Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth.
The destruction of cellular targets during apoptosis is carried out by caspases, which are negatively regulated by the inhibitor of apoptosis proteins (IAP); however, death effector domain (DED) caspases of the extrinsic pathway are refractory to the IAP family. We have isolated a family of apoptotic inhibitors [caspases-8- and -10-associated RING proteins (CARPs)] that bind to and negatively regulate DED caspases. When overexpressed, CARPs, via an IAP-like RING domain, can contribute to the ubiquitin-mediated proteolysis of DED caspases. Furthermore, CARPs are rapidly cleaved during apoptosis. However, in tumors and tumor cell lines, they are overexpressed, and their silencing leads to restoration of efficient apoptosis via enhanced activation of DED caspases. Long-term inhibition of CARP expression results in suppression of cancer cell growth, highlighting their importance in tumor cell survival.
McDonald
E Robert
ER
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
El-Deiry
Wafik S
WS
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D010743:Phospholipids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000502:physiology; D017386:Sequence Homology, Amino Acid
D051017:Apoptosis Regulatory Proteins; C512817:CA11 protein, human; C477529:CCAR1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D034741:RNA, Small Interfering