Inhibition of TIP60 by Latent Gammaherpesviruses in B-cell Lymphomas

项目总结 伽马疱疹病毒感染的特征是通过进入静止状态在宿主细胞中终生持续存在。 这一时期被称为潜伏感染。在潜伏期，只有一组有限的基因被表达，包括基因组 KSHV的维持蛋白LANA和EBV的EBNA1。LANA和EBNA1都已链接到 尽管潜在的机制尚不清楚，但细胞转化。在这份提案中，我们将调查 潜伏的伽马疱疹病毒的致癌机制。我们早期的研究已经认识到EBV中的一种 BGLF4与宿主细胞中的Tip60蛋白相互作用，调节病毒的裂解复制。Tip60是一种 在基因转录、细胞凋亡和DNA损伤中发挥重要作用的细胞乙酰转移酶 回应。Tip60作为肿瘤抑制因子的作用已经在小鼠体内模型和在 人类肿瘤。我们最近证明了KSHV裂解复制也需要Tip60，这表明 它广泛的疱疹病毒作用。有趣的是，我们还发现Tip60与LANA和EBNA1在 潜伏期与Tip60‘S组蛋白乙酰转移酶活性显著降低相关。这些结果 这就引出了我们的假设：潜伏的伽马疱疹病毒暂时调节乙酰转移酶的活性。 Tip60作为肿瘤发生的关键机制。我们研究这一假设的具体目的是：(I) 首次探讨Tip60抑制丙型肝炎病毒潜伏期(II)的机制及影响 研究Tip60在伽马疱疹病毒感染的淋巴瘤中的抗肿瘤活性。这些措施的结果 研究将确定伽马疱疹病毒相关肿瘤的独特分子特征，这些肿瘤可以 解释为什么潜伏的伽马疱疹病毒是致癌的。这也将为今后研究提供基础 艾滋病相关淋巴瘤治疗策略的发展。

PROJECT SUMMARY Gammaherpesviruses infection is characterized by lifelong persistence in the host cells by entering quiescent period known as latent infection. During latency, only limited set of genes is expressed that include genome maintenance proteins LANA for KSHV and EBNA1 for EBV. Both LANA and EBNA1 have been linked to cellular transformation although the underlying mechanism is still unclear. In this proposal, we will investigate this oncogenesis mechanism of latent gammaherpesviruses. Our earlier study has recognized that one of EBV kinases, BGLF4, interacts with TIP60 protein in the host cells to regulate viral lytic replication. TIP60 is a cellular acetyltransferase that plays important roles in gene transcription, cell apoptosis, and DNA damage response. The role of TIP60 as a tumor suppressor has been established in vivo in mouse model and in human tumors. We recently demonstrated that TIP60 was required for KSHV lytic replication as well, indicating its broad herpesviruses role. Interestingly, we also found that TIP60 interacted with LANA and EBNA1 during latency that correlated with significant reduction of TIP60’s histone acetyltransferase activity. These results lead us to our hypothesis that latent gammaherpesviruses temporally regulate acetyltransferase activities of TIP60 as the critical mechanism in cancer development. Our specific aims to study this hypothesis are: (i) to first investigate the mechanism and impact of TIP60 inhibition in gammaherpesviruses latency (ii) and to characterize anti-tumor activities of TIP60 in gammaherpesviruses-infected lymphoma. Outcome from these investigations will identify the unique molecular features of gammaherpesviruses-related tumors that can explain why latent gammaherpesviruses are oncogenic. It will also provide the basis for future studies on development of therapeutic strategy for AIDS-related lymphoma.