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Dev Cell. 2014 May 27;29(4):377-91. doi: 10.1016/j.devcel.2014.04.022.

APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction.

Author information

1
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Chongqing Road, Shanghai 200025, China.
4
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institute of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
6
Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
9
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.

Abstract

Anaphase-promoting complex Cdc20 (APC(Cdc20)) plays pivotal roles in governing mitotic progression. By suppressing APC(Cdc20), antimitotic agents activate the 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 APC(Cdc20) 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 T cell leukemia cells that acquire elevated APC(Cdc20) activity via expressing the Tax viral oncoprotein exhibit reduced Bim levels and resistance to anticancer agents. These results reveal an important role for APC(Cdc20) in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anticancer agents.

PMID:
24871945
PMCID:
PMC4081014
DOI:
10.1016/j.devcel.2014.04.022
[Indexed for MEDLINE]
Free PMC Article

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