Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anaphase-Promoting Complex-Cyclosome
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Benomyl / pharmacology
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CDC28 Protein Kinase, S cerevisiae / antagonists & inhibitors
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CDC28 Protein Kinase, S cerevisiae / metabolism
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Cell Cycle / drug effects
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Cell Division / drug effects
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Cell Line
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Enzyme Activation / drug effects
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G2 Phase / drug effects
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Gene Expression
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Genes, Lethal
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Humans
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Ligases / metabolism*
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Macromolecular Substances
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Mitosis / drug effects
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Phosphoprotein Phosphatases / metabolism*
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Protein Phosphatase 2
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Reactive Oxygen Species / metabolism
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Saccharomyces cerevisiae / cytology
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / metabolism*
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Transfection
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Ubiquitin-Protein Ligase Complexes*
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Ubiquitin-Protein Ligases
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Viral Proteins / genetics
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Viral Proteins / metabolism*
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Viral Proteins / pharmacology
Substances
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E4orf4 protein, adenovirus
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Macromolecular Substances
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Reactive Oxygen Species
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Viral Proteins
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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Ubiquitin-Protein Ligases
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CDC28 Protein Kinase, S cerevisiae
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Ligases
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Benomyl