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系統識別號 U0026-0812200915264561
論文名稱(中文) 探討微小球蛋白MSP58調控細胞週期和細胞老化的分子機制
論文名稱(英文) Molecular Mechanism of Cell Cycle Control and Senescence by the 58-kDa Microspherule Protein (MSP58)
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 97
學期 2
出版年 98
研究生(中文) 許哲嘉
研究生(英文) Che-Chia Hsu
電子信箱 hsuaga@hotmail.com
學號 s2696407
學位類別 碩士
語文別 中文
論文頁數 86頁
口試委員 指導教授-張文昌
指導教授-林鼎晏
口試委員-郭毓良
口試委員-蔣輯武
中文關鍵字 細胞老化  MSP58 
英文關鍵字 MSP58  senescence 
學科別分類
中文摘要 中文摘要

58-kDa微小球蛋白(MSP58)是一個分子量大小約為58-kDa的核仁蛋白,已經被報導和許多蛋白質有交互作用,比如核仁蛋白p120、Mi-2b、RNA結合蛋白FMRP和轉錄因子Stra13以及Daxx。 這些蛋白質交互作用暗示著MSP58在細胞核與核仁中扮演基因轉錄調控的功能。 除此之外,MSP58也被報導在中心體(centrosome)被偵測到以及會與中心體蛋白Nde l和DIPA有蛋白質交互作用。 另外,研究指出MSP58的鳥類同源基因,TOJ3,可透過v-Jun的調控而增加其表現並且具有細胞轉型的活性。 最近研究更提到MSP58可能擔任一個致癌基因(Oncogene)的角色並且因為與腫瘤抑制因子PTEN的交互作用因而抑制其細胞轉型的能力。 然而人類MSP58的一個異構物(isoform),MCRS2,發現會與端粒酶抑制蛋白LPTX/PinX1以及端粒酶催化次單位hTERT有蛋白質交互作用。 本實驗室初步實驗結果顯示,過度表現MSP58基因會依賴不同細胞的形式而對細胞增生速率有不同影響。 持續大量表現MSP58在人類子宮頸上皮細胞株HeLa中,會增加細胞增生的速率; 而以基因剔除方法將MSP58剔除掉後,會抑制HeLa細胞增生的速率。 但是在人類纖維肉瘤細胞株HT1080中,持續大量表現MSP58基因則會誘導細胞走向類似細胞老化的生長抑制過程,並觀察到細胞週期中,S時期和G2時期的進行受到延遲以及抑制了端粒酶的活性。 這些結果暗示出MSP58蛋白質的功能可能具有調控細胞老化的能力。
英文摘要 英文摘要

The 58-kDa microspherule protein (MSP58) has been reported to interact with several proteins, such as nucleolus proteins p120, Mi-2; RNA-binding protein FMRP and transcription factors STRA13, Daxx. These findings suggest that MSP58 may have functions of transcriptional regulation in the nucleus and nucleolus. In addition, MSP58 can be detected on the centrosome and interacted with centrosomal proteins Nde1 and DIPA. A study of the quail homologue of MSP58, TOJ3, showed that this protein can be up-regulated by v-Jun and exhibits cell transformating activity. Recently, a study revealed that MSP58 behaves as an oncogene and that its transformation activity can be inhibited by physical interaction with PTEN tumor suppressor. Moreover, a splice isoform of human MSP58, MCRS2, binds the LPTX/PinX1 telomerase inhibitor and the catalytic hTERT subunit of telomerase. In the preliminary studies, we show that overexpression of MSP58 gene alter cell proliferation rate in a cell type dependent manner. Stably transfection of MSP58 promotes cell growth whereas knockdown MSP58 inhibits cell proliferation in HeLa cells. Unexpectedly, forced expression of MSP58 induces senescence-like growth arrest , delays S and G2 progression and reduces telomerase activity in HT1080 cells. These observations provides a previously uncharacterized biological function of MSP58 in its ability to regulate cellular senescence.
論文目次 目錄
中文摘要……………………………………………………………………...I
英文摘要……………………………………………………………………..II
誌謝………………………………………………………………………….III
目錄…………………………………………………………………………..V
圖目錄…………………………………………………………………...…VII
附錄目錄…………………………………………………………………..VIII
縮寫指引……………………………………………………………………IX
第一章 緒論………………………………………………………………….1
第一節 Microspherule Protein 58 (MSP58)之介紹……………………1
第二節 細胞老化與其訊息傳遞路徑………………………………....3
第三節 細胞老化與癌症的關係………………………………………4
第四節 SWI/SNF染色質重組複合體和癌症………………………...5
第五節 研究動機與目的……………………………………………....6
第二章 實驗方法…………………………………………………………....8
第一節 細胞培養……………..………………………………………..8
第二節 質體之建構…………………………………………………....9
第三節 持續表現MSP58蛋白質細胞株之製備…………………….13
第四節 全細胞液之抽取與蛋白質定量……………………………...15
第五節 硫酸十二酯鈉聚丙烯醯胺凝膠電泳法(SDS-PAGE)/西方點墨
法(Western blot)………………………………………………17
第六節 免疫螢光染色(Immunofluorescence)………………………..24
第七節 端粒重複序列放大反應(Telomere Repeat Amplification Protocol, TRAP assay)………………………………………27
第八節 Senescence associated -galatosidase(SA--gal)之活性試驗..32
第九節 免疫沉澱法(Immunoprecipitation)…………………………...33
第十節 染色質免疫沉澱分析(Chromatin immunoprecipitation assay,
ChIP assay)…………………………………………………34
第十一節 全量的RNA抽取………………………………………...39
第十二節 及時定量反轉錄-聚合酶連鎖反應(Quantitative real-time
RT-PCR)………………………………………………….40
第十三節 報告基因分析法(reporter assay)………………………….42
第三章 實驗結果…………………………………………………………..44
第一節 過度表現MSP58蛋白質誘導HT1080細胞老化…………….44
第二節 MSP58所誘導細胞老化過程是透過改變細胞週期中相關因子表現……………………………………………………………...45
第三節 MSP58調控p53和p21的轉錄活性…………………………..46
第四節 利用酵母菌雙雜交技術找出MSP58新穎的結合蛋白質…….47
第五節 MSP58結合在p21啟動子上…………………………………..48
第六節 MSP58結合至p21啟動子上需要p53存在…………………..49
第七節 過度表現MSP58在SW-13細胞中影響其造成
細胞扁平的能力………………………………………………...50
第八節 MSP58抑制E2F1所調控的啟動子轉錄活性…………………51
第九節 MSP58影響DNA損傷訊息傳遞路徑………………………….52
第四章 討論………………………………………………………………...54
第五章 參考文獻…………………………………………………………...61
附圖………………………………………………………………………….68
附錄………………………………………………………………………….79
自述………………………………………………………………………….86
參考文獻 參考文獻

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