Identification of a Conserved Anti-Apoptotic Protein That Modulates the Mitochondrial Apoptosis Pathway

被引:17
|
作者
Zhang, Yu [1 ]
Johansson, Elisabet [2 ]
Miller, Marian L. [2 ]
Jaenicke, Reiner U. [3 ]
Ferguson, Donald J. [4 ]
Plas, David [5 ]
Meller, Jarek [6 ,7 ]
Anderson, Marshall W. [8 ]
机构
[1] Univ Cincinnati, Sch Pharm, Cincinnati, OH 45221 USA
[2] Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA
[3] Univ Dusseldorf, Lab Mol Radiooncol, Clin & Policlin Radiat Therapy & Radiooncol, Ctr Clin, Dusseldorf, Germany
[4] Miami Univ, Dept Microbiol, Oxford, OH 45056 USA
[5] Univ Cincinnati, Coll Med, Dept Canc & Cell Biol, Cincinnati, OH USA
[6] Univ Cincinnati, Med Ctr, Childrens Hosp, Div Biomed Informat,Dept Environm Hlth, Cincinnati, OH 45267 USA
[7] Univ Cincinnati, Med Ctr, Childrens Hosp, Div Biomed Informat,Dept Biomed Engn, Cincinnati, OH 45267 USA
[8] Med Coll Wisconsin, Dept Med, Ctr Canc, Milwaukee, WI 53226 USA
来源
PLOS ONE | 2011年 / 6卷 / 09期
关键词
DRUG-INDUCED APOPTOSIS; KINASE-C INHIBITOR; PHASE-I TRIAL; ACTIVATION; COMBINATION; CASPASE-8; UCN-01; CELLS; 7-HYDROXYSTAUROSPORINE; CLEAVAGE;
D O I
10.1371/journal.pone.0025284
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Here we identified an evolutionarily highly conserved and ubiquitously expressed protein ( C9orf82) that shows structural similarities to the death effector domain of apoptosis-related proteins. RNAi knockdown of C9orf82 induced apoptosis in A-549 and MCF7/casp3-10b lung and breast carcinoma cells, respectively, but not in cells lacking caspase-3, caspase-10 or both. Apoptosis was associated with activated caspases-3, -8, -9 and -10, and inactivation of caspases 10 or 3 was sufficient to block apoptosis in this pathway. Apoptosis upon knockdown of C9orf82 was associated with increased caspase-10 expression and activation, which was required for the generation of an 11 kDa tBid fragment and activation of Caspase-9. These data suggest that C9orf82 functions as an anti-apoptotic protein that modulates a caspase-10 dependent mitochondrial caspase-3/9 feedback amplification loop. We designate this ubiquitously expressed and evolutionarily conserved anti-apoptotic protein Conserved Anti-Apoptotic Protein (CAAP). We also demonstrated that treatment of MCF7/casp3-10b cells with staurosporine and etoposides induced apoptosis and knockdown of CAAP expression. This implies that the CAAP protein could be a target for chemotherapeutic agents.
引用
收藏
页数:14
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