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Regulation of HSV Gene Expression by HCF

HCF 对 HSV 基因表达的调节

基本信息

批准号：
7595040
负责人：
ANGUS WILSON
金额：
$ 30.74万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7595040
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-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 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

项目摘要

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 periodicepisodes 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 DMA- 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 1we will 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 DMAdouble-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.

本研究旨在探讨宿主细胞因子-1（HCF-1）在单纯疱疹病毒（HSV）生命调控中的作用周期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，角膜疤痕和危及生命的脑炎上皮细胞中的生产性或溶解性感染由以下启动：病毒转录因子VP 16，其从病毒体释放到胞质溶胶中。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也定植于感觉神经元，在那里它可以建立潜伏期，重新出现为局部溶解性复制的尽管进行了广泛的分析，但阻止潜伏性细胞裂解复制的分子障碍仍然存在。神经元仍然难以捉摸。IE基因表达不足可能是一个重要的影响因素。HCF-1 在大多数细胞的细胞核中发现，作为细胞增殖的必需转录辅因子，胞质分裂然而，在神经元中，HCF-1位于细胞质中，但在DMA作用下移动到细胞核中。有害物质、毒素或机械应力。同样的刺激诱导潜伏的HSV重新进入裂解细胞，复制，暗示HCF-1定位和HSV裂解性复制之间的因果关系。这该提案研究了控制HCF-1在不同区域的定位和功能的机制。原子核我们专注于HPIP和Brd 7，这两种细胞蛋白与HCF-1的保守结构域结合。HPIP 是一种穿梭因子，将HCF-1从细胞核输出到胞质溶胶。我们的研究表明，HPIP存在于在Aim 1中，我们将研究允许HPIP在这些细胞质和线粒体之间分配的信号细胞质区室，并更精确地定义线粒体内的定位。Brd 7是一个染色质结合布罗莫结构域蛋白和异位表达引起核仁的主要变化，结构，导致压力传感器p53的稳定和HCF-1在新的核仁中的掺入。结构.当细胞持续DNA双链断裂时，也会发生类似的变化，我们假设， HCF-1和Brd 7是响应基因组损伤的关键参与者。目的2研究分子 Brd 7和HCF-1启动核仁分解的机制，目的3解决了生理学上的细胞周期、rRNA转录和HSV裂解性复制方面的后果。