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.

项目概要 伽玛疱疹病毒感染的特点是通过进入静止期而在宿主细胞中终生持续存在。 潜伏感染期间，仅表达有限的基因组，包括基因组。 KSHV 的维持蛋白 LANA 和 EBV 的 EBNA1 LANA 和 EBNA1 均与相关。 尽管潜在的机制仍不清楚，但在本提案中，我们将进行研究。 我们早期的研究已经认识到 EBV 的这种肿瘤发生机制。 激酶 BGLF4 与宿主细胞中的 TIP60 蛋白相互作用，调节病毒裂解复制。 细胞乙酰转移酶在基因转录、细胞凋亡和 DNA 损伤中发挥重要作用 TIP60 作为肿瘤抑制因子的作用已在小鼠模型和体内得到证实。 我们最近证明 TIP60 也是 KSHV 裂解性复制所必需的，这表明 其广泛的疱疹病毒作用表明，我们还发现 TIP60 与 LANA 和 EBNA1 相互作用。 这些结果与 TIP60 组蛋白乙酰转移酶活性的显着降低相关。 导致我们假设潜伏的伽马疱疹病毒暂时调节乙酰转移酶活性 TIP60 作为癌症发展的关键机制，我们研究这一假设的具体目标是：(i) 首先研究 TIP60 抑制对伽马疱疹病毒潜伏期的影响 (ii) 并 表征 TIP60 在伽马疱疹病毒感染的淋巴瘤中的抗肿瘤活性。 研究将确定伽玛疱疹病毒相关肿瘤的独特分子特征，这些特征可以 解释为什么潜伏的伽马疱疹病毒具有致癌性，这也将为未来的研究提供基础。 艾滋病相关淋巴瘤治疗策略的制定。