Biology of the Epstein-Barr Virus R Transactivator in Human B Cells

EB病毒（EBV）是一种人肿瘤病毒，其在病因学上与鼻咽和淋巴瘤相关。 胃癌、伯基特氏病、霍奇金病和免疫母细胞性淋巴瘤以及其它人类癌症。在所有EBV相关的 在肿瘤和正常B细胞中，病毒保持在有限基因表达的潜伏状态。的 病毒必须被重新激活进入其裂解周期，以便在细胞之间和个体之间传播。的 在病毒BRLF 1基因中编码的EBV/Rta蛋白在介导EBV/Rta之间的转换中起着强制性的作用。 潜伏期和裂解周期基因表达，作为转录因子和复制蛋白。RTA是 因此是发病机制和肿瘤发生的关键因素。我们的全球目标是了解 BRLF 1的表达，Rta的作用机制以及Rta可能操纵表达的方式， 细胞蛋白质的定位。所提出的实验来自许多最近的出版物， 研究EBV/Rta的表达和活性调节的广泛的初步数据， 其同源物KSHV/ORF 50。我们将解决未解之谜：哪些细胞蛋白质调节 Rta的表达？为什么一些细胞通过表达Rta来响应裂解诱导刺激，而另一些细胞通过表达Rta来响应裂解诱导刺激？ 难治性吗Rta是如何同时作为转录因子和复制蛋白发挥作用的？Rta如何 改变关键细胞蛋白质的功能和定位？因此，我们的具体目标是：1）确定 细胞立即早期蛋白的能力和重要性，如早期反应和孤儿核 受体蛋白，以激活Rta表达; 2）了解Rta在EBV DNA复制中的功能， 特别是磷酸化和DNA结合调节的作用; 3）阐明Rta的功能 在DNA损伤反应cohesin、SMC 1、STAT 3和PolyA的表达、激活和再定位中， 结合蛋白拟议的研究，利用细胞生物学，生物化学，分子遗传学， 免疫学解决了真核基因表达控制的两个基本问题， 癌症和特定的未解决的问题的分子发病机制的一个重要的人类癌症病毒， 目前还没有具体的预防或治疗方法。

Epstein-Barr virus (EBV) is a human tumor virus that is etiologically associated with nasopharyngeal and gastric cancer, Burkitt's, Hodgkin's and immunoblastic lymphoma and other human cancers. In all EBVassociated tumors and in normal B cells, the virus remains in a latent state of limited gene expression. The virus must be reactivated into its lytic cycle in order to spread between cells and among individuals. The EBV/Rta protein encoded in the viral BRLF1 gene plays an obligatory role in mediating the switch between latency and lytic cycle gene expression, acting both as a transcription factor and a replication protein. Rta is thus is a key factor in pathogenesis and oncogenesis. Our global objectives are to understand the control of BRLF1 expression, the mechanism of action of Rta and the ways Rta might manipulate expression and localization of cellular proteins. The proposed experiments are derived from many recent publications and extensive preliminary data that investigated control of expression and regulation of activity of EBV/Rta and its homologue KSHV/ORF50. We will address unsolved mysteries: Which cellular proteins regulate expression of Rta? Why do some cells respond to lytic inducing stimuli by expression of Rta while other cells are refractory? How does Rta function both as a transcription factor and replication protein? How does Rta alter the function and localization of key cellular proteins? Accordingly, our specific aims are 1) To determine the capacity and importance of cellular immediate-early proteins, such as early response and orphan nuclear receptor proteins, to activate Rta expression; 2) To understand the function of Rta in EBV DNA replication, particularly the role of phosphorylation and regulation of DNA binding; and 3) To delineate the function of Rta in expression, activation and re-Iocalization of the DNA damage response cohesin, SMC1, STAT3 and PolyA binding protein. The proposed studies, utilizing tools of cell biology, biochemistry, molecular genetics, and immunology address both basic questions of control of eukaryotic gene expression that are relevant to cancer and specific unresolved issues about molecular pathogenesis of an important human cancer virus for which there is yet no specific prevention or treatment.