{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T22:54:22Z","timestamp":1783551262958,"version":"3.55.0"},"reference-count":92,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2015,5,7]],"date-time":"2015-05-07T00:00:00Z","timestamp":1430956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["399\/11"],"award-info":[{"award-number":["399\/11"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Deutsche Forschungsgemeinschaft (DFG) within the framework of the German-Israeli Project Cooperation (DIP)","award":["KL 2275\/1-1"],"award-info":[{"award-number":["KL 2275\/1-1"]}]},{"DOI":"10.13039\/501100003975","name":"Israel Cancer Association","doi-asserted-by":"publisher","award":["20150008"],"award-info":[{"award-number":["20150008"]}],"id":[{"id":"10.13039\/501100003975","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001698","name":"Israel Cancer Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001698","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Rappaport Faculty of Medicine and Research Institute, Technion \u2013 Israel Institute of Technology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/v7052334","type":"journal-article","created":{"date-parts":[[2015,5,7]],"date-time":"2015-05-07T10:54:29Z","timestamp":1430996069000},"page":"2334-2357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mechanisms of Cancer Cell Killing by the Adenovirus  E4orf4 Protein"],"prefix":"10.3390","volume":"7","author":[{"given":"Tamar","family":"Kleinberger","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Technion\u2014Israel Institute of Technology,  1 Efron St., Bat Galim, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9381","DOI":"10.1128\/JVI.00791-08","article-title":"Adenovirus E4orf4 protein downregulates MYC expression through interaction with the PP2A-B55 subunit","volume":"82","author":"Sharf","year":"2008","journal-title":"J. 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