REGULATION OF HSV GENE EXPRESSION BY HCF

HCF 对 HSV 基因表达的调节

• 批准号: 6520215
• 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/6520215
• 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; 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（取自研究者的摘要）：疱疹的生产感染 通过病毒编码的转录因子刺激单纯形病毒（HSV） VP16，它与细胞转录因子HCF-1相关联 在五个病毒的即时（IE）基因上的每个病毒蛋白-DNA复合物上 发起人。 HSV无法表达足够水平的IE基因产品 导致在适当的细胞类型中建立潜在感染 作为感官神经元。 HCF-1对病毒生产周期的重要性是 通过有条件的细胞感染最清楚地证明了 HCF-1的灭活版。这会导致病毒基因显着延迟 表达并严重降低病毒产量。威尔逊博士提出 HCF-1在感觉神经元中的活性或定位差异 有助于建立或维持病毒潜伏期。在这些 细胞，HCF-1主要在细胞质中发现，与大多数形成鲜明对比 HCF-1主要是核的其他细胞类型。促进的信号 重新激活还会触发HCF-1快速重新定位到核。到 他们已经确定了一种新型的HCF-1相关蛋白 可能是负责的核质班车因子的特征 HCF-1在神经元中的动态定位。 HCF-1的调节 本地化在其他情况下也可能很重要。 HCF-1是必需的 通过许多DNA结合蛋白的转录激活和丧失 HCF-1导致细胞周期的G1阶段停滞。这个目的 建议是：（目标1）了解VP16和新型班车蛋白如何 （指定的HPIP）有选择地靶向HCF-1，而不是近距离的靶向 HCF-2; （AIM 2）证明候选者对IE基因表达的抑制 穿梭蛋白（HPIP）并在感觉神经元中建立其作用方式 其他细胞类型； （目标3）检验HCF-1刺激IE基因的假设 通过与与站点结合的其他转录因子相互作用来激活 每个IE启动子中VP16响应元件的侧面。调查员 表明HCF-1在启动病毒IE基因表达中的关键作用 是设计新治疗策略的重要目标 作战是由HSV感染引起的人类疾病。