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  • Original Paper
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Toxicity of human adenovirus E4orf4 protein in Saccharomyces cerevisiae results from interactions with the Cdc55 regulatory B subunit of PP2A

Oncogene volume 20, pages 5279–5290 (2001)Cite this article

Abstract

The E4orf4 protein of human adenovirus induces p53-independent apoptosis, a process that may promote cell death and viral spread. When expressed alone, E4orf4 kills transformed cells but not normal human cells. The only clear target of E4orf4 in mammalian cells is the Bα (B55) subunit of protein phosphatase 2A (PP2A), a member of one of three classes of regulatory B subunits. Here we report the effects of E4orf4 in Saccharomyces cerevisiae, which encodes two PP2A regulatory B subunits, CDC55 and RTS1, that share homology with mammalian B and B′ subunits, respectively. E4orf4 expression was found to be toxic in yeast, resulting in the accumulation of cells in G2/M phase that failed to grow upon removal of E4orf4. E4orf4-expressing yeast also displayed an elongated cell morphology similar to cdc55 deletion strains. E4orf4 required CDC55 to elicit its effect, whereas RTS1 was dispensable. The recruitment of the PP2A holoenzyme by E4orf4 was entirely dependent on Cdc55. These studies indicate that E4orf4-induced apoptosis in mammalian cells and cell death in yeast require functional interactions with B-type subunits of PP2A. However, some inhibition of growth by E4orf4 was observed in the cdc55 strain and with an E4orf4 mutant that fails to interact with Cdc55, indicating that E4orf4 may possess a second Cdc55-independent function affecting cell growth.

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Acknowledgements

We wish to thank James Broach for the Tpd3 antibody, Doug Kellogg for the Clb2 antibody, Albert Lai, David Pallas and David Thomas for helpful discussions, and Ken McDonald for technical assistance. This work was supported by grants to PE Branton from the National Cancer Institute of Canada and the Canadian Institutes for Health Research.

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Authors and Affiliations

  1. Department of Biochemistry, McGill University, McIntyre Medical Building, Montreal, H3G 1Y6, Quebec, Canada

    Diana E Roopchand, Joseph M Lee & Philip E Branton

  2. Department of Oncology, McGill University, McIntyre Medical Building, Montreal, H3G 1Y6, Quebec, Canada

    Philip E Branton

  3. Department of Biology, McGill University, Stewart Biology Building, Montreal, H3A 1B1, Quebec, Canada

    Serge Shahinian & Howard Bussey

  4. GeminX Biotechnologies Inc., PO Box 477, Place du Parc, Montreal, H2W 2M9, Quebec, Canada

    Denis Paquette

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  1. Diana E Roopchand
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Correspondence to Philip E Branton.

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Roopchand, D., Lee, J., Shahinian, S. et al. Toxicity of human adenovirus E4orf4 protein in Saccharomyces cerevisiae results from interactions with the Cdc55 regulatory B subunit of PP2A. Oncogene 20, 5279–5290 (2001). https://doi.org/10.1038/sj.onc.1204693

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