Role of PML nuclear body proteins for establishment of EBV latent infection

PML核体蛋白在EBV潜伏感染建立中的作用

• 批准号: 7629627
• 负责人: Paul Dalling Ling
• 金额: $ 25.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-26 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629627
• 关键词: Acquired Immunodeficiency Syndrome; Acute Promyelocytic Leukemia; Address; Amino Acids; Antiviral Agents; B Cell Proliferation; B lymphocyte immortalization; B-Cell Lymphomas; B-Lymphocytes; Cell Line; Cells; Collection; Complex; Defense Mechanisms; Development; Dimerization; Dominant-Negative Mutation; Gene Expression; Genes; Genome; Goals; HIV; Herpesviridae; Human; Human Herpesvirus 4; Investigation; Knowledge; Laboratories; Lead; Location; Malignant Neoplasms; Mediating; Modeling; Notch Signaling Pathway; Nuclear; Patients; Proteins; Publications; RNA Interference; Relative (related person); Research; Role; Testing; Therapeutic; Transcription Coactivator; Transcriptional Activation; Viral; Viral Genes; Virus; Work; base; cell transformation; cofactor; design; immunosuppressed; inhibitor/antagonist; insight; interest; latent infection; mimicry; practical application; promoter; protein function; transcription factor; transforming virus

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is one of the most potent transforming viruses and it is found in several human cancers, including B cell lymphomas in patients with AIDS who are immunosuppressed by HIV. The long- term goal of our laboratory is to understand how EBV latent proteins mediate B cell transformation. Of particular interest are the EBNA2 and EBNA-LP transcription factors. EBNA2 functions in part through mimicry of cellular Notch signaling pathways to induce expression of viral and cellular genes. EBNA-LP is a coactivator of EBNA2, but the mechanism(s) by which it coactivates EBNA2 remains elusive. Recent observations from our laboratory indicate that EBNA-LP interacts with and displaces the promyelocytic nuclear body (PML NB) protein Sp100 from PML NBs, suggesting that Sp100 is an important cellular cofactor that mediates EBNA-LP coactivation function. In addition, we have demonstrated that EBNA2 amino acid residues 1-58 comprise an oligomerization domain that is able to act as a dominant negative inhibitor of EBNA2 transcriptional activation function. To further clarify how Sp100 mediates EBNA-LP coactivation function and to test whether the EBNA2 oligomerization domain can be harnessed to inhibit EBV-driven B cell immortalization, we have developed the following aims: 1) To determine how EBNA-LP mediates Sp100 displacement from PML NBs and if Sp100 is essential for EBNA2 coactivation, 2) To determine the mechanism by which Sp100 contributes to EBNA-LP coactivation function, and 3) To determine whether dominant negative forms of EBNA2 can inhibit EBV-induced B lymphocyte immortalization. Herpesviruses modify and/or modulate PML and PML-associated NB proteins. However, it remains unclear whether PML NBs are a collection of proteins that mediate an antiviral cellular defense mechanism that herpesviruses have evolved to counteract or if viruses co-opt factors in PML-NBs to their advantage to help facilitate virus gene expression and/or replication. Our investigations into the unique interaction between EBNA-LP and Sp100 will help to yield new insights into the relationship of herpesviruses and PML NBs. Design of EBNA2 and/or EBNA-LP inhibitors is a potential practical application that will be derived from our studies.

描述（由申请人提供）：EB病毒（EBV）是最有效的转化病毒之一，在几种人类癌症中发现，包括HIV免疫抑制的AIDS患者的B细胞淋巴瘤。我们实验室的长期目标是了解EB病毒潜伏蛋白如何介导B细胞转化。特别感兴趣的是EBNA 2和EBNA-LP转录因子。EBNA 2部分通过模拟细胞Notch信号传导途径来诱导病毒和细胞基因的表达。EBNA-LP是EBNA 2的共活化剂，但其共活化EBNA 2的机制仍然难以捉摸。我们实验室最近的观察表明，EBNA-LP与早幼粒细胞核体（PML NB）蛋白Sp100相互作用并从PML NB中置换，这表明Sp100是介导EBNA-LP共激活功能的重要细胞辅因子。此外，我们已经证明EBNA 2氨基酸残基1-58包含能够作为EBNA 2转录激活功能的显性负抑制剂的寡聚化结构域。为了进一步阐明Sp100如何介导EBNA-LP共激活功能，并测试EBNA 2寡聚化结构域是否可用于抑制EBV驱动的B细胞永生化，我们开发了以下目标：1）为了确定EBNA-LP如何介导Sp100从PML NB的置换以及Sp100是否是EBNA 2共活化所必需的，2）确定Sp100参与EBNA-LP共激活功能的机制; 3）确定EBNA 2的显性阴性形式是否能抑制EBV诱导的B淋巴细胞永生化。疱疹病毒修饰和/或调节PML和PML相关NB蛋白。然而，目前尚不清楚PML NB是否是介导疱疹病毒已经进化以抵消的抗病毒细胞防御机制的蛋白质集合，或者病毒是否利用PML-NB中的因子来帮助促进病毒基因表达和/或复制。我们对EBNA-LP和Sp100之间独特相互作用的研究将有助于对疱疹病毒和PML NB之间的关系产生新的见解。EBNA 2和/或EBNA-LP抑制剂的设计是一个潜在的实际应用，将来自我们的研究。