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題名 蛋白激酶 CK2 在大鼠腦部之抗細胞凋亡機制的探討
The anti-apoptotic mechanisms of protein kinase CK2 in the brain of rat作者 張家銘 貢獻者 趙知章
張家銘關鍵詞 蛋白激酶 CK2
血清反應因子
Mcl-1
DARPP-32
Bcl-xL
抗細胞凋亡
protein kinase CK2
SRF
Mcl-1
DARPP-32
Bcl-xL
anti-apoptosis日期 2010 上傳時間 29-九月-2011 18:26:08 (UTC+8) 摘要 蛋白激酶 CK2 是一種具有多種功能的絲胺酸/蘇胺酸蛋白質激酶，CK2 作用的受質眾多且廣泛表現在哺乳類動物細胞中，對於細胞週期的發展、轉錄作用以及抗細胞凋亡等機制扮演非常重要的角色。在神經系統中，CK2 已知可以保護神經細胞以抵抗外來的傷害，但是其分子層面的機制目前尚未釐清。本篇論文的研究重點在於探討 CK2 保護作用可能參與的細胞分子機制。血清反應因子 SRF 是一種哺乳類動物細胞的轉錄因子，調控基因的轉錄作用來促進細胞的存活。Mcl-1 是抗細胞凋亡家族 Bcl-xL 家族蛋白成員之一，可以促進細胞的存活能力。先前研究指出，SRF 會受到 CK2 的磷酸化作用而增加本身的 DNA 結合能力。在其他研究也指出，Mcl-1 會受到 SRF 的調控。在本篇論文的第一部份，著重於 Mcl-1 的表現是否會受到 CK2 調控 SRF 的路徑所影響，實驗結果顯示，轉染野生型 CK2α 質體 DNA 可以增加海馬迴 CA1 腦區的 SRF 磷酸化，而轉染不活化的突變型 CK2αΑ156 質體 DNA 則會減少 SRF 的磷酸化。更進一步，轉染野生型 CK2α 會增加 Mcl-1 的 mRNA 及蛋白質表現，轉染突變型 CK2αΑ156 則減少 Mcl-1 的表現。此外，轉染突變型 SRF99A 也會減少 Mcl-1 的 mRNA 及蛋白質表現；而且在共同轉染實驗中，SRF99A 會拮抗野生型 CK2α 對促進的 Mcl-1 蛋白質表現的作用。 另一方面，DARPP-32 是一個在新紋狀體神經細胞中具有調控多巴胺訊息效力的訊息傳遞分子。先前研究指出，DARPP-32 具有抗細胞凋亡的功能，且發現在 DARPP-32 Ser102 氨基酸會受 CK2 的磷酸化作用。因此，本篇論文的第二部份主要是探討 CK2 的抗細胞凋亡能力是否是透過磷酸化 DARPP-32 來調控。實驗結果顯示，轉染野生型 CK2α 可以增加紋狀體 DARPP-32 的磷酸化，而轉染不活化的突變型 CK2αΑ156 則會減少 DARPP-32 的磷酸化。此外，轉染 CK2α 的小干擾 RNA (siRNA) 可以抑制內生性的 CK2 表現，同時也會減少 DARPP-32 的磷酸化以及抗細胞凋亡蛋白, Bcl-xL 的表現。綜合這些實驗結果，CK2α可以分別透過 SRF 或 DARPP-32 調控的訊息傳遞來促進 Mcl-1 或 Bcl-xL 的表現進而調控神經系統的抗細胞凋亡機制。
Protein kinase CK2 is a multifunctional serine/threonine protein kinase with many protein substrares and is ubiquitously expressed in mammalian cells to play an important role in cell cycle progression, transcription, and anti-apoptosis. In the nervous system, CK2 is shown to protect neurons against injury, but the cellular mechanisms are not well studies. In the present studies, we investigate which cellular mechanism might involve in the CK2 protection effects. The serum response factor (SRF) is a mammalian transcription factor which mediates some gene transcriptions relevent to promote the cell survival. The Myeloid cell leukemin 1 (Mcl-1) is one of the anti-apoptotic Bcl-2 family members and is involved in promoting cell viability. Previous studied have revealed that the SRF phosphorylation by CK2 can enhance its DNA-binding activity. The regulation of Mcl-1 by SRF has also been reported in other studies. In the first part of the present studies, we investigate whether the Mcl-1 expression is regulated by CK2 through SRF mediated pathway. The results from wildtype CK2α plasmid DNA transfection revealed that the phosphorylated SRF were increased in hippocampus CA1 region, whereas transfection of the catalytically inactive CK2αA156 mutant plasmid DNA decreased phosphorylated SRF. Further, wildtype CK2α increased, whereas CK2αA156 mutant decreased the mRNA and protein levels of Mcl-1. Moreover, transfection of the mutant SRF99A also decreased the mRNA and protein levels of Mcl-1. Furthermore, the mutant SRF99A antagonized the upregulatory effects of wildtype CK2α on Mcl-1 protein level in the co-transfection experiments. In the other side, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) is a signal transduction molecule that regulates the efficacy of dopamine signaling in neostriatal neurons. Previous studies have revealed that DARPP-32 might involve in the anti-apoptosis and its Ser102 residue is phosphorylated by CK2. Therefore, in the second part of this study, we investigate whether one of the anti-apoptotic effects of CK2 is through DARPP-32 phosphorylation by CK2 in the present study. The results revealed that the phosphorylated DARPP-32 is increased in stratum by wildtype CK2α transfection and decreased by catalytically inactive CK2αA156 mutant transfection. Further, transfection of CK2α siRNA can inhibit endogenous CK2 expression and also decrease phosphorylation of DARPP-32 as well as the anti-apoptotic protein, Bcl-xL. These results together suggest that CK2α-mediated anti-apoptotic effects are partially through SRF mediated or DARPP-32 mediated signaling to regulate Mcl-1 or Bcl-xL expression, respectively.參考文獻 Abdallah, B., Hassan, A., Benoist, C., Goula, D., Behr, J.P., and Demeneix, B.A. (1996). A powerful nonviral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine. Hum Gene Ther 7, 1947-1954.
