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Science 330 (6009): 1390-1393

Copyright © 2010 by the American Association for the Advancement of Science

BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program

Decheng Ren,1,* Ho-Chou Tu,1,* Hyungjin Kim,1 Gary X. Wang,1 Gregory R. Bean,1 Osamu Takeuchi,2 John R. Jeffers,3 Gerard P. Zambetti,3 James J.-D. Hsieh,1 Emily H.-Y. Cheng1,4,{dagger},{ddagger}

Abstract: Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c–mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.

1 Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
3 St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

* These authors contributed equally to this work.

{dagger} Present address: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

{ddagger} To whom correspondence should be addressed. E-mail: chenge1{at}mskcc.org


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