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-knockou...

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Published in:Science (American Association for the Advancement of Science) 2010-12, Vol.330 (6009), p.1390-1393
Main Authors: Ren, Decheng, Tu, Ho-Chou, Kim, Hyungjin, Wang, Gary X, Bean, Gregory R, Takeuchi, Osamu, Jeffers, John R, Zambetti, Gerard P, Hsieh, James J.-D, Cheng, Emily H.-Y
Format: Article
Language:English
Subjects:
Ageing, cell death
Animals
Apoptosis
Apoptosis Regulatory Proteins - deficiency
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - metabolism
bcl-2 Homologous Antagonist-Killer Protein - chemistry
bcl-2 Homologous Antagonist-Killer Protein - genetics
bcl-2 Homologous Antagonist-Killer Protein - metabolism
bcl-2-Associated X Protein - chemistry
bcl-2-Associated X Protein - genetics
bcl-2-Associated X Protein - metabolism
Bcl-2-Like Protein 11
BH3 Interacting Domain Death Agonist Protein - deficiency
BH3 Interacting Domain Death Agonist Protein - genetics
BH3 Interacting Domain Death Agonist Protein - metabolism
Biological and medical sciences
Caspases - metabolism
Cell death
Cell physiology
Cells, Cultured
Cerebellum - cytology
Cytochromes
Cytochromes c - metabolism
Cytokines
Fundamental and applied biological sciences. Psychology
Intracellular Membranes - metabolism
Membrane Proteins - deficiency
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
Mitochondria
Mitochondria - metabolism
Models, Biological
Molecular and cellular biology
Neurons
Neurons - physiology
Permeability
Potassium
Protein Multimerization
Proto-Oncogene Proteins - deficiency
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Stress, Physiological
T lymphocytes
T-Lymphocytes - physiology
Thymocytes
Tumor Suppressor Proteins - deficiency
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1190217