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國立政治大學
神經科學研究所
96754002
99資料來源 http://thesis.lib.nccu.edu.tw/record/#G0096754002 資料類型 thesis dc.contributor.advisor 趙知章 zh_TW dc.contributor.author (作者) 張家銘 zh_TW dc.creator (作者) 張家銘 zh_TW dc.date (日期) 2010 en_US dc.date.accessioned 29-九月-2011 18:26:08 (UTC+8) - dc.date.available 29-九月-2011 18:26:08 (UTC+8) - dc.date.issued (上傳時間) 29-九月-2011 18:26:08 (UTC+8) - dc.identifier (其他 識別碼) G0096754002 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/50995 - 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) 96754002 zh_TW dc.description (描述) 99 zh_TW dc.description.abstract (摘要) 蛋白激酶 CK2 是一種具有多種功能的絲胺酸/蘇胺酸蛋白質激酶，CK2 作用的受質眾多且廣泛表現在哺乳類動物細胞中，對於細胞週期的發展、轉錄作用以及抗細胞凋亡等機制扮演非常重要的角色。在神經系統中，CK2 已知可以保護神經細胞以抵抗外來的傷害，但是其分子層面的機制目前尚未釐清。本篇論文的研究重點在於探討 CK2 保護作用可能參與的細胞分子機制。血清反應因子 SRF 是一種哺乳類動物細胞的轉錄因子，調控基因的轉錄作用來促進細胞的存活。Mcl-1 是抗細胞凋亡家族 Bcl-xL 家族蛋白成員之一，可以促進細胞的存活能力。先前研究指出，SRF 會受到 CK2 的磷酸化作用而增加本身的 DNA 結合能力。在其他研究也指出，Mcl-1 會受到 SRF 的調控。在本篇論文的第一部份，著重於 Mcl-1 的表現是否會受到 CK2 調控 SRF 的路徑所影響，實驗結果顯示，轉染野生型 CK2α 質體 DNA 可以增加海馬迴 CA1 腦區的 SRF 磷酸化，而轉染不活化的突變型 CK2αΑ156 質體 DNA 則會減少 SRF 的磷酸化。更進一步，轉染野生型 CK2α 會增加 Mcl-1 的 mRNA 及蛋白質表現，轉染突變型 CK2αΑ156 則減少 Mcl-1 的表現。此外，轉染突變型 SRF99A 也會減少 Mcl-1 的 mRNA 及蛋白質表現；而且在共同轉染實驗中，SRF99A 會拮抗野生型 CK2α 對促進的 Mcl-1 蛋白質表現的作用。 另一方面，DARPP-32 是一個在新紋狀體神經細胞中具有調控多巴胺訊息效力的訊息傳遞分子。先前研究指出，DARPP-32 具有抗細胞凋亡的功能，且發現在 DARPP-32 Ser102 氨基酸會受 CK2 的磷酸化作用。因此，本篇論文的第二部份主要是探討 CK2 的抗細胞凋亡能力是否是透過磷酸化 DARPP-32 來調控。實驗結果顯示，轉染野生型 CK2α 可以增加紋狀體 DARPP-32 的磷酸化，而轉染不活化的突變型 CK2αΑ156 則會減少 DARPP-32 的磷酸化。此外，轉染 CK2α 的小干擾 RNA (siRNA) 可以抑制內生性的 CK2 表現，同時也會減少 DARPP-32 的磷酸化以及抗細胞凋亡蛋白, Bcl-xL 的表現。綜合這些實驗結果，CK2α可以分別透過 SRF 或 DARPP-32 調控的訊息傳遞來促進 Mcl-1 或 Bcl-xL 的表現進而調控神經系統的抗細胞凋亡機制。 zh_TW dc.description.abstract (摘要) Protein kinase CK2 is a multifunctional serine/threonine protein kinase with many protein substrares and is ubiquitously expressed in mammalian cells to play an important role in cell cycle progression, transcription, and anti-apoptosis. In the nervous system, CK2 is shown to protect neurons against injury, but the cellular mechanisms are not well studies. In the present studies, we investigate which cellular mechanism might involve in the CK2 protection effects. The serum response factor (SRF) is a mammalian transcription factor which mediates some gene transcriptions relevent to promote the cell survival. The Myeloid cell leukemin 1 (Mcl-1) is one of the anti-apoptotic Bcl-2 family members and is involved in promoting cell viability. Previous studied have revealed that the SRF phosphorylation by CK2 can enhance its DNA-binding activity. The regulation of Mcl-1 by SRF has also been reported in other studies. In the first part of the present studies, we investigate whether the Mcl-1 expression is regulated by CK2 through SRF mediated pathway. The results from wildtype CK2α plasmid DNA transfection revealed that the phosphorylated SRF were increased in