title: Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis.
abstract: BACKGROUND
  Apoptosis is a form of programmed cell death that is regulated by the Bcl-2 family and caspase family of proteins. The caspase cascade responsible for executing cell death following cytochrome c release is well described; however the distinct roles of caspases-9, -3 and -7 during this process are not completely defined.
  
  
  RESULTS
  Here we demonstrate several unique functions for each of these caspases during cell death. Specific inhibition of caspase-9 allows for efficient release of cytochrome c, but blocks changes in mitochondrial morphology and ROS production. We show that caspase-9 can cleave Bid into tBid at amino acid 59 and that this cleavage of Bid is required for ROS production following serum withdrawal. We also demonstrate that caspase-3-deficient MEFs are less sensitive to intrinsic cell death stimulation, yet have higher ROS production. In contrast, caspase-7-deficient MEFs are not resistance to intrinsic cell death, but remain attached to the ECM.
  
  
  CONCLUSIONS
  Taken together, these data suggest that caspase-9 is required for mitochondrial morphological changes and ROS production by cleaving and activating Bid into tBid. After activation by caspase-9, caspase-3 inhibits ROS production and is required for efficient execution of apoptosis, while effector caspase-7 is required for apoptotic cell detachment.
authors.affiliation: Departments of Hematology and Medical Oncology and Cell Biology, Winship Cancer Institute of Emory University, 1365 Clifton Road NE Bldg:C, Rm:4012, Atlanta, GA 30322, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brentnall
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez-Menocal
authors.forename: Rebeka Ladron
authors.initials: RL
authors.lastname: De Guevara
authors.forename: Enrique
authors.initials: E
authors.lastname: Cepero
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000473:pathology* / Q000502:physiology; D053148:Caspase 3 / Q000502:physiology*; D053179:Caspase 7 / Q000502:physiology*; D053453:Caspase 9 / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D045304:Cytochromes c / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D023421:Models, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D045304:Cytochromes c; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9