2012-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656041摘要：為了確保所有生物體中基因體的穩定性，細胞內的DNA 複製及細胞週期的進行會相互協調，並受到嚴密的調控。細胞週期的進行是由許多不同的cyclin-dependent kinases (CDKs)及細胞週期檢查點蛋白所控制。疱疹病毒為了能在宿主細胞核中複製病毒基因體，演化出了許多機制影響細胞正常週期，並提供一個適合的環境以利病毒DNA 複製。但這個對於正常細胞週期進行的擾亂可能促使異常的細胞生長及宿主細胞基因體的不穩定性。這可能也解釋了為何Epstein-Barrvirus (EBV)相關的惡性疾病常發生於初次病毒感染的較長一段時間之後。最近的研究指出疱疹病毒中高度保守的protein kinase 可能扮演類似於細胞CDK 的功能；我們發現EBV BGLF4 protein kinase 的表現會造成類似發生於細胞複製前期的染色體濃縮及核板蛋白溶解，同時也會藉由延遲細胞週期由S 期進入G2/M 期而延緩細胞生長。透過基因微陣列分析更顯示BGLF4 對基因轉錄系統會造成劇烈的變化。因此這個研究的目的在於進一步探討EBV BGLF4 protein kinase 對於細胞週期進行及宿主細胞基因體穩定性之影響。在未來三年的計畫中，我們將近一步探討： (1)BGLF4 是否可以促進一個類似於S 期 (S-phase-like) 的細胞環境。 (2) BGLF4 是否引起宿主細胞基因體不穩定性。 (3) BGLF4 是透過影響何種訊息傳遞途徑引起的細胞骨架變化，並了解其與細胞核及基因轉錄系統變化的相關性。 (4) BGLF4 抑制IRF3 訊息傳遞的機制及其對細胞生長的影響。(5) BGLF4 可能具有在酵母菌系統中的類CDK 活性。<br> Abstract: DNA replication and cell cycle progression are sophistically coordinated in all organisms to ensure genome stability. Cell cycle is governed by different cyclin-dependent kinases (CDKs) and cell cycle check point proteins. For herpesviruses to replicate their DNA genome in host nucleus, various strategies are evolved to interfere normal cell cycle progression and to provide a optimal environment for maximal viral DNA replication. Thus the disturbance of normal cell cycle control may promote abnormal cell growth and genome instability. It may also explain why human Epstein-Barr virus (EBV) associated malignant diseases usually occur long after the primary infection of EBV. Recent studies indicate the conserved protein kinases of herpesvirus may function as cellular CDK-like kinases. We found the expression of EBV BGLF4 induces prometaphase-like chromosome condensation and disassembly of nuclear lamina. Expression of BGLF4 also leads to cell growth retardation by delaying cell cycle progression from S phase into G2/M. Microarray analysis revealed that BGLF4 induces dramatic changes of cellular transcription program. The purpose of this study is to examine how EBV BGLF4 kinase may affect cell cycle progression in different systems, and its possible effects on genome stability. Specific aims are (1) To examine whether BGLF4 promotes the S-phase-like environment in cells; (2) To examine whether BGLF4 elicits host genome instability; (3) To identify the signaling pathways involved in BGLF4-induced cytoskeleton change, and its correlation to nuclear remodeling and transcriptional program change; (4) To analyze the mechanism involved in BGLF4 mediated suppression of IRF3 signaling and its effect on cell growth; (5) To study the conserved-CDK like activity of BGLF4 in yeast system.EB病毒鼻咽癌蛋白質激脢Epstein-Barr virusNasopharyngeal Carcinomaprotein kinase