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標題: | Ets-1在調控介白素二中所扮演之角色 The Roles of Ets-1 in IL-2 Regulation |
作者: | Hsiao-Wei Tsao 曹孝瑋 |
指導教授: | 繆希椿(Shi-Chuen Miaw) |
關鍵字: | 介白素二,基因調控, Ets-1,IL-2,NRON,NFAT,Blimp-1, |
出版年 : | 2013 |
學位: | 博士 |
摘要: | E26轉型特異性序列1(Ets-1)是ETS轉錄因子家族蛋白之原型,也是第一個被發現的ETS家族成員,其對於小鼠體內輔助型T細胞(Th cells)的介白素二(Interleukin-2, IL-2)表現非常重要,然而目前對於Ets-1如何促進介白素二的表現,其機制仍然不明。
我們的研究顯示,Ets-1不僅對小鼠的介白素二表現重要,它也是人類介白素二重要的調控因子。雖然Ets-1可負調控一已知的介白素二抑制者Blimp-1,但在Ets-1基因剔除的輔助型T細胞中再剔除Blimp-1並無法讓介白素二的生成恢復正常。 另一方面,Ets-1可以和NFAT蛋白產生交互作用,除了促進NFAT蛋白的功能之外,也是NFAT聚集並活化至介白素二之啟動子所必須。除此之外,在未活化的輔助型T細胞中,Ets-1同時分布於細胞核和細胞中,當受到鈣離子的訊號刺激之後,核中的Ets-1會快速的離開細胞核並和細胞質中的NFAT蛋白競爭與NRON 複合體的結合,讓NFAT蛋白離開NRON 複合體。這個Ets-1在細胞受到刺激後從細胞核進入細胞質的過程是發生在NFAT蛋白進入核之前,所以當細胞缺少Ets-1時,NFAT蛋白進入核的能力就會受到影響,但其被去磷酸化的能力則沒有變化。 因此,我們認為Ets-1調控介白素二的主要機制乃是透過控制NFAT蛋白的活性而達成的。這篇論文不只增進了我們對於介白素二轉錄機制的了解,另一方面更指出了Ets-1控制下游基因的特殊機制。 Ets-1, the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 in murine and human T cells. Although IL-2 is a well characterized cytokine, how Ets-1 regulates the expression of IL-2 remains unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by murine CD8+ T cells and primary human T helper (Th) cells. We also observed an elevated Blimp-1 expression in Ets-1 KO T cells. Although Blimp-1 plays as a suppressor for IL-2, our data indicated that Blimp-1 is not responsible for the impaired IL-2 production in Ets-1 KO cells. The defects we observed in Ets-1-deficient cells cannot be rescued by Blimp-1 deficiency in Ets-1 KO cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) through multiple domains and is required for the recruitment of NFAT to the IL-2 promoter. In resting Th cells, Ets-1 is located both in nucleus and cytoplasm. When receiving calcium dependent signals from T cell receptors (TCR), nuclear Ets-1 starts to exit the nucleus and competes with NFAT proteins for binding to protein components of NRON (non-coding RNA repressor of NFAT) complex. NRON complex serves as a cytoplasmic trap for phosphorylated NFAT proteins in cytoplasm and this competition results in the release of NFAT from the complex. Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. We also found that the nuclear resident Ets-1 can interact with NFAT proteins to facilitate the transcription activity of NFAT in nucleus. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT. To the best of our knowledge, Ets-1 is the first transcription factor that is known to interact with NRON complex and facilitate nuclear entry of NFAT proteins. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58933 |
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