Abstract |
The adenovirus E4orf4 protein regulates the progression of viral infection, and when expressed alone in mammalian tissue culture cells it induces protein phosphatase 2A (PP2A)-B55- and Src-dependent cell death, which is more efficient in oncogene-transformed cells than in normal cells. This form of cell death is caspase-independent, although it interacts with classic caspase-dependent apoptosis. PP2A-B55-dependent E4orf4-induced toxicity is highly conserved in evolution from yeast to mammalian cells. In this work we investigated E4orf4-induced cell death in a whole multicellular organism, Drosophila melanogaster. We show that E4orf4 induced low levels of cell killing, caused by both caspase-dependent and -independent mechanisms. Drosophila PP2A-B55 (twins/abnormal anaphase resolution) and Src64B contributed additively to this form of cell death. Our results provide insight into E4orf4-induced cell death, demonstrating that in parallel to activating caspase-dependent apoptosis, E4orf4 also inhibited this form of cell death induced by the proapoptotic genes reaper, head involution defective, and grim. The combination of both induction and inhibition of caspase-dependent cell death resulted in low levels of tissue damage that may explain the inefficient cell killing induced by E4orf4 in normal cells in tissue culture. Furthermore, E4orf4 inhibited JNK-dependent cell killing as well. However, JNK inhibition did not impede E4orf4-induced toxicity and even enhanced it, indicating that E4orf4-induced cell killing is a distinctive form of cell death that differs from both JNK- and Rpr/Hid/Grim-induced forms of cell death.
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Authors | Antonina Pechkovsky, Maoz Lahav, Eliya Bitman, Adi Salzberg, Tamar Kleinberger |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 110
Issue 19
Pg. E1724-33
(May 07 2013)
ISSN: 1091-6490 [Electronic] United States |
PMID | 23613593
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Drosophila Proteins
- E4orf4 protein, adenovirus
- Viral Proteins
- src-Family Kinases
- Phosphoprotein Phosphatases
- tws protein, Drosophila
- Caspases
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Topics |
- Animals
- Apoptosis
- Caspases
(metabolism)
- Conserved Sequence
- Drosophila Proteins
(metabolism)
- Drosophila melanogaster
(metabolism)
- Female
- Gene Expression Regulation, Enzymologic
- Male
- Models, Genetic
- Phenotype
- Phosphoprotein Phosphatases
(metabolism)
- Photoreceptor Cells, Invertebrate
(physiology)
- Transgenes
- Viral Proteins
(genetics, metabolism)
- Wings, Animal
(physiology)
- src-Family Kinases
(metabolism)
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