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題名 蛋白磷酸水解酶PP1在蛋白激酶CK2a調控 抗凋亡蛋白Bcl-xL基因表現過程中的角色
The role of protein phosphatase 1 in the protein kinase CK2a-mediated anti-apoptotic Bcl-xL gene expression作者 許焙琹 貢獻者 趙知章
許焙琹關鍵詞 蛋白激酶CK2
DARPP-32蛋白
蛋白磷酸水解酶PP1
抗細胞凋亡Bcl-xL蛋白
氧化壓力
細胞存活
Protein kinase CK2
DARPP-32
protein phosphatase PP1
Bcl-xL
oxidative stress
cell viability日期 2015 上傳時間 1-九月-2015 16:18:28 (UTC+8) 摘要 蛋白激酶 CK2 是一種具有多功能的絲胺酸/蘇胺酸蛋白激酶，大量表現於哺乳類動物的腦中，對於調控細胞週期的發展、基因表現、訊息傳遞以及抗細胞凋亡機制扮演相當重要的角色。許多研究顯示 CK2 也參與調節許多神經系統功能，包括神經保護及神經存活，但是其中調控機制目前尚未釐清。DARPP-32 (dopamine- and cAMP- regulated phosphoprotein with a molecular mass of 32 kDa) 主要表現在紋狀體中型多刺狀神經元中，過去研究已證實 DARPP-32 Ser102 胺基酸是CK2 的磷酸化作用受質。雖然DARPP-32 被發現主要透過抑制蛋白磷酸水解酶 PP1 參與藥物成癮的細胞調控機制，但近年研究指出DARPP-32 也參與抗細胞凋亡作用。PP1 是真核細胞的絲胺酸/蘇胺酸磷酸水解酶，能調節多種細胞功能，如轉錄、細胞訊息傳遞及細胞凋亡。過去文獻已指出 PP1 可以調節 Bcl-x 基因的 pre-mRNA 選擇性剪切，再經由轉譯過程合成抗細胞凋亡 Bcl-xL 異構蛋白，研究也發現抑制 PP1 可以防止細胞週期的停滯及細胞凋亡，強調細胞在壓力的情況下，PP1 扮演了相當關鍵性的角色。因此論文以人類神經母細胞瘤 SH-SY5Y 為實驗模式，探討透過 CK2 調控 DARPP-32 Ser102 的磷酸化是否具有抑制 PP1 的活性並促進細胞存活的作用。實驗結果顯示，抑制 CK2或DARPP-32 蛋白含量會導致細胞存活率下降，轉染 CK2 siRNA 會降低 DARPP-32 Ser102 的磷酸化現象、Bcl-xL 的蛋白質表現；轉染DARPP-32 siRNA 及突變型DARPP-32 S102A DNA 質體也會降低 Bcl-xL 的蛋白質表現，PP1 活性則會因轉染突變型DARPP-32 S102A DNA 質體而增加；此外，給予 PP1 抑制劑的實驗結果發現會促進 Bcl-xL/Bcl-xS mRNA 的比例以及 Bcl-xL 的蛋白質表現量。利用過氧化氫誘導細胞造成氧化壓力狀況下，同時給予 PP1 抑制劑，發現 Bcl-xL 的蛋白質表現量會回復以及促進細胞存活。轉染 CK2-EGFP 或 DARPP-32 S102D DNA 質體可以顯著回復Bcl-xL 的蛋白質表現量及Bcl-xL/Bcl-xS mRNA 的比例，轉染 DARPP-32 S102D DNA 質體亦可降低 PP1 的活性。論文的實驗結果提供 CK2 調節抗細胞凋亡基因表現的新機制，是經由促進 DARPP-32 Ser102 磷酸化作用進而抑制 PP1 活性，此條細胞訊息傳遞路徑將可提供應用於在氧化壓力下提升神經存活的臨床治療。
Protein kinase casein kinase II (CK2) is a multifunctional serine/threonine protein kinase and is highly abundant expression in the mammalian brain. CK2 plays an important role in the regulation of the cell cycle, gene expression, signal transduction and anti-apoptotic mechanisms. A number of studies have indicated that CK2 is involved in several neuronal functions including the neuroprotection and neuron survival, but its cellular mechanisms are not well-studied. The DARPP-32 (dopamine- and cAMP-regulated phosphoprotein with a molecular mass of 32 kDa) is highly enriched in the striatal medium spiny neurons and the Ser102 residue is identified as the phosphorylation site for CK2. Although DARPP-32 is known as a prominent cellular mediator of drug abuse through the inhibition of protein phosphatase 1 (PP1), the recent studies indicate that DARPP-32 may also be involved in the anti-apoptotic effects. Protein phosphatase PP1 is a major eukaryotic serine/threonine phosphatase that regulates diverse cellular functions such as transcription, cell signaling and apoptosis. PP1 is indicated to regulate the pre-mRNA alternative splicing of Bcl-x gene to encode the anti-apoptotic Bcl-xL isoform. Inhibition of PP1 prevents the induction of cell cycle arrest and apoptosis, underlines