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：
10402055
负责人：
ERLE S. ROBERTSON
金额：
$ 53.94万
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/10402055
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 Regulation Cell Survival Cell model Cells Complex Cyclin D1 Cyclins DNA Damage Degradation Pathway Disease E2F transcription factors 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 Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Polyomavirus Post-Translational Protein Processing Proteins Recombinants Regulation Repressor Proteins Retinoblastoma Protein Role Site Testing Therapeutic Intervention Transcription Repressor Translations 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HIV阳性患者与机会性有严重的并发症可能导致B细胞淋巴瘤的致癌病毒感染。爱泼斯坦 - 巴尔病毒（EBV）和 Kaposi的肉瘤相关病毒（KSHV）是两个人类致癌性伽马病毒与B细胞淋巴瘤单独或作为共同感染相关。与EBV相关的B细胞淋巴瘤作为潜伏期III的感染也以表达的主要潜在基因感染而确定作为小型非编码RNA。 EBV转化的B细胞驱动潜伏期III，在HIV中也可见相关的EBV阳性淋巴瘤。 EBV还与其他淋巴瘤有关伯基特的淋巴瘤，霍奇金和非霍奇金的淋巴瘤以及移植后和艾滋病免疫功能低下的HIV患者中的相关淋巴瘤。 EBV还有效地转换在体外的人类原发性B细胞进入永生的淋巴母细胞系（LCLS）。这些新生转化的B细胞表达潜在基因，其中之一是爱泼斯坦 - 巴尔核抗原EBNA3C，对于B细胞的永生化至关重要。 EBNA3C调节细胞和病毒通过与转录反射器相互作用的基因表达和哺乳动物细胞周期，其中包括cyclina和SCF蛋白体的成分退化途径。我们的长期目标是确定EBNA3C在重编程中的作用病毒和感染的细胞基因组通过与肿瘤抑制剂RB和这些相互作用与细胞存活，细胞周期调节有关的调节后果和增殖。我们将通过特定的特定后调节RB调节的机制 EBV感染后的翻译修饰，其中包括磷酸化和乙酰化对于靶向泛素化很重要。我们将确定增强的磷酸化/乙酰化是否 RB的of通过EBNA3C对细胞重要循环进展。这导致RB通过泛素化损失，从而导致细胞和病毒基因组通过激活细胞E2F途径的重新编程，细胞周期进程，增加生存和恶性转化。这些研究将研究 EBNA3C在调节中的RB/Cyclind/E2F网络对于B细胞永生很重要对KSHV和EBV对艾滋病毒潜伏期III淋巴瘤贡献的新见解的影响患者。