Moore, M.; Kong, J.; Akmel, A.; Thomas, M. A.

Abnormal DNA levels, such as aneuploidy and polyploidy, can indicate cellular transformation and cancer; however, the mechanisms remain poorly understood. All tumor viruses inherently cause abnormal DNA content in cells due to their oncogenes. During infections, adenovirus (Ad) oncogenes--early region 1A (E1A), early region 4 open reading frame 3 (E4orf3), and E4 open reading frame 1 (E4orf1)--promote the abnormal buildup of cellular DNA. Previous studies have described how E1A and E4orf3 cause infected cells to accumulate abnormal DNA content; however, the role of E4orf1 remains speculative. In this study, we generated cells that express E4orf1 to investigate its role in abnormal DNA content. The E4orf1-expressing cells initially showed no increase in DNA content compared to the control group. However, after Ad infection, they displayed higher ploidy levels. To detail how E4orf1 influences ploidy levels in Ad-infected cells, we employed pharmacological agents that target E4orf1 signaling. Our results show that E4orf1 enhances signaling from insulin and growth factor receptors to AKT and NF-{kappa}B, creating a feedback loop that elevates levels of cellular DNA in Ad-infected cells. This study provides insights into E4orf1 signaling, which is significant due to its conservation across human Ads.