REGULATION OF HSV GENE EXPRESSION BY HCF

描述(摘自调查者摘要)：疱疹的生产性感染 单纯疱疹病毒(HSV)由病毒编码的转录因子刺激 VP16，它与细胞转录因子HCF-1结合形成一个 5种病毒即刻早期(IE)基因上的多蛋白-DNA复合体 推动者。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，如 作为感觉神经元。HCF-1在病毒生产周期中的重要性是 最明显的证明是有条件地感染细胞 灭活版的HCF-1。这导致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 人绒毛膜促性腺激素释放因子-1在感觉神经元的活性或定位差异 有助于建立或维持病毒潜伏期。在这些 细胞中，hcf-1主要存在于细胞质中，这与大多数 其他类型的细胞，其中HCF-1以核为主。促进的信号 重新激活也会引发HCF-1迅速重新定位到细胞核。至 为此，他们发现了一种新的与HCF-1相关的蛋白质 可能与核质穿梭因子有关的特性 用于HCF-1在神经元中的动态定位。人绒毛膜促性腺激素-1的调控 本地化在其他情况下也可能很重要。需要HCF-1才能 一些DNA结合蛋白的转录激活和丢失 HCF-1使细胞周期停滞于G1期。这样做的目的是 建议是：(目标1)了解VP16和新的穿梭蛋白如何 (指定为HPIP)选择性地以HCF-1为目标，而不是近亲 Hcf-2；(目标2)显示候选人抑制IE基因的表达 穿梭蛋白(HPIP)，并建立其在感觉神经元和 其他细胞类型；以及(目标3)检验HCF-1刺激IE基因的假设 通过与结合位点的额外转录因子相互作用而激活 在每个IE启动子的VP16反应元件两侧。调查员 提示HCF-1在启动病毒IE基因表达中起关键作用 代表了设计新的治疗策略的重要目标 抗击由单纯疱疹病毒感染引起的人类疾病。

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.