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Open Access Highly Accessed Research article

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

Matthew Brentnall12, Luis Rodriguez-Menocal3, Rebeka Ladron De Guevara3, Enrique Cepero3 and Lawrence H Boise1*

Author Affiliations

1 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

2 Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA

3 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA

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BMC Cell Biology 2013, 14:32  doi:10.1186/1471-2121-14-32

Published: 9 July 2013

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.

Keywords:
Caspase; Bid; ROS; Intrinsic apoptosis; Mitochondria; Cell detachment