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標題: | 探討Notch訊息活化Akt之機制 Study on the mechanism of the Notch-mediated Akt activation |
作者: | Yu-Hsuan Yang 楊鈺璇 |
指導教授: | 賴明宗(Ming-Zong Lai) |
關鍵字: | Notch 訊息傳遞,Akt 活化, Notch,Akt activation, |
出版年 : | 2008 |
學位: | 碩士 |
摘要: | Notch 訊息的傳遞可以調控多項生物性功能,而已知Notch可藉由活化PI3K-Akt的訊息傳遞調控細胞凋亡。但目前對於Notch如何活化PI3K-Akt訊息並不清楚。在本研究中,我們探討Notch 活化 Akt 的幾個可能途徑: ㄧ個是透過Notch本身的轉錄能力,另ㄧ個藉由先活化Lck ,第三個則經由XIAP的訊息,而造成Akt 之活化。我們先在利用Notch配體Jagged 1與DLL1 刺激DO11.10 與NIH3T3 細胞皆可造成 Akt 的活化。證實Notch 的活化確實能誘導 Akt 的活化。在Notch 活化 Akt 是否透過轉錄活性方面,我們使用不同NICD的突變型。在探討Lck的參與方面,我們利用Lck抑制劑阻斷Lck的活化,觀察Akt活化是否受影響。在分析XIAP角色的方面,我們大量表現XIAP或下調細胞內的XIAP,研究其對Akt活化的影響。我們發現Notch 活化 Akt於DO11.10和NIH3T3細胞有些不同。Notch在DO11.10細胞活化Akt涉及Notch的轉錄活性,也需要Lck的參與,而XIAP的存在也是需要的。Notch在NIH3T3細胞則除利用其轉錄活性參與之外,不具轉錄活性的TAD也可以尚未清楚的機制活化Akt,但XIAP則未參與Notch活化Akt。我們的結果顯示了多種訊息分子參與了Notch引發Akt的活化,而詳細的活化機制需要更近一步的探討。 Notch signaling regulate several key biological functions, Notch inhibits apoptosis through activation of PI3K-Akt signaling. The mechanism how Notch activates PI3K-Akt remains unclear. In this study, we examined three possible mechanisms involved in the activation of Akt by Notch. First, Notch may activate Akt through transcription activation of target genes. Second, Notch may activate Lck for subsequent activation of Akt. Third, Notch may stimulate Akt through enhanced XIAP signaling. We first used Notch ligands Jagged1 and Delta-like ligand1(DLL1) to stimulate DO11.10 T cell hybridoma and NIH3T3 fibroblast, and detected Akt phosphorylation, confirming the capacity of Notch to activate Akt. To determine the requirement of Notch transcription activity, we used different mutants carrying truncated forms of Notch intracellular domain (NICD). To study the potential involvement of Lck, Notch induced Akt activation was evaluated by using Lck inhibitor to block Lck activation. To investigate the possible involvement of XIAP, effect on Akt activation was determined when XIAP was either overexpressed or downregulated. We found similarity and difference between DO11.10 and NIH3T3 cells on the activation of Akt by Notch. In DO11.10 cells, the activation of Akt by Notch requires the transcription activity of Notch, Lck activation, and presence of XIAP. In NIH3T3 cells, the activation of Akt by Notch is involved the transcription activity of Notch and its transcription-inactive TAD domain, acting in unknown mechanism, but not XIAP. Our results illustrate the involvement of multiple signaling molecules in Notch-stimulated Akt activation, and point to the necessity for further investigation the detailed activation mechanisms. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40574 |
全文授權: | 有償授權 |
顯示於系所單位: | 免疫學研究所 |
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