The broad objective of this research is to understand how the regulation of gene expression by specific transcription factors impacts on the proliferative capacity of cells and the growth properties of DNA tumor viruses. The model system that we study is the regulation of the E2F family of transcription factors by adenovirus infection. E2F transcription factors are key players in the regulation of proliferation, apoptosis, and differentiation. The central role that the E2F family plays in the regulation of cell growth and death is underscored by the fact that the E2F-retinoblastoma tumor suppressor regulatory cascade is found mutated or deregulated in virtually all human cancers. E2F over-expression or conversely the loss of E2F expression promotes tumor formation in animal models, and E2F plays a key role in the regulation of p53-mediated apoptosis. Thus, the regulation of gene expression by E2Fs makes life or death decisions for the cell, and impacts on two key growth suppression pathways, the Rb pathway and the p53 pathway. E2Fs are regulated at multiple levels and by different mechanisms. The loss of E2F regulation leads to the induction of cell cycle arrest and apoptosis. Adenovirus proteins impact on many of the processes that regulate E2F activity. We have made novel observations concerning the regulation of E2F by adenovirus proteins in three different areas.
The specific aims of this proposal are: 1) To determine the mechanisms by which adenovirus infection increases E2F protein levels and induces cell growth arrest; 2) To understand the regulation of E2F transactivation by the Ad E1A and E4-6/7 proteins; and 3) To study the regulation of E2F localization by the Ad E1A and E4-6/7 proteins. The proposed studies will provide new insights into the molecular mechanisms that regulate E2F activity and how adenovirus proteins impact on both cellular and viral growth properties.
