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The Gonda Center of Molecular Microbiology, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

Address correspondence to T. Kleinberger, The Gonda Center of Molecular Microbiology, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel. Tel.: 972-4-829-5257. Fax: 972-4-829-5225. E-mail: tamark{at}tx.technion.ac.il

Adenovirus early region 4 open reading frame 4 (E4orf4) protein has been reported to induce p53-independent, protein phosphatase 2A (PP2A)–dependent apoptosis in transformed mammalian cells. In this report, we show that E4orf4 induces an irreversible growth arrest in Saccharomyces cerevisiae at the G₂/M phase of the cell cycle. Growth inhibition requires the presence of yeast PP2A-Cdc55, and is accompanied by accumulation of reactive oxygen species. E4orf4 expression is synthetically lethal with mutants defective in mitosis, including Cdc28/Cdk1 and anaphase-promoting complex/cyclosome (APC/C) mutants. Although APC/C activity is inhibited in the presence of E4orf4, Cdc28/Cdk1 is activated and partially counteracts the E4orf4-induced cell cycle arrest. The E4orf4–PP2A complex physically interacts with the APC/C, suggesting that E4orf4 functions by directly targeting PP2A to the APC/C, thereby leading to its inactivation. Finally, we show that E4orf4 can induce G₂/M arrest in mammalian cells before apoptosis, indicating that E4orf4-induced events in yeast and mammalian cells are highly conserved.

Key Words: adenovirus; E4orf4; PP2A; anaphase-promoting complex/cyclosome; yeast

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