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研究生:許哲嘉
研究生(外文):Che-ChiaHsu
論文名稱:研究MSP58在調控端粒酶/hTERT和細胞老化中所扮演的角色
論文名稱(外文):Studying the role of MSP58 in regulation of telomerase/hTERT and cellular senescence
指導教授:林鼎晏
指導教授(外文):Ding-Yen Lin
學位類別:博士
校院名稱:國立成功大學
系所名稱:生物資訊與訊息傳遞研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:123
中文關鍵詞:MSP58細胞老化端粒酶hTERTBrg1TEIF
外文關鍵詞:MSP58cellular senescencetelomerasehTERTBrg1TEIF
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58-kDa微小球蛋白(MSP58)在維持細胞功能上扮演很重要的角色,包括轉錄調控、細
胞增生以及細胞轉型等。而到目前為止,對於MSP58扮演致癌基因的角色仍然需要進
一步的釐清研究。在我們的研究結果發現,MSP58由小干擾RNA將其基因剔除會導
致染色體非整倍體和細胞凋亡。而MSP58過度表現時會誘導細胞老化或是轉型主要依
賴於控制老化過程中p53是否有完整的功能存在。然而,過度表現MSP58在HT1080、
NIH3T3、人類乳腺表皮細胞株(H184B5F5/M10)以及正常人類雙套纖維母細胞株(Hs68
和IMR90)會誘導細胞提早老化,主要透過Rb的磷酸化減少、DNA損害活化以及活化
p53/p21訊息傳遞路徑。更重要的是,MSP58誘導細胞老化,p53是必須存在的。此外,
利用酵母菌雙雜交篩選找到兩個新穎MSP58交互作用蛋白質,Brg1和TEIF。我們證明
MSP58、Brg1和p53會形成複合體座落在p21啟動子上並啟動基因轉錄。利用小干擾
RNA將Brg1或p53基因剔除後會抑制MSP58所調控的老化。除此之外,MSP58也擔任
一個hTERT轉錄負向調控因子並且抑制TEIF所調控的hTERT轉錄活性、端粒酶活性、
細胞增生以及腫瘤生成。而MSP58抑制hTERT轉錄主要是透過抑制TEIF和DNA結合
的能力。利用組織晶片分析MSP58在腫瘤和正常樣品中的表現,結果顯示MSP58在不
同形態腫瘤中有過度表現和減少表現的情況存在。總結以上的結果,這些研究使我們
對於MSP58經由不同的交互作用蛋白質去調控細胞老化和端粒酶活性有更深入的了
解並且也暗示著MSP58可能同時具有致癌和抑癌基因的雙重特性。
58-kDa microspherule protein (MSP58) plays an important role in a variety of cellular function including transcriptional regulation, cell proliferation and oncogenic transformation. To date, the mechanisms underlying the oncogenic effect of MSP58 remain elusive. In our study, MSP58 silencing by siRNA results in aneuploidy and apoptosis. Forced expression of MSP58 induces either cellular senescence or transformation dependent on the integrity of a senescence program controlled by functional p53. MSP58 overexpression induces premature senescence in HT1080, NIH3T3 cell lines, human mammary epithelial cell line (H184B5F5/M10) and normal human diploid fibroblasts (Hs68 and IMR90) through hypophosporylated Rb, activation of the DNA damage response and upregulation of p53/p21 pathway. Importantly, p53 is required for MSP58-induced premature senescence. Furthermore, novel MSP58-interacting proteins
were identified by yeast two-hybrid screen, including the Brg1 (Brahma-related gene 1) and TEIF (telomerase transcriptional elements-interacting factor). Notably, MSP58 complex colocalizes with both p53 and Brg1 on the p21 promoter and collaborate to activate p21 gene transcription. Brg1 or p53 knockdown by RNA interferences results in MSP58-mediated senescence bypassed. Additionally, MSP58 serves as a negative regulator of hTERT transcription and suppresses TEIF-induced hTERT transcriptional activity, telomerase activity, cell proliferation and tumor formation. The inhibitory effect
of MSP58 on hTERT transcription occurred through inhibition of TEIF binding to DNA. Analysis the expression level of MSP58 in tumor and normal samples in tissue microarrays showed that MSP58 was both up-regulated and down-regulated in different types of tumors compared to the normal tissue counterparts. Taken together, these studies provide new
insights into the role of MSP58 in regulation of cellular proliferation and telomerase
activity via different interacting proteins and suggest that MSP58 has both oncogenic and
tumor-suppressive properties.
