Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis

• Type of Material: Article
• Authors: Matthew Brentnall, Emory University; Luis Rodrigues-Menocal, University of Miami; Rebeka Ladron De Guevara, University of Miami; Enrique Depero, University of Miami; Lawrence Boise, Emory University
• Language: English
• Date: 2013-07-09
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Brentnall et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.biomedcentral.com/1471-2121/14/32
• Title of Journal or Parent Work: BMC Cell Biology
• ISSN: 1471-2121
• Volume: 14
• Issue: 32
• Start Page: 1
• End Page: 9
• Grant/Funding Information: The work was funded through NIH grants R01 GM65813 (LHB), R01 CA127910 (LHB), F31 GM20435 (EC).; Additional support was provided by the Georgia Cancer Coalition and the TJ Martell Foundation (LHB).
• Keywords: Cell detachment; Caspase; Intrinsic apoptosis; Mitochondria; ROS; Bid
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

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.