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Polyoma small T antigen triggers cell death via mitotic catastrophe

Oncogene volume 34, pages 2483–2492 (2015)Cite this article

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Abstract

Polyoma small T antigen (PyST), an early gene product of the polyoma virus, has been shown to cause cell death in a number of mammalian cells in a protein phosphatase 2A (PP2A)-dependent manner. In the current study, using a cell line featuring regulated expression of PyST, we found that PyST arrests cells in mitosis. Live-cell and immunofluorescence studies showed that the majority of the PyST expressing cells were arrested in prometaphase with almost no cells progressing beyond metaphase. These cells exhibited defects in chromosomal congression, sister chromatid cohesion and spindle positioning, thereby resulting in the activation of the spindle assembly checkpoint. Prolonged mitotic arrest then led to cell death via mitotic catastrophe. Cell cycle inhibitors that block cells in G1/S prevented PyST-induced death. PyST-induced cell death that occurs during M is not dependent on p53 status. These data suggested, and our results confirmed, that PP2A inhibition could be used to preferentially kill cancer cells with p53 mutations that proliferate normally in the presence of cell cycle inhibitors.

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Acknowledgements

This work was supported by an National Institutes of Health PO1 grant CA50661 to TMR, BSS and DML; and an RO1 grant to TMR (CA30002) and BSS (CA34722); and a Ramalingaswami fellowship and a CREST fellowship to SA. JMGH is supported by the Association for International Cancer Research, and is a Scholar of the Leukemia and Lymphoma Society. We thank Drs Jennifer Spangle and Meera Bhanu for their helpful comments on this manuscript.

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Author notes

  1. S Andrabi

    Present address: 7Current address: Department of Biochemistry, University of Kashmir, Srinagar, India.,

  2. A T Pores Fernando and S Andrabi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A T Pores Fernando, S Andrabi, O Cizmecioglu, D M Livingston & T M Roberts

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    A T Pores Fernando, O Cizmecioglu & T M Roberts

  3. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA

    C Zhu & J M G Higgins

  4. Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle-upon-Tyne, UK

    J M G Higgins

  5. Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA

    B S Schaffhausen

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  1. A T Pores Fernando
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Correspondence to T M Roberts.

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Pores Fernando, A., Andrabi, S., Cizmecioglu, O. et al. Polyoma small T antigen triggers cell death via mitotic catastrophe. Oncogene 34, 2483–2492 (2015). https://doi.org/10.1038/onc.2014.192

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