BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program.
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.
Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Decheng
D
Ren
Ho-Chou
HC
Tu
Hyungjin
H
Kim
Gary X
GX
Wang
Gregory R
GR
Bean
Osamu
O
Takeuchi
John R
JR
Jeffers
Gerard P
GP
Zambetti
James J-D
JJ
Hsieh
Emily H-Y
EH
Cheng
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000502:physiology*; D010539:Permeability; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D013601:T-Lymphocytes / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases