitro and in vivo. LiCl, a well-known GSK3β inhibitor, can increase HIC1 sumoylation level in a GSK3β-dependent manner. GSK3β interacts with and phosphorylates HIC1. HIC1 phosphorylated by GSK3β reduces HIC1 sumoylation. Further study revealed that LiCl treatment increases HIC1 sumoylation by enhancing the interaction between HIC1 and SUMO E2 UBC9. These results suggest a novel pathway modulating HIC1 sumoylation. In addition, we found that HIC1 associates with cullin-3/ROC1 through its BTB domain. This raises a possibility that HIC1 may function as an adaptor of BCR (BTB-Cullin-3-ROC1) E3 ligase for protein degradation. Interestingly, HIC1 also associates with Cullin-1 and FBX7, which can enhance HIC1 ubiquitination. These results suggest that HIC1 may be a substrate for SCFFBX7 ubiquitin E3 ligase. Collectively, our findings not only demonstrate how HIC1 regulates diverse cellular responses through protein-protein interactions, but also provide a possible regulation of HIC1 by sumoylation and ubiquitination.
中文摘要 1
Abstract 3
Chapter I Introduction 5
1. HIC1 6
1.1 The genomic organization of HIC1 6
1.2 The protein structure of HIC1 6
1.3 Posttranslational modification of HIC1 7
1.4 The target genes of HIC1 8
1.5 The mouse models of HIC1 and cancer 10
2. STAT3 11
2. 1 STAT signaling 11
2.2 Negative regulators of STAT signaling 12
2.3 STAT3 and cancer 12
3. Protein sumoylation 13
4. Regulation of sumoylation 14
5. Ubiquitin-proteasome system (UPS) 14
5.1 Ubiquitin ligase 15
5.2 Skp1-Cul1-F-box (SCF) E3 ligases 15
5.3 BTB-Cul3-Roc1 (BCR) E3 ligases 16
Experimental rationales and specific aims 17
Chapter II Materials and Methods 18
1. Cell culture and transfection 19
2. Plasmid, antibodies and reagents 19
3. Protein purification and GST pull down assays 20
4. Luciferase assay 21
5. Quantitative RT-PCR 21
6. Chromatin Immunoprecipitation 22
7. Subcellular fractionation 23
8. Electrophoretic mobility shift assay 24
9. LC-MS/MS analysis 24
10. Virus production and infection 25
11. Short hairpin RNA (shRNA) 26
12. Immunoprecipitation and Western blot analysis 26
13. In vitro and in vivo sumoylation assay 26
14. In vitro kinase assay 27
15. Statistical analysis 27
Chapter III Results 29
1. HIC1 interacts with STAT3 and suppresses IL-6/STAT3-mediated activity 30
1.1 HIC1 interacts with STAT3 30
1.2 HIC1 suppresses the STAT3-mediated transcriptional activity and cell growth 31
1.3 HIC1 attenuates the DNA binding activity of STAT3 33
1.4 HIC1 interacts with STAT3 DNA binding domain 34
1.5 HIC1 C-terminal domain is essential for STAT3 interaction and regulation 34
2. LiCl-mediated HIC1 sumoylation is GSK3β-dependent manner 36
2.1 HIC1 is the sumoylated in vitro and in vivo 36
2.2 Lysine 314 of HIC1 is the sumoylation site 36
2.3 LiCl could enhance the sumoylation of HIC1 37
2.4 LiCl-mediated HIC1 sumoylation is via GSK3β 37
2.5 GSK3β binds and phosphorylates HIC1, as well as mediates HIC1 sumoylation 38
2.6 LiCl enhances the interaction of HIC1 and SUMO E2 UBC9 followed by regulating HIC1 sumoylation level 39
3. HIC1 and protein ubiquitination 40
3.1 HIC1 forms a complex with Cullin3 and Ring-finger protein, ROC1 40
3.2 HIC1 interacts with Cullin1 40
3.3 HIC1 associates with F-box protein, FBX7 40
3.4 FBX7 enhances HIC1 ubiquitination 41
3.5 HIC1/CUL1/FBX7 from a SCFFBX7/substrate complex 41
Chapter IV Discussion 42
Figures 49
References 77

List of Figures
FIGURE 1. HIC1 INTERACTS WITH STAT3 IN VIVO AND IN VITRO. 50
FIGURE 2. HIC1 SUPPRESSES IL-6/STAT3-ACTIVATED REPORTER ACTIVITY. 52
FIGURE 3. HIC1 REPRESSES THE PROMOTER ACTIVITY AND EXPRESSION OF VEGF AND C-MYC GENES AND CELL COLONY FORMATION. 53
FIGURE 4. HIC1 ATTENUATES THE DNA BINDING ACTIVITY OF STAT3. 55
FIGURE 5. INTERACTION DOMAIN MAPPING OF HIC1 AND STAT3. 57
FIGURE 6. HIC1 C-TERMINAL DOMAIN IS IMPORTANT TO SUPPRESS VEGF AND C-MYC GENE EXPRESSION AND CELL GROWTH. 59
FIGURE 7. LYSINE 314 IS THE SUMOYLATION SITE OF HIC1. 61
FIGURE 8. LICL ENHANCES HIC1 SUMOYLATION AT LYSINE 314. 63
FIGURE 9. LICL-MEDIATED HIC1 SUMOYLATION IS GSK3Β-DEPEMDENT. 65
FIGURE 10. GSK3Β BINDS AND PHOSPHORYLATES HIC1, AS WELL AS MEDIATES HIC1 SUMOYLATION. 66
FIGURE 11. LICL COULD NOT AFFECT THE GLOBAL SUMOYLATION PATTERN AND LICL-MEDIATED HIC1 SUMOYLATION IS NOT THROUGH SUMO E3 LIGASES. 68
FIGURE 12. LICL-MEDIATED HIC1 SUMOYLATION IS NOT VIA DE-SUMOYLATION ENZYME, SENP. 70
FIGURE 13. LICL COULD ENHANCE THE INTERACTION OF HIC1 AND UBC9. 71
FIGURE 14. BTB DOMAIN OF HIC1 IS REQUIRED FOR CULLIN-3/ROC1 INTERACTION. 72
FIGURE 15. HIC1 INTERACTS WITH CULLIN-1. 73
FIGURE 16. HIC1 ASSOCIATES WITH F-BOX PROTEIN, FBX7. 74
FIGURE 17. FBX7 ENHANCES HIC1 UBIQUITINATION. 75
FIGURE 18. HIC1/CUL1/FBX7 FROM A SCFFBX7/SUBSTRATE COMPLEX. 76


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