hippocampus CA1 region, whereas transfection of the catalytically inactive CK2αA156 mutant plasmid DNA decreased phosphorylated SRF. Further, wildtype CK2α increased, whereas CK2αA156 mutant decreased the mRNA and protein levels of Mcl-1. Moreover, transfection of the mutant SRF99A also decreased the mRNA and protein levels of Mcl-1. Furthermore, the mutant SRF99A antagonized the upregulatory effects of wildtype CK2α on Mcl-1 protein level in the co-transfection experiments. In the other side, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) is a signal transduction molecule that regulates the efficacy of dopamine signaling in neostriatal neurons. Previous studies have revealed that DARPP-32 might involve in the anti-apoptosis and its Ser102 residue is phosphorylated by CK2. Therefore, in the second part of this study, we investigate whether one of the anti-apoptotic effects of CK2 is through DARPP-32 phosphorylation by CK2 in the present study. The results revealed that the phosphorylated DARPP-32 is increased in stratum by wildtype CK2α transfection and decreased by catalytically inactive CK2αA156 mutant transfection. Further, transfection of CK2α siRNA can inhibit endogenous CK2 expression and also decrease phosphorylation of DARPP-32 as well as the anti-apoptotic protein, Bcl-xL. These results together suggest that CK2α-mediated anti-apoptotic effects are partially through SRF mediated or DARPP-32 mediated signaling to regulate Mcl-1 or Bcl-xL expression, respectively. en_US dc.description.tableofcontents 謝 誌…………………………………………………………………………………………II 中文摘要……………………………………………………………………………………...III 英文摘要………………………………………………………………………………………V 目 錄…………………………………………….………………………………………….VII 圖 次…………………………………………………….…………………………………...X 縮寫對照表……………………………………………………….………………………….XII 第一章 緒 論………………………………………………………………………………1 第一節、蛋白激酶 Protein kinase Casein kinase 2 (CK2)……………….……………...1 一、蛋白激酶 CK2 的結構……………………………………………………...….…3 二、蛋白激酶 CK2 的調控作用………………………………………..…………….4 三、蛋白激酶 CK2 對轉錄因子 (transcription factor) 的調控………...…………..6 四、蛋白激酶 CK2 對細胞凋亡 (apoptosis) 的調控作用…………...…………….7 第二節、血清反應因子 serum response factor (SRF)…………………………………...8 第三節、Myeloid cell leukemia-1 (Mcl-1)………………………………………………...10 第四節、計畫性的細胞凋亡機制 (apoptosis)……………………………………………14 一、細胞死亡 (cell death) 及細胞凋亡 (apoptosis)……………………………….15 二、細胞凋亡 (apoptosis) 機制……………………………………………………..16 第五節、DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa)……………………………………………………………………..............19 第六節、本論文之研究目的……………………………………………………...............23 第二章 材料與方法………………………………………………………………………..24 第一節、實驗動物…………………………………………………………………………..25 第二節、立體定位手術 (stereotaxic surgery)……………………………………………25 第三節、質體 DNA之製備與菌種保存…………………………………………………...26 一、質體 DNA 之萃取………………………………………………………………..26 二、菌種保存…………………………………………………………………………..26 第四節、質體 DNA 與小干擾 RNA (siRNA) 的轉染作用………………………..……26 一、質體 DNA 與聚乙烯亞胺 (polyethylenimine, PEI) 之製備與轉染反應…….