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    題名: JAK-STAT訊息傳遞路徑參與Endothelin-1誘導肺部纖維母細胞結締組織生長因子表現
    Studies on the Role of JAK-STAT Signaling Pathway in Endothelin-1-Induced Connective Tissue Growth Factor Expression in Human Lung fibroblasts
    作者: 楊雯婷
    Yang, Wen-Ting
    關鍵詞: 內皮素;纖維化疾病;肺部纖維母細胞;Endothelin-1;lung disease;lung fibroblast;connective tissue growth factor;JAK2;STAT3;PI3K;Akt;p300
    日期: 2012-07-20
    上傳時間: 2018-11-09 17:36:07 (UTC+8)
    摘要: 內皮素 (endothelin-1, ET-1)是一種血管收縮胜肽，在調節血管收縮功能及組織修復上扮演重要的角色。除了正常的生理性角色外，最近的研究對於ET-1在纖維化疾病中所扮演的角色也逐漸被證實，研究報告顯示，ET-1會刺激肺部纖維母細胞表現connective tissue growth factor (CTGF)基因。在本篇論文中，我們將探討JAK/STAT、PI3K/Akt及p300訊息傳遞路徑參與人類肺纖維母細胞WI-38中ET-1誘導CTGF表現機轉。首先我們發現使用JAK2DN、STAT3DN與p300 siRNA皆可抑制ET-1誘導CTGF表現。進一步將CTGF promoter 的STAT3 結合位置突變 (CTGF mt-STAT3) 後，發現可以抑制由ET-1所刺激的CTGF-luciferase的活性。此外ET-1可以依時間相關性造成Akt Ser473位置磷酸化，透過PI3K抑制劑 (LY294002及Wortamanin) 及AktDN可以抑制由ET-1誘導的CTGF表現。ET-1可依時間相關性誘導STAT3 Tyr705的磷酸化，並提高p300的histone acetyltransferase活性，ET-1可誘導p300 Ser1834的磷酸化，增加p300的活性，進一步的造成STAT3乙醯化，趨使STAT3與p300結合CTGF promoter上形成複合物，進行下游基因的轉錄調控。綜合以上所有研究結果，在人類肺纖維母細胞中，ET-1會經由活化JAK2/STAT3、PI3K/Akt及p300訊息傳遞路徑誘導p300的活化，啟動CTGF promoter並促使CTGF表現。

    Endothelin-1(ET-1) is a vasoconstrictive peptide, as a key mediator of vasoconstriction and tissue repair. ET-1 plays an important role in lung disease. ET-1 can induce the expression of connective tissue growth factor (CTGF) in lung fibroblasts. In this study, we investigated the role of JAK/STAT、PI3K/Akt, and p300 in ET-1-induced CTGF expression in human lung fibroblasts. ET-1-induced CTGF expression was inhibited by the dominant negative mutant of JAK2 (JAK2DN), and STAT3DN and p300 small interfere RNA (p300 siRNA). ET-1-induced CTGF luciferase was inhibited by CTGF mt-STAT3. ET-1 caused a time-dependent increase in Akt Ser473 phosphorylation. ET-1-induced CTGF expression was inhibited by PI3K inhibitor (LY294002 and Wortmannin) and tranfection AktDN. ET-1 caused a time-dependent increase in STAT3 Tyr705 phosphorylation. ET-1 incresed p300 histone acetyl-transferase (HAT) activity. We also found that ET-1 induced a time-dependent increases in p300 Ser1834 phosphorylation and caused a time-dependent increase in STAT3 Lys685 acetylation. Treatment of cells with ET-1 induced STAT3 and p300 complex binding CTGF promoter. These results indicated that ET-1 induces JAK/STAT and PI3K/Akt signaling cascade resulting in STAT and p300 activation, p300 then binds to CTGF promoter which in turns induces CTGF expression in human lung fibroblasts.
    描述: 碩士
    指導教授-林建煌
    共同指導教授-陳炳常
    委員-蕭哲志
    委員-黃聰龍
    委員-顏茂雄
    資料類型: thesis
    顯示於類別:[醫學科學研究所] 博碩士論文

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