Induction of cancer-specific cell death by the adenovirus E4orf4 protein.

The adenovirus E4orf4 protein is a multifunctional viral regulator that contributes to temporal regulation of the progression of viral infection. When expressed alone, outside the context of the virus, E4orf4 induces p53-independent cell-death in transformed cells. Oncogenic transformation of primary cells in tissue culture sensitizes them to cell killing by E4orf4, indicating that E4orf4 research may have implications for cancer therapy. It has also been reported that E4orf4 induces a caspase-independent, non-classical apoptotic pathway, which maintains crosstalk with classical caspase-dependent pathways. Furthermore, several E4orf4 activities in the nucleus and in the cytoplasm and various protein partners contribute to cell killing by this viral protein. In the following chapter I summarize the current knowledge of the unique mode of E4orf4-induced cell death and its underlying mechanisms. Although several explanations for the cancer-specificity of E4orf4-induced toxicity have been proposed, a better grasp of the mechanisms responsible for E4orf4-induced cell death is required to elucidate the differential sensitivity of normal and cancer cells to E4orf4.