(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) Introduction 1
1. The regulation of cellular senescence and telomerase activity in cancer development 1
1.1. Cellular senescence and signaling pathway 1
1.2. The role of oncogene-induced senescence in tumor progression 2
1.3. Transcriptional regulation of telomerase 2
2. 58-kDa microsohere protein (MSP58) 3
2.1. The role of MSP58 in transcriptional regulation 3
2.2. The functional roles of MSP58 in cellular transformation and telomerase activity 4
3. Brahma-related gene-1 (Brg1) 4
3.1. SWI/SNF chromatin-remodeling complexes 4
3.2. The role of Brg1 in cell growth and senescence 5
4. Telomerase transcriptional elements-interacting factor (TEIF) 6
4.1. Identification of TEIF using hTERT promoter-based yeast one-hybrid assay 6
4.2. TEIF is a potential oncogene 6
5. Research significances 6
(IX) Materials and methods 8
1. Materials 8
2. Methods 13
2.1. Plasmids Construction and Antibodies 13
2.2. Cell Culture 15
2.3. Transient, Stable Transfection and Retroviral/Lentiviral Transduction 16
2.4. Immunoprecipitation, Western Blotting Analyses, Immunofluorescence 16
2.5. RNA Extraction, Real-Time Reverse Transcriptase (RT) -Polymerase Chain Reaction (PCR) and Luciferase Reporter Assay 17
2.6. Growth Curve, Soft Agar and Focus Assay 18
2.7. Yeast Two-Hybrid Screen and β-Galactosidase Assay 19
2.8. Glutathione S-Transferase (GST) Pull-Down Assay 19
2.9. Telomeric Repeat Amplification Protocol (TRAP) Assay 19
2.10. Chromatin Immunoprecipitation (ChIP) and Re-Chromatin Immunoprecipitation (re-ChIP) Assay 20
2.11. Electrophoretic Mobility Shift Assay (EMSA) 22
2.12. Senescence-Associated β-galactosidase Staining (SA-β-gal) 22
2.13. Matching Normal/Tumor Expression Array and Tissue Immunohistochemical (IHC) Staining 23
2.14. Statistical Analysis 23
(X) Results 24
1. MSP58 is essential for cell viability and controls cell proliferation in a cell-context dependent manner 24
1.1. MSP58 knockdown cells undergo apoptosis 24
1.2. Ectopic MSP58 expression alters cellular morphology, proliferation and transformation in a cell context-dependent manner 25
2. MSP58 is a potential inducer of oncogene-induced senescence triggering DNA damage response-p53/p21 senescence pathway 26
2.1. Ectopic MSP58 expression induces premature senescence 26
2.2. MSP58 regulates cellular senescence through the DNA damage-p53/p21 signaling pathway 28
2.3. MSP58-induced cellular senescence is mediated through a p53-dependent pathway 30
3. BRG1 associates with MSP58 and is required for MSP58-induced senescence 31
3.1. MSP58 interacts with Brg1 in yeast and in vivo 31
3.2. MSP58, Brg1 and p53 form a complex and cooperate to regulate p21 gene
transcription 32
3.3. Brg1 is an important mediator of MSP58-induced senescence 32
4. MSP58 expression is heterogenous in human tumors 33
4.1. Expression of MSP58 mRNA in human cancers 33
4.2. Expression of MSP58 protein in human cancers 34
5. MSP58 protein functions as a negative regulator of hTERT transcription 35
5.1. MSP58 regulates hTERT expression 35
5.2. MSP58 represses telomerase activity in telomerase-positive 293T and HT1080 cells 36
6. MSP58 inhibits TEIF-mediated hTERT transactivation and telomerase activity through protein-protein interaction 37
6.1. MSP58 interacts with TEIF in vitro and in vivo. 37
6.2. TEIF-mediated activation of hTERT promoter and telomerase activity is
repressed by MSP58 39
7. MSP58 prevents TEIF binding on hTERT promoter 41
7.1. MSP58 does not alter TEIF or hTERT nuclear localization 41
7.2. MSP58 inhibits TEIF DNA-binding activity 42
8. MSP58 inhibits TEIF-mediated promotion of cell proliferation and tumor formation 43
8.1. MSP58 represses TEIF-promoted cell proliferation via S and G2/M cell cycle accumulation 43
8.2. MSP58 antagonizes TEIF-promoted tumor formation 45
(XI) Discussion 46
1. MSP58 may be a potential inducer of oncogene-induced senescence 46
2. Dissection of molecular mechanism of cellular senescence and telomerase activity repression by MSP58 47
3. The effect of MSP58 on cell proliferation and tumorigenesis 50
4. Concluding remarks 54
(XII) References 56
(XIII) Figures 67
(XIV) Appendixes 104
(XV) Publications 120
(XVI) Curriculum vitae 121

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