the crucial role of PP1 in the cellular response to the stress. In my thesis study, the neuroblastoma SH-SY5Y cell line system was used to investigate whether the promotion of cell survival by PP1 inhibition is through the signaling pathway of DARPP-32 Ser102 phosphorylation by CK2. The current results reveals that the cell viability is decreased under down-regulations of CK2 and DARPP-32. The Ser102 phosphorylation status of DARPP-32, Bcl-xL mRNA and protein level are decreased by CK2 siRNA transfection. Transfection of either DARPP-32 siRNA or mutant DARPP-32 S102A plasmid DNA decreased the Bcl-xL protein level. The PP1 activity was increased by mutant DARPP-32 S102A plasmid DNA transfection. Furthermore, the PP1 inhibitor treatment increased the Bcl-xL/Bcl-xS mRNA ratio and Bcl-xL protein level. Under oxidative stress, inhibition of PP1 activity can reverse the H2O2-induced decrease in Bcl-xL protein level and promote the cell viability. The transfection of CK2-EGFP or DARPP-32 S102D plasmid DNA both can antagonize the effects of H2O2 on Bcl-xL protein level and the Bcl-xL/Bcl-xS mRNA ratio. The DARPP-32 S102D plasmid DNA transfection also attenuated the induction of PP1 activity under oxidative stress. These findings provide another insight for the regulation of anti-apoptotic gene expression by inhibition of PP1 activity through DARPP-32 phosphorylation on Ser102 by CK2. 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國立政治大學
神經科學研究所
102754007資料來源 http://thesis.lib.nccu.edu.tw/record/#G0102754007 資料類型 thesis dc.contributor.advisor 趙知章 zh_TW dc.contributor.author (作者) 許焙琹 zh_TW dc.creator (作者) 許焙琹 zh_TW dc.date (日期) 2015 en_US dc.date.accessioned 1-九月-2015 16:18:28 (UTC+8) - dc.date.available 1-九月-2015 16:18:28 (UTC+8) - dc.date.issued (上傳時間) 1-九月-2015 16:18:28 (UTC+8) - dc.identifier (其他 識別碼) G0102754007 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/78091 - 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) 102754007 zh_TW dc.description.abstract (摘要) 蛋白激酶 CK2 是一種具有多功能的絲胺酸/蘇胺酸蛋白激酶，大量表現於哺乳類動物的腦中，對於調控細胞週期的發展、基因表現、訊息傳遞以及抗細胞凋亡機制扮演相當重要的角色。許多研究顯示 CK2 也參與調節許多神經系統功能，包括神經保護及神經存活，但是其中調控機制目前尚未釐清。DARPP-32 (dopamine- and cAMP- regulated phosphoprotein with a molecular mass of 32 kDa) 主要表現在紋狀體中型多刺狀神經元中，過去研究已證實 DARPP-32 Ser102 胺基酸是CK2 的磷酸化作用受質。雖然DARPP-32 被發現主要透過抑制蛋白磷酸水解酶 PP1 參與藥物成癮的細胞調控機制，但近年研究指出DARPP-32 也參與抗細胞凋亡作用。PP1 是真核細胞的絲胺酸/蘇胺酸磷酸水解酶，能調節多種細胞功能，如轉錄、細胞訊息傳遞及細胞凋亡。過去文獻已指出 PP1 可以調節 Bcl-x 基因的 pre-mRNA 選擇性剪切，再經由轉譯過程合成抗細胞凋亡 Bcl-xL 異構蛋白，研究也發現抑制 PP1 可以防止細胞週期的停滯及細胞凋亡，強調細胞在壓力的情況下，PP1 扮演了相當關鍵性的角色。因此論文以人類神經母細胞瘤 SH-SY5Y 為實驗模式，探討透過 CK2 調控 DARPP-32 Ser102 的磷酸化是否具有抑制 PP1 的活性並促進細胞存活的作用。實驗結果顯示，抑制 CK2或DARPP-32 蛋白含量會導致細胞存活率下降，轉染 CK2 siRNA 會降低 DARPP-32 Ser102 的磷酸化現象、Bcl-xL 的蛋白質表現；轉染DARPP-32 siRNA 及突變型DARPP-32 S102A DNA 質體也會降低 Bcl-xL 的蛋白質表現，PP1 活性則會因轉染突變型DARPP-32 S102A DNA 質體而增加；此外，給予 PP1 抑制劑的實驗結果發現會促進 Bcl-xL/Bcl-xS mRNA 的比例以及 Bcl-xL 的蛋白質表現量。