Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome.
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.
Kornitzer
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The Gonda Center of Molecular Microbiology, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Sharf
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Kleinberger
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D064173:Anaphase-Promoting Complex-Cyclosome; D001542:Benomyl / Q000494:pharmacology; D017489:CDC28 Protein Kinase, S cerevisiae / Q000037:antagonists & inhibitors / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D015870:Gene Expression; D005804:Genes, Lethal; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D046911:Macromolecular Substances; D008938:Mitosis / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
C121517:E4orf4 protein, adenovirus; D046911:Macromolecular Substances; D017382:Reactive Oxygen Species; D014764:Viral Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases; D017489:CDC28 Protein Kinase, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D008025:Ligases; D001542:Benomyl