Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome

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.

Viral infections and cell cycle G2/M regulation

“…Similar to the Vpr effects, both adenoviral E4orf4 [63][64][65] and HTLV Tax protein induce cell cycle G2 arrest [59]. These two viral proteins both bind to PP2A and affect its enzymatic activity [63,66]. Interestingly, similar to Vpr, Tax-induced G2 arrest is reversed by caffeine [59].…”

“…Even though these viruses are not otherwise related, they all seem to have adapted a similar strategy to affect cellular processes by direct interaction with PP2A. Similar to the Vpr effects, both adenoviral E4orf4 [63][64][65] and HTLV Tax protein induce cell cycle G2 arrest [59]. These two viral proteins both bind to PP2A and affect its enzymatic activity [63,66].…”

Human Gyrovirus-Apoptin Interferes with the Cell Cycle and Induces G2/M Arrest Prior to Apoptosis

“…Two viral PKTCs E4orF4 and CAV-Apoptin kill cancer cells by interference with the cell cycle, and by induction of G2/M arrest and apoptosis (Kornitzer et al 2001;Lanz et al 2013;Maddika et al 2009). Earlier research from our group shows that CAV-apoptin presence in the cell leads to the activation of CDK2, and that the activated CDK2 is responsible for the phosphorylation of CAVApoptin at critical for nuclear retention, Thr-108 (Maddika et al 2009).…”

“…The adenoviral protein E4orF4 induces G2/M arrest and apoptosis in cancer cells in a p53-independent manner (Kornitzer et al 2001). In addition to E4orF4, CAVApoptin, another avian-derived viral PKTC, also induces G2/M cell cycle arrest and apoptosis in a p53-independent manner in human malignant cells, while having no deleterious effect on normal cells.…”

Fusion protein of adenovirus E4orf4 and human epidermal growth factor inhibits tumor cell growth

“…The E4orf4 induced apoptosis is p53 protein-independent 7-9 and may activate some signals through interaction with protein phosphatase 2A (PP2A) [10][11][12][13] and Src kinase. [14][15][16] Although the mechanism is yet not clear, some methods such as gene therapy have been developed to use E4orf4 in cancer therapy.…”