Regulation of apoptosis by XIAP ubiquitin-ligase activity

被引:151
作者
Schile, Andrew J. [1 ]
Garcia-Fernandez, Maria [1 ]
Steller, Hermann [1 ]
机构
[1] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA
关键词
XIAP; ubiquitin; caspase; apoptosis; cancer; lymphoma;
D O I
10.1101/gad.1663108
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Inhibitor of Apoptosis Proteins (IAPs) can bind to and inhibit caspases, the key executioners of apoptosis. Because IAPs are frequently overexpressed in human tumors, they have become major pharmacological targets for developing new cancer therapeutics. However, the precise physiological function of individual mammalian IAPs and their role as E3 ubiquitin-ligases in situ remain largely obscure. Here, we investigated the function of XIAP ubiquitin-ligase activity by inactivating the RING motif via gene targeting in the mouse. Removing the RING stabilized XIAP in apoptotic thymocytes, demonstrating that XIAP ubiquitin-ligase activity is a major determinant of XIAP protein stability. Surprisingly, the increased amounts of "XIAP-BIR-only" protein did not lead to attenuated but rather increased caspase activity and apoptosis. Delta RING embryonic stem cells and fibroblasts had elevated caspase-3 enzyme activity, and XIAP Delta RING embryonic fibroblasts were strongly sensitized to TNF-alpha-induced apoptosis. Similar results were obtained with XIAP deficient mice. Furthermore, deletion of the RING also improved the survival of mice in the E mu-Myc lymphoma model. This demonstrates a physiological requirement of XIAP ubiquitin-ligase activity for the inhibition of caspases and for tumor suppression in vivo.
引用
收藏
页码:2256 / 2266
页数:11
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