The adenovirus E4orf4 protein: a cancer cell killer
The adenovirus E4orf4 protein is a multifunctional viral regulator.
When adenovirus infects cells, E4orf4 regulates the progression of virus infection from the early to the late phase. Our recent studies revealed that E4orf4 also inhibits the cellular DNA damage response, allowing efficient viral replication.
When E4orf4 is expressed alone in cells it induces non-classical, caspase-independent cell death which is more efficient in cancer cells than in normal cells. Thus the study of E4orf4 signaling may have implications for cancer therapy.
At least part of the E4orf4 signaling network is highly conserved in evolution from yeast through Drosophila to mammalian cells, underscoring its importance to cell regulation, and facilitating study of E4orf4 biology in various model organisms. Indeed, our studies of the mechanisms underlying E4orf4-induced cell death utilize genetic model systems such as yeast and Drosophila, as well as mammalian tissue culture cells.
Our studies revealed that interactions of E4orf4 with protein phosphatase 2A and with the ACF chromatin remodeling factor in the nucleus, as well as an interaction with a Golgi UDPase in the cytoplasm are important to E4orf4-induced cell death. Studies in Drosophila demonstrated that in parallel to induction of cell death, E4orf4 can also protect against apoptosis in normal fly tissues thus minimizing tissue damage. The ability of E4orf4 to induce cell death more efficiently in cancer cells in vivo is currently under study.
Understanding the mechanisms underlying E4orf4 functions will allow us to probe why cancer cells are more sensitive to killing by this viral protein and will pave the way to future design of new E4orf4-based modes of cancer therapy.