Role of cellular factors FUBP1 and DREF in regulation of viral and cellular gene expression via adenovirus E1A.

细胞因子 FUBP1 和 DREF 在通过腺病毒 E1A 调节病毒和细胞基因表达中的作用。

• 批准号: 435375-2013
• 负责人: Pelka, Peter
• 金额: $ 2.33万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=596661
• 关键词: Role; cellular; factors; FUBP1; DREF

Cellular regulatory networks are inherently redundant, representing a multi-node scale-free network that is resistant to disruptions. This type of organization is necessary in order to avoid critical network failure upon disruption of a single node. The inherent weakness of a cellular regulatory network lies in key regulators of network function, known as "hub proteins". Pathogens have evolved exquisite ways in which to target these hubs in order to remodel the network and enable pathogen propagation and host evasion. Therefore, utilization of viral proteins that remodel the cell provides a useful means of identifying key cellular regulators of important processes. I have identified two novel cellular regulators by their virtue of binding to the adenovirus immediate early gene product E1A: DREF and FUBP1. Both of these proteins are poorly understood and their function within cells is enigmatic. DREF is a transcriptional regulator that is involved in activation of cell cycle and growth control genes. FUBP1 is a protein that appears to play a role in transcriptional regulation by binding to enhancers within gene regulatory regions as well as regulating protein translation by interacting with untranslated regions within mRNAs. The E1A protein of adenovirus is a small protein composed of 289 amino acids for the largest isoform. E1A can be considered a "hub detector" because of its ability to target key cellular regulators. E1A has been an invaluable tool in the study and understanding of a wide variety of cellular processes. E1A is encoded by a gene that contains 2 exons. Exon 1 codes for a region of E1A that has been found to bind to a large number of cellular proteins, modulating their function. Exon 2 of E1A encodes for 103 amino acids that comprise more than a third of the total size of E1A yet very few proteins have been found to bind in that region. I have added to the limited list of proteins binding to the region encoded by exon 2 by showing that DREF and FUBP1 bind to E1A within that region. Study of E1A-binding proteins teaches us not only about E1A but also about the proteins that bind to it. By studying DREF and FUBP1 and their association with E1A we will learn more about their cellular functions and why a viral protein targets them.

细胞调控网络具有内在冗余性，代表了一个多节点的无标度网络，可以抵抗中断。这种类型的组织是必要的，以避免在单个节点中断时发生关键网络故障。细胞调控网络的固有弱点在于网络功能的关键调控因子，称为“枢纽蛋白”。病原体已经进化出针对这些枢纽的精妙方式，以重塑网络，使病原体繁殖和宿主逃避成为可能。因此，利用病毒蛋白重塑细胞提供了一个有用的手段，确定重要的过程中的关键细胞调节。通过与腺病毒立即早期基因产物E1A的结合，我鉴定了两种新的细胞调节因子：DREF和FUBP 1。这两种蛋白质都知之甚少，它们在细胞内的功能也是个谜。DREF是一种转录调节因子，参与细胞周期和生长控制基因的激活。FUBP 1是一种蛋白质，其似乎通过结合基因调控区内的增强子以及通过与mRNA内的非翻译区相互作用来调节蛋白质翻译而在转录调控中发挥作用。腺病毒的E1A蛋白是由289个氨基酸组成的最大同种型的小蛋白。E1A可以被认为是一个“枢纽检测器”，因为它能够靶向关键的细胞调节因子。E1A是研究和理解各种细胞过程的宝贵工具。E1A由一个包含2个外显子的基因编码。外显子1编码E1A的一个区域，该区域已被发现与大量细胞蛋白质结合，调节其功能。E1A的外显子2编码103个氨基酸，占E1A总大小的三分之一以上，但很少有蛋白质被发现在该区域结合。我已经通过显示DREF和FUBP 1与该区域内的E1A结合，增加了与外显子2编码区域结合的蛋白质的有限列表。对E1A结合蛋白的研究不仅告诉我们E1A，而且告诉我们与E1A结合的蛋白质。通过研究DREF和FUBP 1及其与E1A的关系，我们将更多地了解它们的细胞功能以及为什么病毒蛋白质靶向它们。