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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 11:51:18 (UTC+8)
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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描述 碩士
國立政治大學
神經科學研究所
99754007
101
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0099754007
資料類型 thesis
dc.contributor.advisor 趙知章zh_TW
dc.contributor.advisor Chao, Chih Changen_US
dc.contributor.author (Authors) 羅之懿zh_TW
dc.contributor.author (Authors) Lo, Chih Yien_US
dc.creator (作者) 羅之懿zh_TW
dc.creator (作者) Lo, Chih Yien_US
dc.date (日期) 2012en_US
dc.date.accessioned 1-May-2013 11:51:18 (UTC+8)-
dc.date.available 1-May-2013 11:51:18 (UTC+8)-
dc.date.issued (上傳時間) 1-May-2013 11:51:18 (UTC+8)-
dc.identifier (Other Identifiers) G0099754007en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/57970-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 99754007zh_TW
dc.description (描述) 101zh_TW
dc.description.abstract (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。zh_TW
dc.description.abstract (摘要) 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.en_US
dc.description.tableofcontents 謝　誌………………………………………………………………………………………….I
     中文摘要…………………………………………………………………………..…………..………...II
     英文摘要……………………………………………………………………………..……………....III
     目　錄..........................................................................................................................V
     圖　次......................................................................................................................VIII
     縮寫表......................................................................................................................IX
     第一章 緒論................................................................................................................01
     　第一節、大腦神經滋養因子 BDNF ..........................................................................02
     一、 BDNF 的生理功能......................................................................................02
     二、 BDNF 的訊號傳遞機制…………………….………………….……..…………03
     　第二節、蛋白激酶Protein Kinase CK2（Casein Kinase 2）........................................05
     一、 CK2 的生理功能.........................................................................................05
     二、 CK2 的訊號傳遞機制………………………………...…………………………06
     　第三節、血清反應因子 Serum Response Factor（SRF）..........................................08
     一、 SRF 的生理功能..........................................................................................08
     二、 SRF 的訊號傳遞機制...................................................................................09
     　第四節、計畫性細胞凋亡（Apoptosis）.......................................................................10
     　第五節、抗細胞凋亡蛋白B-cell Lymphoma-2 （Bcl-2） 家族....................................12
     　第六節、抗細胞凋亡蛋白Myeloid Cell Leukemia Sequence 1 （Mcl-1）...................13
     一、 Mcl-1 的結構與生理功能..............................................................................13
     二、 Mcl-1 的訊號傳遞機制.................................................................................14
     　第七節、本論文之研究目的.......................................................................................15
     第二章、實驗材料與研究方法.......................................................................................16
     　第一節、細胞培養.....................................................................................................17
     一、 培養皿覆蓋 poly-L-lysine.............................................................................17
     二、 細胞種類.......................................................................................................17
     三、 細胞繼代培養與計數.....................................................................................18
     　第二節、質體 DNA 製備..........................................................................................18
     一、 細菌培養液與固體培養基製備......................................................................18
     二、 小量質體 DNA 之製備.................................................................................19
     三、 瓊脂膠體電泳分析........................................................................................20
     　第三節、藥物處理與轉染..........................................................................................20
     一、 藥物處理（Drug treatment）...........................................................................20
     二、 細胞之 Plasmid DNA 與 siDNA 製備.........................................................20
     三、 細胞之 Plasmid DNA 與 siDNA 轉染.........................................................21
     　第四節、啟動子-冷光酶試劑（Promoter-Luciferase Assay）.......................................21
     　第五節、西方點墨法（Western Boltting）...................................................................22
     一、 蛋白質萃取...................................................................................................22
     二、 蛋白質濃度測定............................................................................................23
     三、 蛋白質樣品配製............................................................................................23
     四、 鑄膠和聚丙烯硫胺膠體電泳（SDS-PAGE）....................................................24
     五、 轉漬（Transfer）............................................................................................24
     六、 免疫轉印（Immunoblotting）...........................................................................25
     　第六節、及時定量聚合酶連鎖反應（q-PCR）........................................................26
     一、 RNA萃取......................................................................................................26
     二、 反轉錄互補 DNA（cDNA） .........................................................................27
     三、 即時定量聚合酶連鎖反應..............................................................................28
     　第七節、細胞存活率分析- MTT 試驗法（MTT assay）............................................28
     　第八節、統計分析....................................................................................................29
     第三章、實驗結果.........................................................................................................30
     　第一節、 BDNF 會增加 SRF 磷酸化及 Mcl-1 蛋白質的含量...............................31
     　第二節、 轉染突變型 SRF99A DNA 會降低 BDNF 促進轉錄作用的效果............33
     　第三節、 抑制 CK2會降低 SRF蛋白質磷酸化含量及 Mcl-1基因表現………..35
     第四節、突變 SRF Ser99 胺基酸會降低 CK2 促進 Mcl-1 蛋白質含量及 mRNA
     　　　　　表現的效果................................................................................................38
     　第五節、氧化壓力狀態之下抑制 CK2 會降低BDNF 對細胞的保護作用.............41
     　
     
     第六節、氧化壓力狀態之下抑制 CK2 會降低 BDNF 促進細胞 Mcl-1 基因
      表現..................................................................................44
     　第七節、氧化壓力狀態之下抑制 CK2會降低 BDNF 對細胞的轉錄作用效果......46
     　第八節、氧化壓力狀態之下 SRF Ser99 點突變會降低 BDNF 對細胞的 Mcl-1 的
     　　　　　蛋白質含量及 mRNA 的表現量................................................................48
     　第九節、氧化壓力狀態之下 SRF Ser99 點突變會降低 CK2對增加細胞的存活
     　　　　　能力..........................................................................................................50
     　第十節、氧化壓力狀態之下 SRF Ser99 點突變會降低 CK2促進細胞 Mcl-1 蛋白
     　　　　　質含量及 mRNA 的表現量.......................................................................52
     第四章　討論..............................................................................................................54
     第五章　結論..............................................................................................................61
     參考文獻		zh_TW
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0099754007en_US
dc.subject (關鍵詞) 大腦神經滋養因子zh_TW
dc.subject (關鍵詞) 蛋白激酶 CK2zh_TW
dc.subject (關鍵詞) 血清反應因子zh_TW
dc.subject (關鍵詞) 血清反應要素zh_TW
dc.subject (關鍵詞) 轉錄作用zh_TW
dc.subject (關鍵詞) 骨髓細胞白血病蛋白-1zh_TW
dc.subject (關鍵詞) 細胞凋亡zh_TW
dc.subject (關鍵詞) 腎上腺髓質嗜鉻細胞瘤細胞株zh_TW
dc.subject (關鍵詞) Brain-derived neurotrophic factor（BDNF）en_US
dc.subject (關鍵詞) Protein kinase CK2en_US
dc.subject (關鍵詞) Serum response factor（SRF）en_US
dc.subject (關鍵詞) Serum response element（SRE）en_US
dc.subject (關鍵詞) transcriptionen_US
dc.subject (關鍵詞) Myeloid cell leukemia sequence 1（Mcl-1）en_US
dc.subject (關鍵詞) apoptosisen_US
dc.subject (關鍵詞) Pheochromocytoma cell line 12（PC12）en_US
dc.title (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zh_TW
dc.title (題名) BDNF-induced Anti-apoptotic Mcl-1 Gene Expression Through Protein Kinase CK2-mediated SRF Pathwayen_US
dc.type (資料類型) thesisen
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