Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Tumor suppressors: enhancers or suppressors of regeneration?.
J. H. Pomerantz and H. M. Blau (2013)
Development 140, 2502-2512
   Abstract »    Full Text »    PDF »
Formation of normal interdigital web spaces in the hand revisited: implications for the pathogenesis of syndactyly in humans and experimental animals.
M. M. Al-Qattan (2013)
J Hand Surg Eur Vol.
   Abstract »    Full Text »    PDF »
Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation.
S. Din, M. Mason, M. Volkers, B. Johnson, C. T. Cottage, Z. Wang, A. Y. Joyo, P. Quijada, P. Erhardt, N. S. Magnuson, et al. (2013)
PNAS 110, 5969-5974
   Abstract »    Full Text »    PDF »
PUMA and BIM Are Required for Oncogene Inactivation-Induced Apoptosis.
G. R. Bean, Y. T. Ganesan, Y. Dong, S. Takeda, H. Liu, P. M. Chan, Y. Huang, L. A. Chodosh, G. P. Zambetti, J. J.- D. Hsieh, et al. (2013)
Science Signaling 6, ra20
   Abstract »    Full Text »    PDF »
Direct Interaction of Bax and Bak Proteins with Bcl-2 Homology Domain 3 (BH3)-only Proteins in Living Cells Revealed by Fluorescence Complementation.
L. Vela, O. Gonzalo, J. Naval, and I. Marzo (2013)
J. Biol. Chem. 288, 4935-4946
   Abstract »    Full Text »    PDF »
Multiple Functions of BCL-2 Family Proteins.
J. M. Hardwick and L. Soane (2013)
Cold Spring Harb Perspect Biol 5, a008722
   Abstract »    Full Text »    PDF »
Therapeutic Effects of Deleting Cancer-Associated Fibroblasts in Cholangiocarcinoma.
J. C. Mertens, C. D. Fingas, J. D. Christensen, R. L. Smoot, S. F. Bronk, N. W. Werneburg, M. P. Gustafson, A. B. Dietz, L. R. Roberts, A. E. Sirica, et al. (2013)
Cancer Res. 73, 897-907
   Abstract »    Full Text »    PDF »
Where Killers Meet--Permeabilization of the Outer Mitochondrial Membrane during Apoptosis.
T. Bender and J.-C. Martinou (2013)
Cold Spring Harb Perspect Biol 5, a011106
   Abstract »    Full Text »    PDF »
Host Immune Defense Peptide LL-37 Activates Caspase-Independent Apoptosis and Suppresses Colon Cancer.
S. X. Ren, A. S. L. Cheng, K. F. To, J. H. M. Tong, M. S. Li, J. Shen, C. C. M. Wong, L. Zhang, R. L. Y. Chan, X. J. Wang, et al. (2012)
Cancer Res. 72, 6512-6523
   Abstract »    Full Text »    PDF »
Death Protein 5 and p53-Upregulated Modulator of Apoptosis Mediate the Endoplasmic Reticulum Stress-Mitochondrial Dialog Triggering Lipotoxic Rodent and Human {beta}-Cell Apoptosis.
D. A. Cunha, M. Igoillo-Esteve, E. N. Gurzov, C. M. Germano, N. Naamane, I. Marhfour, M. Fukaya, J.-M. Vanderwinden, C. Gysemans, C. Mathieu, et al. (2012)
Diabetes 61, 2763-2775
   Abstract »    Full Text »    PDF »
Apoptotic and Nonapoptotic Caspase Functions in Animal Development.
M. Miura (2012)
Cold Spring Harb Perspect Biol 4, a008664
   Abstract »    Full Text »    PDF »
Metabolic Stress in Autophagy and Cell Death Pathways.
B. J. Altman and J. C. Rathmell (2012)
Cold Spring Harb Perspect Biol 4, a008763
   Abstract »    Full Text »    PDF »
A p53 Axis Regulates B Cell Receptor-Triggered, Innate Immune System-Driven B Cell Clonal Expansion.
H. Lee, S. Haque, J. Nieto, J. Trott, J. K. Inman, S. McCormick, N. Chiorazzi, and P. K. A. Mongini (2012)
J. Immunol. 188, 6093-6108
   Abstract »    Full Text »    PDF »
Mitochondrial Bcl-2 Family Dynamics Define Therapy Response and Resistance in Neuroblastoma.
K. C. Goldsmith, M. Gross, S. Peirce, D. Luyindula, X. Liu, A. Vu, M. Sliozberg, R. Guo, H. Zhao, C. P. Reynolds, et al. (2012)
Cancer Res. 72, 2565-2577
   Abstract »    Full Text »    PDF »
Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function.
M. J. White, S. M. Schoenwaelder, E. C. Josefsson, K. E. Jarman, K. J. Henley, C. James, M. A. Debrincat, S. P. Jackson, D. C. S. Huang, and B. T. Kile (2012)
Blood 119, 4283-4290
   Abstract »    Full Text »    PDF »
A Pharmacologic Inhibitor of the Protease Taspase1 Effectively Inhibits Breast and Brain Tumor Growth.
D. Y. Chen, Y. Lee, B. A. Van Tine, A. C. Searleman, T. D. Westergard, H. Liu, H.-C. Tu, S. Takeda, Y. Dong, D. R. Piwnica-Worms, et al. (2012)
Cancer Res. 72, 736-746
   Abstract »    Full Text »    PDF »
Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies.
M. