During adenovirus (Ad) replication the Ad E4orf4
protein regulates progression from the early to the late phase of
infection. However, when E4orf4 is expressed alone outside the context of the virus it induces a non-canonical mode of programmed cell death, which feeds into known cell death pathways such as apoptosis or
necrosis, depending on the cell line tested. E4orf4-induced cell death has many interesting and unique features including a higher susceptibility of
cancer cells to E4orf4-induced cell killing compared with normal cells,
caspase-independence, a high degree of evolutionary conservation of the signaling pathways, a link to perturbations of the cell cycle, and involvement of two distinct cell death programs, in the nucleus and in the cytoplasm. Several E4orf4-interacting
proteins including its major partners,
protein phosphatase 2A (PP2A) and
Src family kinases, contribute to induction of cell death. The various features of E4orf4-induced cell killing as well as studies to decipher the underlying mechanisms are described here. Many explanations for the
cancer specificity of E4orf4-induced cell death have been proposed, but a full understanding of the reasons for the different susceptibility of
cancer and normal cells to killing by E4orf4 will require a more detailed analysis of the complex E4orf4 signaling network. An improved understanding of the mechanisms involved in this unique mode of programmed cell death may aid in design of novel E4orf4-based
cancer therapeutics.