REGULATION OF HSV GENE EXPRESSION BY HCF

HCF 对 HSV 基因表达的调控

• 批准号: 6636431
• 负责人: ANGUS WILSON
• 金额: $ 27.09万
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636431
• 关键词: Alphaherpesvirinae; chimeric proteins; gene expression; genetic regulation; laboratory mouse; neurons; protein localization; tissue /cell culture; transcription factor; transfection; virus genetics; virus protein

DESCRIPTION (taken from Investigator's abstract):Productive infection by herpes simplex virus (HSV) is stimulated by the virally-encoded transcription factor VP16, which associates with the cellular transcription factor HCF-1 to form a multiprotein-DNA complex on each of the five viral immediate-early (IE) gene promoters. Failure of HSV to express sufficient levels of IE gene products may lead to the establishment of a latent infection in appropriate cell types such as sensory neurons. The importance of HCF-1 to the viral productive cycle is most clearly demonstrated by infection of cells with a conditionally inactivated version of HCF-1. This results in a significant delay in viral gene expression and severely reduced virus yield. Dr. Wilson proposes that differences in the activity or localization of HCF-1 in sensory neurons contribute to the establishment or maintenance of viral latency. In these cells, HCF-1 is found predominantly in cytoplasm, a striking contrast to most other cell types where HCF-1 is predominantly nuclear. Signals that promote reactivation also trigger a rapid relocalization of HCF-1 to the nucleus. To this end, they have identified a novel HCF-1 associated protein with characteristics of a nucleocytoplasmic shuttle factor that may be responsible for the dynamic localization of HCF-1 in neurons. Regulation of HCF-1 localization may also be important in other contexts. HCF-1 is required for transcriptional activation by a number of DNA-binding proteins and loss of HCF-1 leads to an arrest in G1 phase of the cell cycle. The aims of this proposal are to: (Aim 1) understand how VP16 and the novel shuttle protein (designated HPIP) selectively target HCF-1 rather than the close-relative HCF-2; (Aim 2) demonstrate suppression of IE gene expression by the candidate shuttle proteins (HPIP) and establish its mode of action in sensory neurons and other cell types; and (Aim 3) test the hypothesis that HCF-1 stimulates IE gene activation by interacting with additional transcription factors bound to sites flanking the VP16-responsive elements in each IE promoter. The investigator suggests that the pivotal role of HCF-1 in initiating viral IE gene expression represents an important target for the design of new therapeutic strategies to combat human diseases that arise from HSV infection.

描述（摘自研究者摘要）：疱疹引起的生产性感染 单纯病毒（HSV）由病毒编码的转录因子刺激 VP 16，它与细胞转录因子HCF-1结合形成 5种病毒即早（IE）基因中每一种上的多蛋白-DNA复合物 发起人。HSV不能表达足够水平的IE基因产物可能 导致在适当的细胞类型中建立潜伏感染， 作为感觉神经元。HCF-1对病毒生产周期的重要性是 最清楚地证明了感染细胞的条件 HCF-1的灭活版本。这导致了病毒基因的显著延迟， 表达并严重降低病毒产量。威尔逊博士建议， 感觉神经元中HCF-1活性或定位的差异 有助于病毒潜伏期的建立或维持。在这些 HCF-1主要存在于细胞质中，与大多数细胞形成鲜明对比。 HCF-1主要是核的其他细胞类型。促进的信号 重新激活还引发HCF-1快速重新定位到细胞核。到 为此，他们鉴定了一种新的HCF-1相关蛋白， 核质穿梭因子的特性， 用于HCF-1在神经元中的动态定位。HCF-1的调节 本地化在其它环境中也可能是重要的。需要HCF-1 转录激活的DNA结合蛋白和损失的数量 HCF-1导致细胞周期停滞在G1期。其目的是 目的1：了解VP 16和新型穿梭蛋白如何在细胞内表达， （指定为HPIP）选择性靶向HCF-1，而不是近亲 HCF-2;（目的2）证明候选物抑制IE基因表达 穿梭蛋白（HPIP），并建立其在感觉神经元中的作用模式， 目的3：验证HCF-1刺激IE基因的假说 通过与结合位点的额外转录因子相互作用激活 位于每个IE启动子中的VP 16应答元件的侧翼。研究者 提示HCF-1在启动病毒IE基因表达中的关键作用 代表了设计新治疗策略的重要目标， 对抗由HSV感染引起的人类疾病。