EB病毒Rta蛋白質活化AP-1所調控基因的轉錄活性

Activation of AP-1-mediated transcription by Rta of Epstein-Barr virus

葉弘銘(Hong-Mine Yeh)

指導教授 ： 洪義人

共同指導教授 ： 張麗冠(Li-Kwan Chang)

高雄醫學大學/醫學院/醫學遺傳學研究所/碩士(2006年)

https://doi.org/10.6832/KMU.2006.00139

摘要

EB病毒 (Epstein-Barr virus) 含有兩個生活史，在被感染的寄主細胞中，病毒通常以潛伏型態存在。然而在受到一些特定的化學或是物理刺激後病毒會進入溶裂循環。EB病毒表現的兩個轉錄活化因子，Rta和Zta是EB病毒進入溶裂循環的關鍵因子。Rta是一個被EB病毒BRLF1基因所轉譯出的轉錄調控因子，通常Rta在溶裂循環的極早期時被表現出來，並去活化其它溶裂循環所需要的其它基因。MCAF1在細胞內與基因轉錄活性的調控有關，能夠與MBD1結合抑制基因的轉錄活性，也能與Sp1結合活化基因的表現，而AP-1在細胞內是一種轉錄因子，與細胞增生、分化或是細胞凋亡有關。在本研究中我先利用冷光活性分析Rta對BZLF1啟動子轉錄活性的影響，結果發現Rta可以藉由ZII區域影響BZLF1啟動子的轉錄活性。並且證實Rta、MCAF1和AP-1 (ATF2、c-Jun、c-Fos和ATF1) 可以結合至BZLF1啟動子ZII區域上，並且形成AP-1-MCAF1-Rta複合體，另外我證實了在細胞外ATF2 的N端第1至第323胺基酸的位置可以與MCAF1第562胺基酸至第650胺基酸間直接結合，並且證實MCAF1是Rta與ATF2結合的媒介者。因此Rta可以藉由MCAF1與AP-1結合至BZLF1啟動子的ZII區域，並藉由形成AP-1-MCAF1-Rta複合體活化與AP-1相關的轉錄因子。本篇研究顯示出Rta可能藉由與MCAF1的結合而影響受AP-1轉錄因子調控基因的轉錄活性，可能與EB病毒參與癌化的過程有關。

關鍵字

皰疹病毒

並列摘要

Epstein-Barr virus (EBV) has two life cycles. The virus is normally maintained in infected host cell under latent conditions but enters a lytic cycle to proliferate after exposing to specific chemical or physical stimuli. Expression of Rta and Zta by EBV is the key event leading to the lytic activation. Rta is a transcription factor encoded by BRLF1 of EBV, which is expressed during the immediate-early stage of the lytic cycle to activate the genes required for EBV lytic development. Meanwhile, MBD1-containing chromatin-associated factor (MCAF1) interacts with MBD1 and Sp1; this interaction is crucial to MBD1-mediated transcriptional repression. Howerever, when MCAF1 binds to Sp1, MCAF1 becomes a coactivator to enhance Sp1-mediated transcription. AP-1 are transcription factors involving in cellular proliferation, differentiation and apoptosis. In this study, transcription of BZLF1 transactivated by Rta was examined by transient reporter assay, which shows that Rta activates the transcription of BZLF1 through the binding at the ZII domain. Moreover, the study reveals the binding Rta, MCAF1 and AP-1 (ATF2, c-Jun, c-Fos and ATF1) to the ZII domain in the BZLF1 promoter and forms a AP-1-MCAF1-Rta complex. Addtionally, this study aslo shows that the N-terminal 323 amino acids in ATF2 interacts with the region in MCAF1 between amino acids 562 and 650. This study demonstrates that MCAF1 is the mediator between Rta and AP-1, which facilitates an indirect interaction between Rta and AP-1 on the ZII region in the BZLF1 promoter and activates AP-1-mediated transcription. Our study documents the critical role of Rta in regulating AP-1-mediated transcription.

並列關鍵字

EBV ； Rta ； AP-1 ； BZLF1 ； MCAF1 ； Zp ； ATF2 ； Zta

參考文獻

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