利用過氧化氫誘導細胞造成氧化壓力狀況下，同時給予 PP1 抑制劑，發現 Bcl-xL 的蛋白質表現量會回復以及促進細胞存活。轉染 CK2-EGFP 或 DARPP-32 S102D DNA 質體可以顯著回復Bcl-xL 的蛋白質表現量及Bcl-xL/Bcl-xS mRNA 的比例，轉染 DARPP-32 S102D DNA 質體亦可降低 PP1 的活性。論文的實驗結果提供 CK2 調節抗細胞凋亡基因表現的新機制，是經由促進 DARPP-32 Ser102 磷酸化作用進而抑制 PP1 活性，此條細胞訊息傳遞路徑將可提供應用於在氧化壓力下提升神經存活的臨床治療。 zh_TW dc.description.abstract (摘要) Protein kinase casein kinase II (CK2) is a multifunctional serine/threonine protein kinase and is highly abundant expression in the mammalian brain. CK2 plays an important role in the regulation of the cell cycle, gene expression, signal transduction and anti-apoptotic mechanisms. A number of studies have indicated that CK2 is involved in several neuronal functions including the neuroprotection and neuron survival, but its cellular mechanisms are not well-studied. The DARPP-32 (dopamine- and cAMP-regulated phosphoprotein with a molecular mass of 32 kDa) is highly enriched in the striatal medium spiny neurons and the Ser102 residue is identified as the phosphorylation site for CK2. Although DARPP-32 is known as a prominent cellular mediator of drug abuse through the inhibition of protein phosphatase 1 (PP1), the recent studies indicate that DARPP-32 may also be involved in the anti-apoptotic effects. Protein phosphatase PP1 is a major eukaryotic serine/threonine phosphatase that regulates diverse cellular functions such as transcription, cell signaling and apoptosis. PP1 is indicated to regulate the pre-mRNA alternative splicing of Bcl-x gene to encode the anti-apoptotic Bcl-xL isoform. Inhibition of PP1 prevents the induction of cell cycle arrest and apoptosis, underlines the crucial role of PP1 in the cellular response to the stress. In my thesis study, the neuroblastoma SH-SY5Y cell line system was used to investigate whether the promotion of cell survival by PP1 inhibition is through the signaling pathway of DARPP-32 Ser102 phosphorylation by CK2. The current results reveals that the cell viability is decreased under down-regulations of CK2 and DARPP-32. The Ser102 phosphorylation status of DARPP-32, Bcl-xL mRNA and protein level are decreased by CK2 siRNA transfection. Transfection of either DARPP-32 siRNA or mutant DARPP-32 S102A plasmid DNA decreased the Bcl-xL protein level. The PP1 activity was increased by mutant DARPP-32 S102A plasmid DNA transfection. Furthermore, the PP1 inhibitor treatment increased the Bcl-xL/Bcl-xS mRNA ratio and Bcl-xL protein level. Under oxidative stress, inhibition of PP1 activity can reverse the H2O2-induced decrease in Bcl-xL protein level and promote the cell viability. The transfection of CK2-EGFP or DARPP-32 S102D plasmid DNA both can antagonize the effects of H2O2 on Bcl-xL protein level and the Bcl-xL/Bcl-xS mRNA ratio. The DARPP-32 S102D plasmid DNA transfection also attenuated the induction of PP1 activity under oxidative stress. These findings provide another insight for the regulation of anti-apoptotic gene expression by inhibition of PP1 activity through DARPP-32 phosphorylation on Ser102 by CK2. This signaling pathway might be applied in the clinical therapy for neuronal survival under oxidative stress. 