P31comet-induced cell death is mediated by binding and inactivation of Mad2

Hyun Jin Shin, Eun Ran Park, Sun Hee Yun, Su Hyeon Kim, Won Hee Jung, Seon Rang Woo, Hyun Yoo Joo, Su Hwa Jang, Hee Yong Chung, Sung Hee Hong, Myung Haing Cho, Joong Jean Park, Miyong Yun, Kee Ho Lee

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Abstract

Mad2, a key component of the spindle checkpoint, is closely associated with chromosomal instability and poor prognosis in cancer. p31comet is a Mad2-interacting protein that serves as a spindle checkpoint silencer at mitosis. In this study, we showed that p31comet-induced apoptosis and senescence occur via counteraction of Mad2 activity. Upon retroviral transduction of p31comet, the majority of human cancer cell lines tested lost the ability to form colonies in a low-density seeding assay. Cancer cells with p31comet overexpression underwent distinct apoptosis and/or senescence, irrespective of p53 status, confirming the cytotoxicity of p31comet. Interestingly, both cytotoxic and Mad2 binding activities were eliminated upon deletion of the C-terminal 30 amino acids of p31comet. Point mutation or deletion of the region affecting Mad2 binding additionally abolished cytotoxic activity. Consistently, wildtype Mad2 interacting with p31comet, but not its non-binding mutant, inhibited cell death, indicating that the mechanism of p31comet-induced cell death involves Mad2 inactivation. Our results clearly suggest that the regions of p31comet affecting interactions with Mad2, including the C-terminus, are essential for induction of cell death. The finding that p31comet-induced cell death is mediated by interactions with Mad2 that lead to its inactivation is potentially applicable in anticancer therapy.

Original languageEnglish
Article numbere0141523
JournalPLoS One
Volume10
Issue number11
DOIs
Publication statusPublished - 2015 Nov 6

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shin, H. J., Park, E. R., Yun, S. H., Kim, S. H., Jung, W. H., Woo, S. R., Joo, H. Y., Jang, S. H., Chung, H. Y., Hong, S. H., Cho, M. H., Park, J. J., Yun, M., & Lee, K. H. (2015). P31comet-induced cell death is mediated by binding and inactivation of Mad2. PLoS One, 10(11), [e0141523]. https://doi.org/10.1371/journal.pone.0141523