TY - JOUR
T1 - APCCdc20 suppresses apoptosis through targeting Bim for ubiquitination and destruction
AU - Wan, Lixin
AU - Tan, Mingjia
AU - Yang, Jie
AU - Inuzuka, Hiroyuki
AU - Dai, Xiangpeng
AU - Wu, Tao
AU - Liu, Jia
AU - Shaik, Shavali
AU - Chen, Guoan
AU - Deng, Jing
AU - Malumbres, Marcos
AU - Letai, Anthony
AU - Kirschner, Marc W.
AU - Sun, Yi
AU - Wei, Wenyi
N1 - Funding Information:
We thank members of the Wei laboratory for critical reading of the manuscript; Roya Khosravi-Far, Gutian Xiao, Christophe P. Nicot, Peter Jackson, Matthew Meyerson, William Hahn, Frederic D. Sigoillot, and Randall W. King for providing reagents; and Timothy J. Mitchison, Randall W. King, and Susan E. Morgan-Lappe for helpful suggestions. W.W. is a Leukemia and Lymphoma Society Scholar and ACS Research Scholar. This work was supported in part by NIH grants GM089763 and GM094777 to W.W., CA118762 and CA156744 to Y.S., and GM39023 to M.W.K. L.W. was supported by the Lady Tata Memorial Trust International Award for Research in Leukemia. This work was also partially supported by a research grant from University of Michigan Comprehensive Cancer Center to Y.S.
PY - 2014/5/27
Y1 - 2014/5/27
N2 - 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.
AB - 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.
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U2 - 10.1016/j.devcel.2014.04.022
DO - 10.1016/j.devcel.2014.04.022
M3 - Article
C2 - 24871945
AN - SCOPUS:84901433308
VL - 29
SP - 377
EP - 391
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 4
ER -
