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系統識別號 U0026-2512201315014400
論文名稱(中文) 研究CPAP在IKKbeta以及HBx導致的NF-kappaB活化中的角色
論文名稱(英文) Studying the roles of CPAP in IKKbeta-mediated and HBx-induced NF-kappaB activation
校院名稱 成功大學
系所名稱(中) 生物資訊與訊息傳遞研究所
系所名稱(英) Insitute of Bioinformatics and Biosignal Transduction
學年度 102
學期 1
出版年 102
研究生(中文) 楊舒婷
研究生(英文) Shu-Ting Yang
學號 Z18971039
學位類別 博士
語文別 英文
論文頁數 150頁
口試委員 指導教授-洪良宜
口試委員-張文昌
口試委員-林以行
口試委員-蔣輯武
口試委員-王育民
口試委員-蔡亭芬
中文關鍵字 NF-kappaB  CPAP  肝癌  發炎  SUMO 
英文關鍵字 NF-kappaB  CPAP  HCC  Inflammation  SUMO 
學科別分類
中文摘要 慢性發炎與癌症的發展息息相關,而NF-kappaB的持續活化則在慢性發炎中扮演了重要的角色,其中由病毒感染或毒物刺激所引發的肝炎在肝癌病變中尤其重要。 中心體蛋白CPAP在過去的研究中被發現可以做為NF-kappaB的協同活化因子來幫助NF-kappaB的活化,但CPAP是如何被調控以及是否存在多重角色仍然未知。在我們的研究中,發現在發炎因子TNF-alpha的刺激下,CPAP可吸引較多的IKKbeta到未活化的NF-kappaB複合體中,使IkappaBalpha與NF-kappaB的磷酸化增加,造成NF-kappaB的活化也增加。CPAP與活化的NF-kappaB複合體可一同進入細胞核中結合至NF-kappaB下游基因的啟動子上,促進基因的轉錄。我們也發現TNF-alpha可刺激CPAP被SUMO1蛋白後轉譯修飾,而SUMO1修飾後的CPAP對於幫助NF-kappaB的活化是必要的。若將CPAP的SUMO1修飾位突變後則會喪失其對NF-kappaB的協同作用,並且在TNF-alpha處理下也無法進入細胞核中。另外我們也發現,CPAP可增加肝細胞的增生。由肝癌檢體發現,CPAP會大量表現於癌症組織並且座落在HBV病毒感染所引起的肝癌細胞的細胞核中,並且與NF-kappaB的活化呈正相關。並且CPAP與HBV病毒所產生的蛋白HBx可以協同性的增加NF-kappaB的活化。此外,CPAP的表現與預後較差的HBV感染導致之肝癌有正相關。這些結果顯示,SUMO1修飾的CPAP可以調節發炎因子所活化的NF-kappaB,並且在未來可以當作發炎或是其相關疾病的治療標靶。
英文摘要 Constitutive activation of NF-kappaB is an important event involved in chronic inflammation. Hepatocellular carcinoma (HCC) is a type of tumor that results from chronic inflammation triggered by hepatotropic viruses or other toxic chemicals. CPAP, which plays important roles in centrosomal functions, was previously identified as the transcriptional co-activator for NF-kappaB. However, the molecular mechanism is unclear. Herein, we demonstrate that CPAP activates the NF-kappaB signaling pathway by recruiting more IKKbeta to inactivated NF-kappaB complexes, results in enhancing the phosphorylation of IkappaBalpha and NF-kappaB. CPAP could enter nucleus through association with NF-kappaB. Additionally, CPAP can be SUMO1 modified upon TNF-alpha stimulus. SUMOylated CPAP increases the association of NF-kappaB with promoters of target genes. SUMO-deficient CPAP mutant lost its NF-kappaB coactivator activity and failed to enter the nucleus in response to TNF-alpha. Importantly, CPAP expression predominantly occurs in the nuclei of HBV-associated HCC, a kind of inflammation-related diseases. CPAP and HBx synergistically augmented NF-kappaB activation. Taken together, our results suggested that SUMOylation of CPAP modulates NF-kappaB activity, and may thus serve as a therapeutic target for inflammation and inflammation-related diseases.
