Regulation of HSV Gene Expression by HCF

HCF 对 HSV 基因表达的调节

• 批准号: 7201649
• 负责人: ANGUS WILSON
• 金额: $ 30.65万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201649
• 关键词: Acetylation; Address; Afferent Neurons; Area; Binding; Bromodomain; Cell Cycle; Cell Cycle Regulation; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cells; Chromatin; Complex; Cues; Cultured Cells; Cytokinesis; Cytoplasmic Granules; Cytosol; DNA Damage; DNA Double Strand Break; DNA-Binding Proteins; Disease; Early Gene Transcriptions; Ectopic Expression; Encephalitis; Epithelial Cells; Fibronectins; Funding; Gene Expression; Genetic Transcription; Genomics; Goals; Herpes Simplex Virus Protein Vmw65; Histones; Human; Immediate-Early Genes; Infection; Kinetics; Lead; Lesion; Life; Life Cycle Stages; Localized; Lytic; Lytic Phase; Mechanical Stress; Mediating; Mitochondria; Molecular; Molecular Target; Movement; N-terminal; Neurons; Nuclear; Nuclear Export; Pain; Pathway interactions; Physiological; Protein Binding; Proteins; Regulation; Repression; Ribosomal RNA; Role; Signal Transduction; Simplexvirus; Stimulus; Stress; Structure; System; TP53 gene; Toxin; Transcriptional Activation; VP 16; Viral; Virion; Virus; Virus Replication; base; biological adaptation to stress; cofactor; corneal scar; lytic replication; novel; nucleocytoplasmic transport; nucleolin; pathogen; prevent; reactivation from latency; response; sensor; transcription factor

DESCRIPTION (provided by applicant): This project addresses the role of host cell factor-1 (HCF-1) in regulating the herpes simplex virus (HSV) life cycle. HSV is an important human pathogen responsible for a spectrum of diseases including painful lesions, corneal scarring and life-threatening encephalitis. Productive or lytic infection in epithelial cells is initiated by the viral transcription factor VP16, which is released from the virion into the cytosol. There VP16 binds HCF- 1, translocates to the nucleus and together activates the HSV immediate-early (IE) genes. HSV also colonizes sensory neurons where it can establish latency, re-emerging as periodic episodes of localized lytic replication. In spite of extensive analyses, the molecular roadblocks preventing lytic replication in latent neurons remain elusive. Insufficient IE gene expression is likely to be an important contributing factor. HCF-1 is found in the nucleus of most cells, acting as an essential transcriptional cofactor for cell proliferation and cytokinesis. In neurons, however, HCF-1 is cytoplasmic but moves to the nucleus in response to DNA-damaging agents, toxins or mechanical stress. The same stimuli induce latent HSV to re-enter lytic replication, implying a causal relationship between HCF-1 localization and HSV lytic replication. This proposal investigates mechanisms that control localization and function of HCF-1 in different regions of the nucleus. We focus on HPIP and Brd7, two cellular proteins that bind to conserved domains of HCF-1. HPIP is a shuttle factor that exports HCF-1 from the nucleus to the cytosol. Our studies show that HPIP is found in both cytosol and mitochondrial and in Aim 1 we will examine the signals that allow HPIP to partition between these cytoplasmic compartments and more precisely define the localization within mitochondria. Brd7 is a chromatin-binding bromodomain protein and ectopic expression causes major changes in nucleolar structure, leading to stabilization of the stress-sensor p53 and incorporation of HCF-1 in novel nucleolar structures. Similar alterations occur when cells sustain DNA double-strand breaks and we hypothesize that HCF-1 and Brd7 are key players in the response to genomic insults. Aim 2 investigates the molecular mechanisms by which Brd7 and HCF-1 initiate nucleolar breakdown and Aim 3 addresses the physiological consequences with regard to cell cycle, rRNA transcription and HSV lytic replication.

描述（由申请人提供）：本项目旨在研究宿主细胞因子-1（HCF-1）在调节单纯疱疹病毒（HSV）生命周期中的作用。HSV是一种重要的人类病原体，可引起一系列疾病，包括疼痛性病变、角膜瘢痕和危及生命的脑炎。上皮细胞中的生产性或裂解性感染由病毒转录因子VP 16启动，其从病毒体释放到细胞质中。在那里，VP 16结合HCF- 1，易位到细胞核并一起激活HSV立即早期（IE）基因。HSV还定殖感觉神经元，在那里它可以建立潜伏期，作为局部裂解复制的周期性发作重新出现。尽管进行了广泛的分析，但阻止潜伏神经元裂解复制的分子障碍仍然难以捉摸。IE基因表达不足可能是一个重要的影响因素。HCF-1存在于大多数细胞的细胞核中，作为细胞增殖和胞质分裂的必需转录辅因子。然而，在神经元中，HCF-1是细胞质的，但在DNA损伤剂、毒素或机械应力的作用下移动到细胞核。相同的刺激诱导潜伏HSV重新进入裂解复制，这意味着HCF-1定位和HSV裂解复制之间的因果关系。该提案研究了控制HCF-1在细胞核不同区域的定位和功能的机制。我们专注于HPIP和Brd 7，这两种细胞蛋白与HCF-1的保守结构域结合。HPIP是将HCF-1从细胞核输出到细胞质的穿梭因子。我们的研究表明，HPIP被发现在细胞质和线粒体和目标1中，我们将检查信号，使HPIP之间的这些细胞质隔室和更精确地定义线粒体内的定位。Brd 7是一种染色质结合的布罗莫结构域蛋白，异位表达引起核仁结构的重大变化，导致压力传感器p53的稳定和HCF-1在新的核仁结构中的掺入。当细胞维持DNA双链断裂时，也会发生类似的改变，我们假设HCF-1和Brd 7是对基因组损伤反应的关键参与者。目的2研究Brd 7和HCF-1启动核仁分解的分子机制，目的3解决细胞周期，rRNA转录和HSV裂解复制方面的生理后果。