Cellular functions of hub proteins and their deregulation by adenovirus

蜂窝调节网络本质上是冗余的，代表了一个多节点无尺度网络，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出现关键的网络故障。细胞调节网络的固有弱点在于网络功能的关键调节因子，即“枢纽蛋白”。病毒已经进化出精巧的方法来瞄准这些集线器，以重塑网络并使病毒传播和逃避宿主。因此，利用病毒蛋白重塑细胞提供了一种有用的方法来识别重要过程的关键细胞调节因子。通过与腺病毒即时早期基因产物E1A的结合，我发现了两种新的细胞调节因子：DREF和FUBP1。人们对这两种蛋白质知之甚少，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。FUBP1是一种通过与基因调控区域内的增强子结合以及调节蛋白质翻译而在转录调控中发挥作用的蛋白。

Cellular regulatory networks are inherently redundant, representing a multi-node scale-free network that is resistant to disruptions. This type of organization is necessary 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". Viruses have evolved exquisite ways in which to target these hubs in order to remodel the network and enable virus 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. The E1A protein of adenovirus is a small protein composed of 289 amino acids in 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. Recent NSERC--funded studies in my laboratory have begun to unravel the mysteries of cellular hub proteins. We have discovered new functions of DREF and FUBP1, in large part thanks to my use of E1A as a molecular probe for dissection of cellular pathways. Work in my lab has identified, for the first time, that DREF is a component of cellular innate immune response and it is deregulated by alteration of its SUMOylation by E1A during virus-driven cellular reprogramming. My lab has also shown that FUBP1 is utilized by E1A to suppress cellular stress response pathway by locking FUBP1 in a complex with the cellular stress regulator p53, preventing p53 from carrying out its functions. These studies only scratch the surface of what the pathways and functions are of DREF and FUBP1, paving the way for further investigations. Study of E1A--binding proteins teaches us not only about E1A but also about the proteins that bind to it. Importantly, discovery of novel E1A-binding proteins identifies key cellular hubs that can be studied using this powerful viral tool. My research program focuses on the identification and characterizaton of cellular hub proteins to better understand their role in cellular processes governing eukaryotic life. In the short term, studies of DREF and FUBP1, and their association with E1A, will clarify their cellular functions and elucidate the reasons behind their targeting by a virus.