論文目次 (I) Abstract in Chinese I
(II) Abstract II
(III) Acknowledgements III
(IV) Contents IV
(V) Figure index VII
(VI) Appendix index IX
(VII) Abbreviations X
(VIII) Introductions 1
1. The influence of inflammation in cancer development and progression 1
1-1. Inflammation and cancer 1
1-2. Key factors in cancer-related inflammation 3
2. Nuclear factor-kB (NF-kB) 5
2-1. NF-kB proteins and signaling pathway 5
2-2. NF-kB in inflammation-linked cancers 7
2-3. NF-kB as a target for cancer prevention and therapy 8
3. Hepatocarcinoma 9
3-1. An overview of hepatocarcinogenesis 10
3-2. Influence of hepatitis B virus infection 12
3-3. NF-kB in liver cancer 15
4. Centrosomal P4.1-associated protein (CPAP) 16
4-1. The identification of CPAP 16
4-2. The centrosomal functions of CPAP 16
4-3. Other functions of CPAP 17
5. SUMO modification 19
5-1. Post-translational modifications 19
5-2. The SUMO family 20
5-3. The SUMO conjugating pathway 21
5-4. The functions of SUMO modification 22
6. Research significance 24
(IX) Materials and methods 26
1. Materials 26
2. Methods 31
2-1. Cell Culture and Treatments 31
2-2. Plasmid Transfection and Reporter Gene Assay 32
2-3. RNA Interference Technique 32
2-4. Reverse Transcription (RT)-Polymerase Chain Reaction (PCR) and Quantitative PCR (Q-PCR)
33
2-5. Electrophoretic Mobility Shift Assay (EMSA) 33
2-6. Immunoblot Analysis 33
2-7. Co-Immunoprecipitation Assay 34
2-8. Chromatin Immunoprecipitation (ChIP) 34
2-9. Immunofluorescence Analysis 35
2-10. Bacterial SUMOylation Assay and Purification of GST-tagged Proteins
35
2-11. In Vivo SUMOylation Assay 35
2-12. In Situ Proximity Ligation Assay (PLA) Technology 36
2-13. Immunohistochemical Staining 36
2-14. Sampling of Clinical Specimens 37
2-15. Statistical Analysis of Human Clinical HCC Tissues 37
2-16. Statistical Analysis of the reporter assay 38
(X) Results 39
1. CPAP enhances TNF-a-induced NF-kB activation pathway 39
1-1. CPAP is involved in TNF-a-induced NF-kB activation, and is required for the recruitment of IKKb to the NF-kB complex 39
1-1.1 CPAP enhances TNF-a-induced target genes expression of NF-kB 39
1-1.2. CPAP increases the transcriptionl activity of NF-kB 40
1-1.3. CPAP increases the phosphorylation of p65 and degradation of IkBa
40
1-1.4. CPAP is required for TNF-a-induced recruitment of IKK to inactivated NF-kB complexes
40
1-1.5. The effects of CPAP on TNF-a-induced NF-kB activation is dependent on the degradation of IkBa and requires the expression of p65 41
1-2. TNF-a stimulates NF-kB/p65-dependent nuclear translocation and promotes recruitment of CPAP
41
1-2.1. TNF-a induces p65-dependent nuclear translocation of CPAP 41
1-2.2. CPAP increases NF-kB recruitment to the promoters of target genes in response to TNF-a 42
1-3. Summary 42
2. TNF-a-induced SUMOylation of CPAP is essential for NF-kB activation 43
2-1. CPAP is Covalently Modified by SUMO1 after TNF-a Stimulation 43
2-1.1. CPAP is SUMO-modified in vitro 43
2-1.2. CPAP is SUMO-modified by SUMO1 after TNF-a stimulation in vivo
43
2-1.3. CPAP is SUMO-modified by SUMO1 at K921 and K975 44
2-2. SUMO1 modification is essential for the transcriptional co-activity of CPAP in NF-kB pathway 44
2-2.1. SUMOylated CPAP involves in TNF-a-induced NF-kB activation
44
2-2.2. SUMOylated CPAP is important for TNF-a-mediated NF-kB activation
45
2-3. PIASxa is possible SUMO-E3 ligase for SUMO modification of CPAP
45
2-4. Summary 46
3. CPAP is overexpressed and localized in the nuclei in HBV-associated HCC, and synergistically activates NF-kB with HBx
46
3-1. SUMOylated CPAP is involved in cytokines-induced NF-kB activation
46
3-2. CPAP overexpressed and correlated with activated NF-kB in HBV-related HCC
46
3-2.1. Overexpression of CPAP increases colony formation ability and proliferation in HCC cells
47
3-2.2. Overexpression of CPAP is correlated with activated NF-kB in HBV-related HCC tissues
47
3-3. CPAP interacts and cooperates with HBx to increase activation of NF-kB
47
3-3.1. CPAP overexpresses in HBx-expressing cells and interacts with HBx
48
3-3.2. HBx interacts with CPAP and transcriptionally upregulates the expression of CPAP, which in turn cooperatively enhances NF-kB activity

48
3-3.3. SUMOylated CPAP synergically increases HBx-induced NF-kB activation and exists in HBV-related HCC
49
3-4. The physiologic correlation of CPAP in HBV-related HCC 49
3-4.1. Overexpression of CPAP is positive correlated with the clinical pathologic significance in HBV-related HCC
49
3-4.2. The interplay of HBx and CPAP in HCC 49
3-5. Summary 50
(XI) Discussion 51
1. Role of CPAP in TNF-a-induced NF-kB signaling pathway 51
2. SUMOylation of CPAP contributes to the activation of NF-kB 52
3. The relationship between CPAP and HBx in HBV-associated HCC 53
4. The role of CPAP in proinflammatory cytokines-mediated signaling pathway
54
5. Concluding remarks 55
(XII) References 57
(XIII) Figures 68
(XIV) Appendixes 105
(XV) Publications 125
(XVI) Curriculum vitae 126
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