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https://ah.lib.nccu.edu.tw/handle/140.119/57970| 題名: | 蛋白激酶 CK2 與轉錄因子 SRF 訊息傳遞路徑參與神經滋養因子 BDNF 促進抗凋亡基因 Mcl-1 表現之細胞保護機制 BDNF-induced Anti-apoptotic Mcl-1 Gene Expression Through Protein Kinase CK2-mediated SRF Pathway |
作者: | 羅之懿 Lo, Chih Yi |
貢獻者: | 趙知章 Chao, Chih Chang 羅之懿 Lo, Chih Yi |
關鍵詞: | 大腦神經滋養因子 蛋白激酶 CK2 血清反應因子 血清反應要素 轉錄作用 骨髓細胞白血病蛋白-1 細胞凋亡 腎上腺髓質嗜鉻細胞瘤細胞株 Brain-derived neurotrophic factor（BDNF） Protein kinase CK2 Serum response factor（SRF） Serum response element（SRE） transcription Myeloid cell leukemia sequence 1（Mcl-1） apoptosis Pheochromocytoma cell line 12（PC12） |
日期: | 2012 | 上傳時間: | 1-May-2013 | 摘要: | 大腦神經滋養因子（BDNF）是神經生長因子家族成員之一的蛋白質，具有促進神經細胞存活和保護的作用，但其參與調節的細胞機制仍尚未被完全釐清，目前已知可被BDNF調控的蛋白激酶（CK2a）是一個普遍存在於細胞中並可針對其受質蛋白之絲胺酸或酪胺酸進行磷酸化的蛋白質，被發現高度表現於癌細胞中，對於細胞存活的角色十分重要，有研究指出 CK2a透過影響血清反應因子（SRF）接合至Serum response element（SRE）上並調控基因的轉錄作用達到保護細胞的作用。由於，抗細胞凋亡基因 Mcl-1 啟動子區域含有 SRE 序列且可調控細胞增生和存活。因此，本論文的主題是在 Rotenone 誘發細胞凋亡的實驗模式中，探討 BDNF / CK2a / SRF / Mcl-1 這條路徑是否有效抵抗細胞凋亡情形？實驗發現 BDNF 可增加 phospho-SRF 、 Mcl-1 蛋白質含量及 Mcl-1 mRNA 表現；利用小干擾 RNA抑制內生性 CK2a亦會降低 phospho-SRF 、Mcl-1 蛋白質含量及 Mcl-1 mRNA 表現。此外，共同轉染突變型 SRF99A 及野生型 CK2a-WT 質體 DNA會抑制 CK2a對促進 SRF 蛋白質磷酸化、 Mcl-1 蛋白質含量及 Mcl-1 mRNA 表現的作用。更進一步，抑制內生性 CK2a會降低 BDNF 對 Rotenone 氧化壓力的預防保護作用及細胞的存活率，同時抑制SRF轉錄作用、Mcl-1 蛋白質含量及mRNA 表現。在 Rotenone 氧化壓力下，轉染突變型 SRF99A 質體 DNA 同樣會降低 BDNF 對細胞的保護作用，並且抑制 Mcl-1 蛋白質含量及 mRNA 表現；此外，轉染突變型 SRF99A質體 DNA 也會抑制 CK2a-WT 對促進細胞存活率、 Mcl-1 蛋白質含量及 mRNA 表現的作用。綜合論文實驗結果可以得知，在氧化壓力下，BDNF 會透過 CK2a活化 SRF 進而調控下游 Mcl-1 基因表現的細胞訊息傳遞路徑，達到抵抗細胞凋亡的作用。 Brain-derived neurotrophic factor (BDNF), is a member of the nerve growth factors family. Many studies have indicated that BDNF can improve the neuronal survival. Protein kinase CK2 is an ubiquitous and highly conserved Ser/Thr protein kinase in evolution, and its enzyme activity was found to be elevated by BDNF. CK2 was also found to stimulate serum response element (SRE)-mediated gene expression for cellular protection via serum response factors (SRF). Furthermore, the anti-apoptotic Mcl-1 gene can promote cell proliferation and survival which promoter contains the SRE. Therefore, the thesis studies were aimed to investigate whether BDNF can up-regulate the expression of Mcl-1 through CK2a-mediated SRF phosphorylation and against the rotenone-induced apoptosis in PC12 cells. The results showed that BDNF could increase the phosphorylation status of SRF and the expressions of Mcl-1. However, CK2a siRNA treatment decreased the phosphorylation status of SRF and the expressions of Mcl-1 protein and mRNA. Further, co-transfection of mutant SRF99A antagonized CK2a-WT induced phosphorylation status of SRF and the protein and mRNA levels of Mcl-1. Moreover, CK2a siRNA treatments inhibited the protective effects of BDNF under rotenone-induced apoptosis parallel with the decrease in SRE-mediated transcription and Mcl-1 protein/mRNA expression. The mutant SRF99A plasmid transfection also diminished the BDNF-induced protection under rotenone-induced apoptosis parallel with the decrease in Mcl-1 protein and mRNA expression. The co-transfection of mutant SRF99A also blocked the CK2a-mediated effects on Mcl-1 protein and mRNA. Together with the above results suggest that CK2a-activated SRF pathway to enhance the anti-apoptotic Mcl-1 gene expression might be one of cellular mechanisms of BDNF which acts against rotenone-induced apoptosis. |
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