title: Polyoma small T antigen triggers cell death via mitotic catastrophe.
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.
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Pores Fernando
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Andrabi
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: O
authors.initials: O
authors.lastname: Cizmecioglu
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Livingston
authors.affiliation: 1] Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA [2] Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: J M G
authors.initials: JM
authors.lastname: Higgins
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Schaffhausen
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Roberts
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D051379:Mice; D008938:Mitosis / Q000235:genetics; D011120:Polyomavirus / Q000378:metabolism*; D049468:Prometaphase / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D008941:Spindle Apparatus / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000957:Antigens, Viral, Tumor; D016159:Tumor Suppressor Protein p53; D054648:Protein Phosphatase 2