Inhibition of TIP60 by Latent Gammaherpesviruses in B-cell Lymphomas

B 细胞淋巴瘤中潜伏的伽玛疱疹病毒对 TIP60 的抑制

• 批准号: 10012305
• 负责人: Netty G Santoso
• 金额: $ 15.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012305
• 关键词: AIDS related cancer; AIDS-Related Lymphoma; Acetylation; Acetyltransferase; Acquired Immunodeficiency Syndrome; Address; Affect; Apoptosis; B-Cell Lymphomas; B-Lymphocytes; Cancer Etiology; Cell Proliferation; Cells; Cellular Tropism; Chemicals; Chromatin; DNA Damage; Development; Double Stranded DNA Virus; Episome; Epstein-Barr Virus latency; Etiology; Event; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; HIV; HTATIP gene; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunocompromised Host; In Vitro; Infection; Infectious Agent; Investigation; Lead; Life; Link; Lymphocyte; Lymphocyte Activation; Lymphoma; Lytic; Maintenance; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mouth Diseases; Mouth Neoplasms; Mus; Oncogenes; Oncogenic; Oral cavity; Oral health; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Primary Infection; Process; Proteins; Regulation; Role; Solid; Switch Genes; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Ursidae Family; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; Xenograft procedure; experimental study; gammaherpesvirus; histone acetyltransferase; improved; in vivo; inhibitor/antagonist; innovation; knock-down; latent infection; lytic replication; metaplastic cell transformation; mouse model; novel; promoter; response; therapeutic development; treatment planning; treatment strategy; tumor; tumorigenesis

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.

项目摘要 γ疱疹病毒感染的特征是通过进入静止期在宿主细胞中终身持续存在 这一时期被称为潜伏感染。在潜伏期，只有有限的基因表达，包括基因组 KSHV的维持蛋白拉娜和EBV的维持蛋白EBNA 1。拉娜和EBNA 1都与 细胞转化，但其潜在机制尚不清楚。在这份提案中，我们将调查 潜伏性γ疱疹病毒的致癌机制。我们早期的研究已经认识到， 激酶BGLF 4在宿主细胞中与TIP60蛋白相互作用以调节病毒裂解复制。TIP60是一个 一种在基因转录、细胞凋亡和DNA损伤中起重要作用的细胞乙酰转移酶 反应TIP60作为肿瘤抑制因子的作用已经在小鼠模型中体内和小鼠模型中确立。 人类肿瘤我们最近证实KSHV裂解性复制也需要TIP60，表明 其广泛的疱疹病毒作用。有趣的是，我们还发现TIP60与拉娜和EBNA 1在细胞凋亡过程中相互作用。 潜伏期与TIP60组蛋白乙酰转移酶活性显著降低相关。这些结果 这使我们假设潜伏性γ疱疹病毒暂时调节乙酰转移酶活性 TIP60是癌症发展的关键机制。我们研究这一假设的具体目的是：（一） 首先研究TIP60抑制在γ疱疹病毒潜伏期中的机制和影响（ii）， 表征TIP60在γ疱疹病毒感染的淋巴瘤中的抗肿瘤活性。结果从这些 研究将确定γ疱疹病毒相关肿瘤的独特分子特征， 解释为什么潜伏的γ疱疹病毒是致癌的。它还将为今后的研究提供基础， 艾滋病相关淋巴瘤治疗策略的发展。