title: Identification of a conserved anti-apoptotic protein that modulates the mitochondrial apoptosis pathway.
abstract: 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.
authors: School of Pharmacy, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Yu
authors: Y
authors: Zhang
authors: Elisabet
authors: E
authors: Johansson
authors: Marian L
authors: ML
authors: Miller
authors: Reiner U
authors: RU
authors: Jänicke
authors: Donald J
authors: DJ
authors: Ferguson
authors: David
authors: D
authors: Plas
authors: Jarek
authors: J
authors: Meller
authors: Marshall W
authors: MW
authors: Anderson
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D053455:Caspase 10 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000604240:CAAP1 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D005047:Etoposide; D053455:Caspase 10; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D019311:Staurosporine