臺灣博碩士論文加值系統

先前在許多與EB病毒相關的疾病組織中，可以觀察到p53多量累積的情形。同時，在這些病患的血清又可偵測到較高力價的抗EB病毒溶裂期產物抗體，因此在本論文中我們欲探討p53對於EB病毒溶裂期誘發的過程中所扮演的角色。本實驗發現利用siRNA抑制NA細胞株﹙感染EB病毒的鼻咽癌細胞株﹚內生性p53表現之後，利用西方墨點法分析發現TSA與SB這兩種HDAC抑制劑無法誘發EB病毒進入溶裂期，顯示p53很可能是EB病毒進入溶裂期的必備因子。進一步以RT-PCR以及Zta啟動子報導質體證明，p53可以調控EB病毒極早期基因Zta啟動子，因此我們也試圖探討p53調控Zta啟動子的機制。然而EMSA與DAPA實驗顯示p53可能不會與Zta啟動子結合亦可能不透過影響結合於Zta啟動子上的轉錄因子而調控Zta啟動子。由於p53活性最主要受轉譯後修飾影響，因此我們也試圖探討HDAC抑制劑是否會影響p53之轉譯後修飾，以及其對於EB病毒溶裂期的重要性。利用西方墨點法分析發現TSA會造成NA細胞內生性p53-Ser 46之磷酸化增加。同時我們亦證明PKC-δ參與在p53-Ser46磷酸化之調控。然而進一步將p53突變質體﹙S46A，S46D﹚短期轉染至H1299A細胞株，藉由西方墨點法證明p53-Ser46對於HDAC抑制劑所誘發之EB病毒溶裂期基因表現並不扮演重要角色。有趣的是，在H1299細胞株短期轉染另一個DNA結合能力突變的p53會造成HDAC抑制劑無法有效誘發病毒溶裂期，顯示p53的DNA結合能力對於HDAC抑制劑誘發EB病毒溶裂期可能扮演重要角色。
歸納我們的實驗證明p53對於HDAC抑制劑誘發EB病毒溶裂期很可能是一個關鍵因子，而p53很可能透過調控EB病毒極早期基因Zta啟動子的方式，進而影響病毒溶裂期發生。雖然目前我們對於p53調控Zta啟動子的詳細機制仍然不清楚，但是本論文試圖為p53於病毒與宿主交互關係中提供一個新的視野。

It was reported that p53 accumulates in some EBV-infected tissue cells, meanwhile, high titer antibodies against EBV lytic products were also observed in those patients’ sera, suggesting p53 may play a role in EBV reactivation. Here, we show that RNA interference of p53 in NA cells, an NPC cell line infected with Akata EBV, blocks HDAC inhibitor-induced EBV reactivation. Both transcripts and promoter activity of the EBV immediately early gene Zta are no longer induced by HDAC inhibitor in the absence of p53 expression. p53 may regulate EBV reactivation through Zta promoter. However, EMSA and DAPA experiments demonstrate that p53 does not bind to Zta promoter. EMSA experiments are also conducted to compare factors binding to ZIA/B、ZIC、ZII、ZIIIA and ZV in the absence or presence of p53. Knocking down of p53 results in augmentation of ZIA/B complex2. ZIA/B complex2 formation is through the middle region of ZIA/B probe. However, Zp-reporter assay demonstrates that mutation of the complex2-binding site does not alter HDAC inhibitor-induced Zta promoter activity.
Post-translational modification of p53 by HDAC inhibitor may play a role during EBV reactivation. Phosphorylation of p53-Ser46 increases during TSA time course treatment. However, phosphorylation of p53-Ser46 is not important for HDAC inhibitor-induced EBV reactivation. Intriguingly, HDAC inhibitor-induced EBV reactivation is abolished upon ectopically expression of a mutant p53 ( 248m ) in H1299A cel line, suggesting that p53 DNA binding ability is required for HDAC inhibitor-induced EBV reactivation.
We conclude that p53 acts as an important regulator of Zta promoter in the process of HDAC inhibitor-induced EBV reactivation, and it provides a novel role for p53 in virus-host interaction.

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