p31comet Induces cellular senescence through p21 accumulation and Mad2 disruption

Yun Miyong, Young Hoon Han, Hee Yoon Sun, Young Kim Hee, Bu Yeo Kim, Yeun Jin Ju, Chang Mo Kang, Hwa Jang Su, Hee Yong Chung, Su Jae Lee, Myung Haing Cho, Gyesoon Yoon, Hong Park Gil, Hoon Kim Sang, Kee Ho Lee

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Functional suppression of spindle checkpoint protein activity results in apoptotic cell death arising from mitotic failure, including defective spindle formation, chromosome missegregation, and premature mitotic exit. The recently identified p31comet protein acts as a spindle checkpoint silencer via communication with the transient Mad2 complex. In the present study, we found that p31comet overexpression led to two distinct phenotypic changes, cellular apoptosis and senescence. Because of a paucity of direct molecular link of spindle checkpoint to cellular senescence, however, the present report focuses on the relationship between abnormal spindle checkpoint formation and p31comet-induced senescence by using susceptible tumor cell lines. p31comet-induced senescence was accompanied by mitotic catastrophe with massive nuclear and chromosomal abnormalities. The progression of the senescence was completely inhibited by the depletion of p21 Waf1/Cip1 and partly inhibited by the depletion of the tumor suppressor protein p53. Notably, p21Waf1/Cip1 depletion caused a dramatic phenotypic conversion of p31comet-induced senescence into cell death through mitotic catastrophe, indicating that p21Waf1/Cip1 is a major mediator of p31comet-induced cellular senescence. In contrast to wild-type p31comet, overexpression of a p31 mutant lacking the Mad2 binding region did not cause senescence. Moreover, depletion of Mad2 by small interfering RNA induced senescence. Here, we show that p31comet induces tumor cell senescence by mediating p21Waf1/Cip1 accumulation and Mad2 disruption and that these effects are dependent on a direct interaction of p31comet with Mad2. Our results could be used to control tumor growth.

Original languageEnglish
Pages (from-to)371-382
Number of pages12
JournalMolecular Cancer Research
Volume7
Issue number3
DOIs
Publication statusPublished - 2009 Mar 1

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'p31<sup>comet</sup> Induces cellular senescence through p21 accumulation and Mad2 disruption'. Together they form a unique fingerprint.

  • Cite this

    Miyong, Y., Han, Y. H., Sun, H. Y., Hee, Y. K., Kim, B. Y., Ju, Y. J., Kang, C. M., Su, H. J., Chung, H. Y., Lee, S. J., Cho, M. H., Yoon, G., Gil, H. P., Sang, H. K., & Lee, K. H. (2009). p31comet Induces cellular senescence through p21 accumulation and Mad2 disruption. Molecular Cancer Research, 7(3), 371-382. https://doi.org/10.1158/1541-7786.MCR-08-0056