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 神經退化性疾病 (Neurodegenerative diseases) 2 第二節 氧化壓力 (Oxidative stress) 3 第三節 計畫性細胞凋亡 (Apoptosis) 4 第四節 抗細胞凋亡蛋白 Bcl-2 家族 (B-cell lymphoma-2 family) 6 第五節 抗細胞凋亡蛋白 Bcl-xL 6 第六節 蛋白磷酸水解酶 PP1 (Protein phosphatase 1) 7 第七節 DARPP-32 蛋白 (dopamine- and cAMP-regulated phosphoprotein with a molecular mass of 32 kDa) 10 第八節 蛋白激酶CK2 (Protein kinase CK2, Casein kinase 2) 11 第九節 論文目的及研究策略 14 第二章 材料方法 15 第一節 細胞培養 16 一、細胞培養 17 二、細胞計數與繼代培養 17 第二節 細胞轉染 17 第三節 藥物處理 18 第四節 質體培養、萃取、瓊脂膠體電泳分析與菌種保存 18 一、質體培養、萃取 18 二、瓊脂膠體電泳分析 19 三、菌種保存 19 第五節 西方氏點墨法 19 一、蛋白質萃取 19 二、蛋白質濃度測定 20 三、樣品配置 20 四、鑄膠和聚丙烯醯胺膠體電泳 (Sodium dodecyl sulfate polyacrylamide gel electrophoresis,SDS-PAGE) 20 五、蛋白質轉漬 (Protein Transfer) 21 六、免疫反應 (Immunoblotting) 21 第六節 細胞存活試驗 MTT試驗法 (MTT assay) 22 第七節 即時定量聚合酶連鎖反應 (Quantitative real-time polymerase chain reaction) 22 一、RNA萃取 22 二、反轉錄互補DNA (cDNA) 22 三、即時定量聚合酶連鎖反應 23 第八節 蛋白磷酸水解酶PP1活性測試 (Protein phosphatase 1 activity) 24 第九節 統計分析 24 第三章 實驗結果 26 第一節 轉染CK2siRNA或DARPP-32 siRNA對細胞存活率的影響 27 第二節 轉染CK2siRNA對DARPP-32 Ser102的磷酸化和Bcl-xL、Mcl-1蛋白質含量的影響 27 第三節 轉染DARPP-32 siRNA對DARPP-32、DARPP-32 Ser102磷酸化和 Bcl-xL、Mcl-1蛋白質含量的影響 28 第四節 轉染突變型DARPP-32 S102A DNA質體對細胞Bcl-xL蛋白質含量和Bcl-xL與Bcl-xS mRNA表現的影響 28 第五節 轉染突變型DARPP-32 S102A DNA質體對細胞蛋白磷酸水解酶PP1、PP2A活性的影響 29 第六節 蛋白磷酸水解酶PP1抑制劑tautomycin對細胞存活率和抗細胞凋亡蛋白 Bcl-xL、Mcl-1含量以及Bcl-xL/Bcl-xS mRNA表現的影響 30 第七節 蛋白磷酸水解酶PP1抑制劑tautomycin對過氧化氫處理之細胞存活率和蛋白質含量的影響 30 第八節 轉染DARPP-32 S102D DNA質體對過氧化氫處理之細胞存活率、 Bcl-xL/Bcl-xS mRNA表現以及蛋白磷酸水解酶活性的影響 31 第九節 轉染CK2-EGFP DNA質體對過氧化氫處理之細胞存活率、 DARPP-32 Ser102磷酸化、Bcl-xL蛋白質含量和Bcl-xL、Bcl-xS mRNA的影響 32 第四章 討 論 34 第五章 結 論 41 實驗圖表 42 參考文獻 62 zh_TW dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0102754007 en_US dc.subject (關鍵詞) 蛋白激酶CK2 zh_TW dc.subject (關鍵詞) DARPP-32蛋白 zh_TW dc.subject (關鍵詞) 蛋白磷酸水解酶PP1 zh_TW dc.subject (關鍵詞) 抗細胞凋亡Bcl-xL蛋白 zh_TW dc.subject (關鍵詞) 氧化壓力 zh_TW dc.subject (關鍵詞) 細胞存活 zh_TW dc.subject (關鍵詞) Protein kinase CK2 en_US dc.subject (關鍵詞) DARPP-32 en_US dc.subject (關鍵詞) protein phosphatase PP1 en_US dc.subject (關鍵詞) Bcl-xL en_US dc.subject (關鍵詞) oxidative stress en_US dc.subject (關鍵詞) cell viability en_US dc.title (題名) 蛋白磷酸水解酶PP1在蛋白激酶CK2a調控 抗凋亡蛋白Bcl-xL基因表現過程中的角色 zh_TW dc.title (題名) The role of protein phosphatase 1 in the protein kinase CK2a-mediated anti-apoptotic Bcl-xL gene expression en_US dc.type (資料類型) thesis en dc.relation.reference (參考文獻) Ahn J-H, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC (2007) Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit. 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