Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia

摘要： EB病毒（EBV）是一种与多种淋巴和上皮细胞相关的人类γ疱疹病毒， 恶性肿瘤。像所有的癌症一样，EBV相关的癌症必须在营养耗尽的环境中竞争和生存。 环境.对氧气波动的适应是大多数癌症的标志。在本提案中，我们调查 氧代谢如何在EBV潜伏期和肿瘤发生中发挥核心作用。对于目标1，我们将研究 EBV如何调节宿主在原发感染期间的缺氧反应。我们的初步数据表明EBNA1 EBNA 2可以结合和调节控制缺氧反应的细胞基因，包括缺氧诱导的 因子1 α（HIF 1A）。我们将检验EBV感染调节宿主对缺氧反应的假设 以促进受感染细胞存活并促进肿瘤发生。对于目标2，我们将研究病毒如何 表观基因组受氧敏感酶的调节。EBV相关伯基特淋巴瘤（BL）和上皮性 已知恶性肿瘤获得通常称为CpG岛甲基化因子的高DNA甲基化 表型（CIMP）。我们将研究DNA甲基化是如何通过氧敏感的控制来调节的， TET2酶和探索缺氧如何有助于CIMP和肿瘤抑制基因的沉默。为 目的3，我们将测试氧敏感酶如何调节潜伏期期间EBNA1和EBV附加体维持。 我们已经发现脯氨酸和赖氨酸羟化酶调节EBNA1和EBNA2蛋白的稳定性和功能。 我们已经绘制了EBNA 1上结合赖氨酸羟化酶PLOD 1的相互作用位点，并发现了这种相互作用 EBNA1蛋白在常氧条件下的稳定性。我们现在打算研究缺氧是如何调节 PLOD 1与EBNA 1相互作用以控制潜伏感染期间EBV附加体维持和持续。 这些目标是高度集成与其他成员的计划项目探索缺氧的影响， 肿瘤病毒总之，这些目标将提供一个框架，以了解病毒如何应对缺氧， 促进宿主细胞存活并驱动致癌过程。

Abstract: Epstein-Barr Virus (EBV) a human gammaherpesvirus that is associated with diverse lymphoid and epithelial malignancies. Like all cancers, EBV-associated cancers must compete and survive in nutrient depleted environments. Adaptation to oxygen fluctuation is a hallmark of most cancers. In this proposal, we investigate how oxygen metabolism plays a central role in EBV latency and tumorigenesis. For aim 1, we will investigate how EBV modulates the host hypoxic response during primary infection. Our preliminary data indicates EBNA1 and EBNA2 can bind and regulate cellular genes controlling the hypoxic response, including hypoxia inducible factor 1 alpha (HIF1A). We will test the hypothesis that EBV infection modulates the host response to hypoxia to promote infected cell survival and promote tumorigenesis. For aim 2, we will investigate how the viral epigenome is regulated by oxygen sensing enzymes. EBV associated Burkitt lymphoma (BL) and epithelial malignancies are known to acquire high DNA methylation commonly referred to as the CpG island methylator phenotype (CIMP). We will investigate how DNA methylation is regulated through the oxygen-sensitive control of TET2 enzymes and explore how hypoxia contributes to CIMP and silencing of tumor suppressor genes. For aim 3, we will test how oxygen sensing enzymes regulate EBNA1 and EBV episome maintenance during latency. We have found that proline and lysine hydroxylases regulate EBNA1 and EBNA2 protein stability and function. We have mapped interaction sites on EBNA1 that bind the lysine hydroxylase PLOD1 and found this interaction essential for EBNA1 protein stability under normoxia. We now propose to investigate how hypoxia regulates the interaction of PLOD1 with EBNA1 to control EBV episome maintenance and persistence during latent infection. These aims are highly integrated with other members of the program project exploring hypoxia effects on related tumor viruses. Together, these aims will provide a framework to understand how viruses respond to hypoxia to promote host cell survival and drive the oncogenic process.