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Molecular and Cellular Biology, May 2002, p. 3509-3517, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3509-3517.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Generation and Characterization of Smac/DIABLO-Deficient Mice

Hitoshi Okada,1,2 Woong-Kyung Suh,1,2 Jianping Jin,3 Minna Woo,1,2 Chunying Du,4,{dagger} Andrew Elia,1,2 Gordon S. Duncan,1,2 Andrew Wakeham,1,2 Annick Itie,1,2 Scott W. Lowe,3 Xiaodong Wang,4 and Tak W. Mak1,2*

Amgen Institute and Ontario Cancer Institute,1 Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1,2 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724,3 Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 753904

Received 30 November 2001/ Returned for modification 28 January 2002/ Accepted 6 February 2002

The mitochondrial proapoptotic protein Smac/DIABLO has recently been shown to potentiate apoptosis by counteracting the antiapoptotic function of the inhibitor of apoptosis proteins (IAPs). In response to apoptotic stimuli, Smac is released into the cytosol and promotes caspase activation by binding to IAPs, thereby blocking their function. These observations have suggested that Smac is a new regulator of apoptosis. To better understand the physiological function of Smac in normal cells, we generated Smac-deficient (Smac-/-) mice by using homologous recombination in embryonic stem (ES) cells. Smac-/- mice were viable, grew, and matured normally and did not show any histological abnormalities. Although the cleavage in vitro of procaspase-3 was inhibited in lysates of Smac-/- cells, all types of cultured Smac-/- cells tested responded normally to all apoptotic stimuli applied. There were also no detectable differences in Fas-mediated apoptosis in the liver in vivo. Our data strongly suggest the existence of a redundant molecule or molecules capable of compensating for a loss of Smac function.

* Corresponding author. Mailing address: Ontario Cancer Institute/Amgen Institute, 620 University Ave., Suite 706, Toronto, Ontario, Canada M5G 2C1. Phone: (416) 204-2236. Fax: (416) 204-5300. E-mail: tmak{at}oci.utoronto.ca.

{dagger} Present address: Stowers Institute for Medical Research, Kansas City, MO 64110.

Molecular and Cellular Biology, May 2002, p. 3509-3517, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3509-3517.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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