臺灣博碩士論文加值系統

中文摘要
Promyelocytic leukemia protein (簡稱 PML ) 是一種腫瘤抑制蛋白。雖然它參與了許多不同生理功能但是其複雜的作用機制仍未被完全瞭解。PML主要位於細胞核中形成特殊的斑點狀構造，稱為PML nuclear bodies。 除了PML外，PML nuclear bodies中也存在其他調節性蛋白，例如 p53， Daxx，CREB binding protein（CBP）及small ubiquitin-related modifier（SUMO-1）。Nuclear factor of activated T cells (簡稱NFAT) 是T細胞中重要的轉錄因子，可以調控T細胞中關鍵的生理功能。本論文的實驗發現，PML是NFAT活化作用中，一個未預料到的伙伴。PML可以在T細胞及293細胞中，專一性的加強NFAT的轉錄活性。同時在PML基因剔除的胚胎纖維原細胞中，NFATc的轉錄活性幾乎消失，而消失的NFAT活性，可以藉由重新表現PML在PML基因剔除的胚胎纖維原細胞中而恢復。相反的，PML並不能加強NF-kB的轉錄活性。進一步實驗發現，sumoylated 的PML是其主導的NFAT 活性加強所必需，而這種加強能力並不是因為減弱Daxx的轉錄抑制作用所導致。此外，PML異構體對於NFAT轉錄活性加強作用具有選擇性。PML-I及PML-VI可以加強NFAT的活性，但是PML-IV則對NFAT無作用。在共同免疫沈澱法實驗結果中證明了NFAT與PML-I，PML-IV及PML-VI之間的結合能力。進一步由GST結合實驗中發現，NFATc蛋白上NFAT-homology region (NHR)可以直接與PML蛋白上RING finger，B-boxes結合。而在活化的T細胞核中，NFATc與PML重疊於PML nuclear bodies的位置。雖然PML過量表現不會增加NFATc在核內的含量，但是減少PML的表現，確實降低了NFATc在核內的存在。而一些NFAT活性所主導的基因之表現，也會受到PML的調控。 進一步由染色質免疫沈澱(ChIP) 及DNA吸附沈澱(DAPA) 的結果確認，PML 會藉由與NFATc的結合，進而結合在基因啟動子上。而當細胞內PML減少時，也降低了NFAT及CBP結合在基因啟動子的量。因此我們推測PML可能藉由穩定CBP及NFAT所形成之轉錄複合體，進而促使NFAT的轉錄活性達到最佳化。本論文的研究顯示，在PML複雜的生理功能中，PML與NFAT之間未預期的活化調控，展現了新的作用機制。

Abstract
The promyelocytic leukemia protein (PML) is a tumor suppressor. It is involved in many different physiological functions but the complicated action mechanisms are not yet fully understood. PML localizes in the nucleus to form speckles called PML nuclear bodies, containing regulatory proteins, such as p53, Daxx, CREB binding protein (CBP) and small ubiquitin-related modifier(SUMO-1). Nuclear factor of activated T cell (NFAT) is an important transcription factor, regulates many key T cell functions. In this study, we found that NFAT is an unexpected partner of PML: PML specifically enhanced the transcription activation of NFAT in T cells and 293 cells. In PML-null mouse embryonic fibroblasts, no transcription activity of NFAT could be detected, while PML expression restored NFAT activation. In constrast, PML was not regulated for NF-�羠 transcription. Sumoylation of PML was essential for PML to promote the transcription activity of NFAT. The additive effect of PML was not due to sequestration of Daxx by PML. There was a selective requirement of PML isoform in NFAT activation. PML-I and PML-VI, but not PML-IV, enhanced NFAT transactivation. The potential interaction between NFAT and PML was demonstrated by co-immunoprecipitation of NFATc with PML-I, PML-IV, or PML-VI. GST pull down assay further illustrated a direct binding between the NFAT-homology region (NHR) of NFATc and the RING finger, B-boxes of PML. Inside nucleus of activated T cells, NFATc was found co-localized with PML speckles. Even though PML overexpression did not increase nuclear localization of NFATc, knockdown of PML was moderately reduced nuclear presence of NFAT. Some, but not all, of NFAT activity-mediated genes expression were regulated by PML. The interaction of PML with NFATc in vivo was further confirmed by chromatin immunoprecipitation (ChIP) and DNA affinity precipitation assay (DAPA) analysis. Knockdown of PML was also associated with reduced promoter binding of NFAT and CBP. It is suggested that part of mechanisms of underlying enhancement of NFATc transactivation mediated by PML is due to stabilization of NFAT-CBP transcriptional complex. The unexpected coupling of PML with NFAT reveals a novel mechanism underlying the diverse physiological functions of PML.

目錄
中文摘要........................................3
英文摘要……………………………………………………6
第一章、緒論………………………………………………8
1、PML之簡介………………………………………………8
1.1 PML發現......................................8
1.2 PML蛋白結構、分佈及修飾...............................................................9
1.3 PML蛋白功能……………………………………………………....10
2、NFAT之簡介……………………………………………………13
2.1 NFAT家族成員…………………………………………………….13
2.2 NFAT結構…………………………………………………………13
2.3 NFAT的活化與調控..........................................................................14
2.4 NFAT在T細胞的功能......................................................................16
3、研究目的及方向………………………………………………...18
第二章、 材料及方法……………………………………………….19
2.1 細胞株與培養...................................................................................19
2.2 藥品及試劑………………………………………………………...19
2.3 抗體………………………………………………………………..20
2.4 質體構築…………………………………………………………...20
2.5 質體DNA轉染……………………………………………………..21
2.6 CAT酵素活性分析…………………………………………………23
2.7 病毒感染法…………………………………………………………23
2.8 細胞核萃取液之製備………………………………………………..25
2.9 西方墨點法…………………………………………………………25
2.10 免疫沈澱法………………………………………………………...26
2.11 GST結合分析…………………………………………………….26
2.12 共軛焦顯微鏡分析…………………………………………………27
2.13 RNA純化及反轉錄聚合酶反應……………………………………..28
2.14 即時聚合酶連鎖反應(Real-time PCR)………………………………..30
2.15 酵素免疫分析……………………………………………………..30
2.16 DNA吸附沈澱分析………………………………………………...31
2.17 染色質免疫沈澱…………………………………………………...31
第三章、結果.………………………………………………………..34
3.1 PML在T細胞活化時參與IL-CAT活化……………………………....34
3.2 PML在T細胞活化時加強NFAT-CAT的活化…………………………34
3.3 PML加強NFAT的轉錄活性………………………………………….35
3.4細胞內PML蛋白質的含量與NFAT的轉錄活性息息相關……………...36
3.5 無法被sumoylated的PML突變種不會增加NFAT的轉錄活性………...37
3.6 轉錄抑制因子Daxx在PML主導的NFAT活性所扮演的角色………….38
3.7 PML異構體對於NFAT轉錄活性的影響………………………………38
3.8 PML可與NFAT結合…………………………………………………39
3.9 PML影響核內NFAT含量之探討……………………………………...42
3.10 降低PML表現促使部分NFAT標的基因表現量下降…………………43
3.11 PML、NFAT及CBP同時結合在NFAT標的基因啟動子………………44
第四章、討論………………………………………………………….45
結果圖表……………………………………………………………….51
附圖…………………………………………………………………….83
參考文獻……………………………………………………………….91

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