Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function

Shin Ichi Iida, Toru Hirota, Tetsuro Morisaki, Tomotoshi Marumoto, Toshihiro Hara, Shinji Kuninaka, Shinobu Honda, Ken Ichiro Kosai, Michio Kawasuji, David C. Pallas, Hideyuki Saya

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Defects in chromosomes or mitotic spindles activate the spindle checkpoint, resulting in cell cycle arrest at prometaphase. The prolonged activation of spindle checkpoint generally leads to mitotic exit without segregation after a transient mitotic arrest and the consequent formation of tetraploid G 1 cells. These tetraploid cells are usually blocked to enter the subsequent S phase by the activation of p53/pRb pathway, which is referred to as the G1 tetraploidy checkpoint. A human homologue of the Drosophila warts tumor suppressor, WARTS, is an evolutionarily conserved serine-threonine kinase and implicated in development of human tumors. We previously showed that WARTS plays a crucial role in controlling mitotic progression by forming a regulatory complex with zyxin, a regulator of actin filament assembly, on mitotic apparatus. However, when WARTS is activated during cell cycle and how the loss of WARTS function leads to tumorigenesis have not been elucidated. Here we show that WARTS is activated during mitosis in mammalian cells, and that overexpression of a kinase-inactive WARTS in Mat1 fibroblasts significantly induced mitotic delay. This delay resulted from prolonged activation of the spindle assembly checkpoint and was frequently followed by mitotic slippage and the development of tetraploidy. The resulting tetraploid cells then abrogated the G1 tetraploidy checkpoint and entered S phase to achieve a DNA content of 8N. This impairment of G1 tetraploidy checkpoint was caused as a consequence of failure to induce p53 expression by expressing a kinase-inactive WARTS. WARTS thus plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint.

Original languageEnglish
Pages (from-to)5266-5274
Number of pages9
JournalOncogene
Volume23
Issue number31
DOIs
Publication statusPublished - 2004 Jul 8

Keywords

  • Cell cycle
  • Mitotic kinase
  • Polyploid
  • Spindle checkpoint
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Iida, S. I., Hirota, T., Morisaki, T., Marumoto, T., Hara, T., Kuninaka, S., Honda, S., Kosai, K. I., Kawasuji, M., Pallas, D. C., & Saya, H. (2004). Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function. Oncogene, 23(31), 5266-5274. https://doi.org/10.1038/sj.onc.1207623