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Viruses 2015, 7(5), 2334-2357; doi:10.3390/v7052334

Mechanisms of Cancer Cell Killing by the Adenovirus E4orf4 Protein

Department of Microbiology, Faculty of Medicine, Technion—Israel Institute of Technology, 1 Efron St., Bat Galim, Haifa 31096, Israel
Academic Editor: Joanna Parish
Received: 29 March 2015 / Revised: 23 April 2015 / Accepted: 30 April 2015 / Published: 7 May 2015
(This article belongs to the Special Issue Tumour Viruses)
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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. View Full-Text
Keywords: adenovirus; E4orf4; protein phosphatase 2A (PP2A); Src kinase; actin; Ynd1; Golgi UDPase; Acf1; SNF2h; cell-death; cell cycle; chromatin remodeling adenovirus; E4orf4; protein phosphatase 2A (PP2A); Src kinase; actin; Ynd1; Golgi UDPase; Acf1; SNF2h; cell-death; cell cycle; chromatin remodeling

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Kleinberger, T. Mechanisms of Cancer Cell Killing by the Adenovirus E4orf4 Protein. Viruses 2015, 7, 2334-2357.

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