Tumor suppressor reprogramming by EBV through post-translational modification

EBV 通过翻译后修饰重编程肿瘤抑制因子

基本信息

批准号：
10684650
负责人：
ERLE S. ROBERTSON
金额：
$ 53.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684650
关键词：
AIDS-Related Lymphoma Acetylation Acetyltransferase Acquired Immunodeficiency Syndrome Affect Automobile Driving B Cell Proliferation B lymphocyte immortalization B-Cell Lymphomas B-Lymphocytes Binding Biochemical Burkitt Lymphoma Cell Cycle Cell Cycle Progression Cell Cycle Progression Pathway Cell Cycle Regulation Cell Survival Cell model Cells Complex Cyclin D1 Cyclins DNA Damage Degradation Pathway Disease E2F transcription factors Epstein Barr Virus B cell lymphoma Epstein-Barr Virus Infections Epstein-Barr Virus latency Escherichia coli Family Family member Gene Expression Genes Genetic Transcription Genome Goals HIV HIV Seropositivity Hodgkin Disease Human Human Herpesvirus 4 Human Herpesvirus 8 Human Papillomavirus Immune Immunocompromised Host In Vitro Individual Infection Intervention Knock-out Knowledge Lead Link Lymphoma Malignant - descriptor Malignant Neoplasms Mammalian Cell Mediating Modeling Modification Molecular Molecular Biology Molecular Genetics Mutate Non-Hodgkin&apos s Lymphoma Nuclear Antigens Nuclear Protein Oncogenes Oncogenic Oncogenic Viruses Pathology Patients Phenotype Phosphorylation Phosphotransferases Polyomavirus Post-Translational Protein Processing Proliferating Proteins Recombinants Regulation Retinoblastoma Protein Role Satellite Viruses Site Testing Therapeutic Intervention Transcription Repressor Tumor Suppressor Proteins Ubiquitination Untranslated RNA Viral Viral Genes Viral Genome Virus Diseases Western Blotting cell transformation co-infection gammaherpesvirus infected B cell insight lymphoblastoid cell line molecular modeling multicatalytic endopeptidase complex mutant new therapeutic target novel novel therapeutic intervention post-transplant programs recombinant virus recruit response targeted treatment transcription factor transforming virus

项目摘要

Abstract: Immunocompromised HIV-positive patients have serious complications with opportunistic oncogenic viral infections that can lead B-cell lymphomas. Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated virus (KSHV) are two human oncogenic gammaherpesviruses associated with B-cell lymphomas either individually or as co-infections. EBV-associated B-cell lymphomas are established as latency III infection with the major latent genes expressed as well as the small non-coding RNAs. EBV transformed B cells drive latency III, also seen in HIV associated EBV-positive lymphomas. EBV is also associated with other lymphomas including Burkitt’s lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma, and post-transplant and AIDS associated lymphomas in immunocompromised HIV-patients. EBV also efficiently transforms human primary B-cells in vitro, into immortalized lymphoblastoid cell lines (LCLs). These nascent transformed B cells express latent genes, one of which is the Epstein-Barr nuclear antigen EBNA3C, essential for immortalization of B-cells. EBNA3C regulates cellular and viral gene expression through interaction with transcription repressors, and complexes of the mammalian cell cycle which include CyclinA, and components of the SCF proteosome degradation pathway. Our long term goal is to determine the role of EBNA3C in reprogramming viral and infected cell genomes through interactions with the tumor suppressor Rb and the regulatory consequences of these interactions as related to cell survival, cell cycle regulation and proliferation. We will investigate the mechanism of Rb regulation through specific post- translation modifications after infection by EBV, which includes phosphorylation and acetylation important for targeted ubiquitination. We will determine if enhanced phosphorylation/acetylation of Rb occurs through recruitment of CyclinD/Cdk4/6 complexes by EBNA3C important for cell cycle progression. This results in loss of Rb through ubiquitination which leads to cell and viral genome reprogramming by activation of the cellular E2F pathway, cell cycle progression, increased survival and malignant transformation. These studies will examine the role of EBNA3C in regulating the Rb/CyclinD/E2F network important for B-cell immortalization with implications for novel insights into KSHV and EBV contributions to latency III lymphomas in HIV patients.

抽象的：免疫功能低下的艾滋病毒阳性患者会出现严重的机会性并发症致癌病毒感染可导致 B 细胞淋巴瘤 (EBV) 和卡波西肉瘤相关病毒 (KSHV) 是两种人类致癌性伽马疱疹病毒单独或与 EBV 相关 B 细胞感染相关。淋巴瘤被确定为潜伏 III 感染，主要潜伏基因也表达 EBV 转化的 B 细胞驱动潜伏期 III，这也见于 HIV 中。相关 EBV 阳性淋巴瘤也与其他淋巴瘤相关。伯基特淋巴瘤、霍奇金淋巴瘤和非霍奇金淋巴瘤以及移植后和艾滋病免疫功能低下的 HIV 患者的相关淋巴瘤也能有效转化。人类原代 B 细胞在体外转化为永生化类淋巴母细胞系 (LCL)。新生转化的 B 细胞表达潜在基因，其中之一是 Epstein-Barr 核抗原 EBNA3C，对于 B 细胞永生化至关重要 EBNA3C 调节细胞和病毒。通过与转录抑制子和复合物的相互作用来表达基因哺乳动物细胞周期，包括 CyclinA 和 SCF 蛋白酶体成分我们的长期目标是确定 EBNA3C 在重编程中的作用。通过与肿瘤抑制因子 Rb 和这些相互作用的调节后果与细胞存活、细胞周期调节有关我们将通过特定的后处理研究Rb的调节机制。 EBV 感染后的翻译修饰，包括磷酸化和乙酰化对于靶向泛素化很重要，我们将确定磷酸化/乙酰化是否增强。 Rb 的发生是通过 EBNA3C 募集 CyclinD/Cdk4/6 复合物而发生的，这对细胞很重要这导致 Rb 通过泛素化而丢失，从而导致细胞和病毒。通过激活细胞 E2F 通路、细胞周期进程进行基因组重编程，这些研究将探讨增加生存率和恶性转化的作用。 EBNA3C 调节 Rb/CyclinD/E2F 网络，对 B 细胞永生化很重要对 KSHV 和 EBV 对 HIV 潜伏性 III 淋巴瘤的影响的新见解的意义患者。