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

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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.********