…………………………………………………………………………..26 二、海馬迴 CA1 之轉染作用及注射質體 DNA/PEI 混和液……………………..28 三、小干擾 RNA (siRNA) 轉染作用………………………………………………..28 第五節、西方點墨法 (western blot)……………………………………………..............29 一、海馬迴 CA1 區域的組織擷取…………………………………………………..29 二、蛋白質萃取………………………………………………………………………..30 三、蛋白質濃度測定以及標準曲線之製作…………………………………………..30 四、配製 loading sample…………………………………………………………….31 五、鑄膠………………………………………………………………………………..31 六、聚丙烯醯胺凝膠電泳 (sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE)………………………………………………….31 七、轉漬 (transfer)…………………………………………………………..............32 八、 blocking 以及免疫轉印 (Immunoblotting)…………………………………...33 第六節、即時定量聚合酶連鎖反應 (quantitative real-time polymerase chain reaction, Q-PCR)……………………………………………………………….33 一、去氧核糖核酸 (RNA) 之萃取…………………………………………………..33 二、轉 cDNA………………………………………………………………………….34 三、即時定量聚合酶連鎖反應………………………………………………………..34 第七節、統計分析………………………………………………………………..............35 第三章 結 果……………………………………………………………………………..37 第一節、轉染 CK2α 的質體 DNA 對大白鼠海馬迴 CA1 區域的 phospho-SRF 的蛋白質表現的影響…………………………………………………………………38 第二節、轉染 CK2α 的質體 DNA 對大白鼠海馬迴 CA1 區域的 Mcl-1 的蛋白質以及 mRNA 表現的影響………………………………………………………….42 第三節、轉染突變型 SRF99A 的質體 DNA 對大白鼠海馬迴 CA1 區域的 phospho-SRF 蛋白質表現的影響…………………………………………….45 第四節、轉染突變型 SRF99A 的質體 DNA 對大白鼠海馬迴 CA1 區域的 Mcl-1 蛋白質表現以及 mRNA 表現的影響…………………………………………….48 第五節、共同轉染野生型 CK2αWT 與突變型 SRF99A 的質體 DNA 對大白鼠海馬迴 CA1 區域的 Mcl-1 蛋白質以及 mRNA 變化的影響…………………...51 第六節、轉染野生型 CK2αWT 質體 DNA 對大白鼠海馬迴 CA1 腦區的 DARPP-32 蛋白質表現的影響……………….……………………………………………..54 第七節、轉染 CK2α 的質體 DNA 對大白鼠紋狀體區域的 DARPP-32 的蛋白質磷酸化程度的影響……………………………………………………………………..56 第八節、轉染 CK2α siRNA 對大白鼠紋狀體區域的 DARPP-32 的蛋白質磷酸化現象的影響……………………………………………………………………………..60 第九節、轉染突變型 DARPP-32A102 的質體 DNA 對大白鼠紋狀體區域的 DARPP-32 的蛋白質磷酸化程度的影響……………………………………….62 第十節、轉染 DARPP-32 siRNA 對大白鼠紋狀體區域的內生性 DARPP-32 蛋白質表現及 Bcl-xL 蛋白質表現的影響……………………………………………...64 第四章 討 論…………………………………………………………………................66 第五章 結 論……………………………………………………………………………..78 參考文獻……………………………………………………………………………………..79 附錄…………………………………………………………………………………………..91 附錄一、藥品配製……………………………………………………………………………91 附錄二、pcDNA3 載體與圖………………………………………………………………...93 附錄三、pCMV 載體與圖…………………………………………………………………...94 附錄四、Apoptotic signalling pathways……………………………………………………95 zh_TW dc.language.iso en_US - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0096754002 en_US dc.subject (關鍵詞) 蛋白激酶 CK2 zh_TW dc.subject (關鍵詞) 血清反應因子 zh_TW dc.subject (關鍵詞) Mcl-1 zh_TW dc.subject (關鍵詞) DARPP-32 zh_TW dc.subject (關鍵詞) Bcl-xL zh_TW dc.subject (關鍵詞) 抗細胞凋亡 zh_TW dc.subject (關鍵詞) protein kinase CK2 en_US dc.subject (關鍵詞) SRF en_US dc.subject (關鍵詞) Mcl-1 en_US dc.subject (關鍵詞) DARPP-32 en_US dc.subject (關鍵詞) Bcl-xL en_US dc.subject (關鍵詞) anti-apoptosis en_US dc.title (題名) 蛋白激酶 CK2 在大鼠腦部之抗細胞凋亡機制的探討 zh_TW dc.title (題名) The anti-apoptotic mechanisms of protein kinase CK2 in the brain of rat en_US dc.type (資料類型) thesis en dc.relation.reference (參考文獻) Abdallah, B., Hassan, A., Benoist, C., Goula, D., Behr, J.P., and Demeneix, B.A. (1996). 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