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 伽马广播病毒感染的特征是宿主细胞中终生持久性通过静止 时期称为潜在感染。在延迟期间，仅表达了包括基因组的有限基因集 维护蛋白LANA用于KSHV和EBNA1的EBV。 LANA和EBNA1都与 尽管基本机制仍不清楚，但细胞转化虽然仍不清楚。在此提案中，我们将调查 这种潜在伽马病毒的肿瘤生成机制。我们较早的研究已经认识到EBV之一 激酶BGLF4与宿主细胞中的TIP60蛋白相互作用，以调节病毒裂解复制。 TIP60是一个 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 回复。 TIP60作为肿瘤抑制剂的作用已在小鼠模型和 人类肿瘤。我们最近证明了KSHV裂解复制所需的TIP60，表明 它广泛的疱疹病毒角色。有趣的是，我们还发现TIP60与LANA和EBNA1相互作用 与TIP60组蛋白乙酰转移酶活性的显着降低相关的潜伏期。这些结果 引导我们假设潜在的γ掌病毒暂时调节乙酰转移酶活性的活性 TIP60是癌症发展的关键机制。我们研究此假设的具体目的是：（i） 首先研究TIP60抑制在伽马病毒潜伏期（II）和TO上的机制和影响 表征了感染的γ掌病毒淋巴瘤中TIP60的抗肿瘤活性。这些结果 调查将确定γ掌病毒相关肿瘤的独特分子特征，可以 解释为什么潜在的γ掌病毒具有致癌性。它还将为以后的研究提供基础 与艾滋病相关淋巴瘤的理论策略的发展。