APCCdc20 suppresses apoptosis through targeting Bim for ubiquitination and destruction

Lixin Wan, Mingjia Tan, Jie Yang, Hiroyuki Inuzuka, Xiangpeng Dai, Tao Wu, Jia Liu, Shavali Shaik, Guoan Chen, Jing Deng, Marcos Malumbres, Anthony Letai, Marc W. Kirschner, Yi Sun, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

81 Citations (Scopus)

Abstract

Anaphase-promoting complex Cdc20 (APCCdc20) plays pivotal roles in governing mitotic progression. By suppressing APCCdc20, antimitotic agents activatethe spindle-assembly checkpoint and induce apoptosis after prolonged treatment, whereas depleting endogenous Cdc20 suppresses tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here, we report the BH3-only proapoptotic protein Bim as an APCCdc20 target, such that depletion of Cdc20 sensitizes cells to apoptotic stimuli. Strikingly, Cdc20 and multiple APC-core components were identified in a small interfering RNA screen that, upon knockdown, sensitizes otherwise resistant cancer cells to chemoradiation in a Bim-dependent manner. Consistently, human adult Tcell leukemia cells that acquire elevated APCCdc20 activity via expressing the Tax viral oncoprotein exhibit reduced Bim levels and resistance to anticancer agents. These results reveal an important role for APCCdc20 in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anticancer agents.

Original languageEnglish
Pages (from-to)377-391
Number of pages15
JournalDevelopmental cell
Volume29
Issue number4
DOIs
Publication statusPublished - 2014 May 27
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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