title: Killing the Killer: PARC/CUL9 promotes cell survival by destroying cytochrome C.
abstract: Balanced amounts of apoptotic cell death are essential for health; its deregulation plays key roles in neurodegeneration, autoimmunity, and cancer. Mitochondria orchestrate apoptosis through a process called mitochondrial outer-membrane permeabilization (MOMP). After MOMP, mitochondrial cytochrome c is released into the cytoplasm, where it binds the adaptor molecule APAF1, triggering caspase protease activation and cell death. In this issue of Science Signaling, Deshmukh and colleagues define a new survival mechanism downstream of mitochondrial permeabilization. Specifically, they identify proteasomal degradation of cytochrome c as a major determinant of cell survival. In an unbiased approach, PARC (also known as CUL9) was found to be the ubiquitin ligase responsible for the ubiquitination and proteasomal degradation of cytochrome c. The consequences of this survival process may be double-edged because both cancer cells and postmitotic cells use PARC/CUL9-mediated cytochrome c degradation to ensure cell survival. Ultimately, differential targeting of this process may promote survival of postmitotic tissue or enhance tumor-specific killing.
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. stephen.tait@glasgow.ac.uk.
authors.forename: Stephen W G
authors.initials: SW
authors.lastname: Tait
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D059748:Proteolysis; D014166:Transferases
chemical_list: D002352:Carrier Proteins; D045304:Cytochromes c; C400192:Cul9 protein, human; D014166:Transferases