臺灣博碩士論文加值系統

在造血系統中,細胞激素負責傳遞細胞增生,分化與存活的訊息。在那麼多種細胞激素中,其中第三介白質(IL-3)它對於前趨細胞和成熟血球細胞的存活效應扮演著重要的角色。雖然經過數十年的研究,第三介白質存活反應的訊息傳遞途徑與調控機制仍然尚未完全了解。所以在我的論文研究中,我將利用老鼠的第三介白質依賴性前趨B細胞株(Ba/F3)為我的研究模式系統,進一步來探討轉錄因子在存活反應中所扮演的角色。首先,在論文的第一部分,我試著想要找出哺乳動物中能與CES-2/E2A-HLF結合序列(CBE)結合且參與調控細胞凋亡(apoptosis)的結合蛋白。結果我發現CBE的結合體存在於許多哺乳動物的細胞株與組織中,且鑑定出CREB蛋白存在於其中一個主要的CBE結合體中。接著,我再利用能誘導表現且干擾CREB結合能力的突變蛋白(CREB-R287L)來進行研究,研究發現它確實能降低細胞的存活能力。進一步我也找到了抗細胞凋亡基因 Bcl-2上也具有此CBE結合體,所以認為它是其抗細胞凋亡目標基因之一。在我論文的第二部分,我主要研究另一個CBE結合蛋白E4BP4其轉錄的調控機制。E4BP4是一個含有bZIP轉錄因子家族的一員,它能受到第三介白質的調控且在第三介白質存活反應中扮演一個重要的角色。根據實驗指出,第三介白質活化E4bp4基因主要是透過轉錄層次。再經由啟動子分析,我找到在主要轉錄起始點後面有一個GATA結合序列為E4bp4基因表達所需。進一步也發現GATA轉錄因子家族中的GATA-1和GATA-2在活化E4bp4基因上扮演重要的角色,且參與第三介白質存活反應的訊息傳遞。論文的最後,我想要了解第三介白質是透過什麼樣的訊息傳遞途徑來活化E4bp4基因。研究指出,第三介白質能調控E4bp4啟動子上GATA結合序列結合的能力與GATA-1蛋白的磷酸化。接著我也發現第三介白質是透過RAF-MEK-MAPK這條訊息傳遞途徑來調控GATA-1的磷酸化,結合能力與E4bp4基因的表達,若進一步抑制MAPK就能降低E4bp4啟動子的活性與訊息RNA的表達。總之,根據以上我的論文研究指出,有許多轉錄因子能負責傳遞第三介白質的存活訊息且它們的表達與功能在第三介白質存活反應上扮演一個重要的角色。所以在血球細胞細胞凋亡的途徑中,發現GATA轉錄因子在E4bp4上所扮演的角色給我們很大的啟示,且對於未來了解造血過程與血球增生上更提供了另一個思考的方向。

Cytokines transduce signals of proliferation, differentiation, and survival in the hematopoietic system. As one of the most characterized cytokines, interleukin-3 (IL-3) is well known for its survival effect on both progenitors and mature blood cells. Although with the extensive studies in the past decades, the signaling pathways and regulatory mechanism of survival response of IL-3 still is not completely understood. In my thesis, I will use a murine IL-3-dependent pro-B cell line, Ba/F3, as a model system to explore the role of transcriptional factors in survival responses. The first part of my thesis was aiming to identify the mammalian CES-2/E2A-HLF Binding Element (CBE)-binding proteins that may be involved in apoptosis regulation. I was able to demonstrate the existence of multiple binding complexes of CBE in various mammalian cell lines and tissues and identify cyclic AMP (cAMP)-responsive element (CRE)-binding protein (CREB) as the component of one major CBE complex. By conditionally expressing CREB-R287L mutant, which interferes the binding ability of wild-type CREB, I demonstrated that the viability of cell lines was reduced in the presence of mutant CREB. Moreover, my data also suggested the Bcl-2 gene as one candidate cellular target of the CREB-containing CBE complex. In the second part of my thesis, the transcriptional regulatory mechanism of another CBE-binding protein, E4BP4, is studied. E4bp4, a member of the basic region-leucine zipper (bZIP) transcriptional factor superfamily, is up-regulated by the IL-3 and plays an important role in IL-3’s antiapoptotic response. In this study, I have demonstrated that IL-3 activation of the E4bp4 gene is regulated at the transcriptional level. Through promoter analysis, I showed that a GATA motif downstream of the transcriptional initiation site is essential for E4bp4 expression in the Ba/F3 cells. I also demonstrated that GATA-binding factors, most likely GATA-1 and GATA-2, play an important role in the transcriptional activation of E4bp4, and are involved in the antiapoptotic signaling of IL-3. The third part of my thesis is devoted to investigate the signaling pathway responsible for induction of the survival gene E4bp4 by IL-3 in Ba/F3 cells. In this study, I demonstrated that both the GATA site binding ability and phosphorylation of the GATA-1 protein are regulated by IL-3. Furthermore, I demonstrated that the RAF-MEK-MAPK signaling pathway mediates the IL-3-induced phosphorylation and binding activity of GATA-1, and inhibition of MAPK leads to decrease the promoter activity and reduce the expression of the endogenous mRNA of E4bp4. In summary, the works in my dissertation clearly demonstrated that there are some transcriptional factors involved in transducing survival signal of IL-3 and their expression and function are both critical to IL-3’s survival responses. Furthermore, the discovery of GATA factors functioning in the upstream of the E4bp4 gene may extend our knowledge on the apoptotic pathway in hematopoietic cells, and may contribute to our further understanding of the processes of hematopoiesis and leukemogenesis.

Contents I
List of Figures III
List of Tables V
List of Abbreviation VI
Chinese Summary VIII
English Summary X
Chapter I: General Introduction 1
Chapter II: CREB is one component of the binding complex of the CES-2/E2A-HLF
binding element and is an integral part of the interleukin-3 survival signal 23
Abstract 24
Introduction 25
Materials and Methods 28
Results 33
Discussion 38
Figures 41
Chapter III: GATA factors are essential for transcription of the survival gene E4bp4 and
the viability response of interleukin-3 in Ba/F3 hematopoietic cells 50
Abstract 51
Introduction 52
Materials and Methods 54
Results 66
Discussion 76
Figures 80
Chapter IV: The RAF-MEK-MAPK signaling pathway mediates interleukin-3-dependent
E4bp4 expression and the function of GATA-1 93
Abstract 94
Introduction 95
Materials and Methods 98
Results 103
Discussion 108
Figures 111
Chapter V: General Discussion 117
References 124
Appendixes

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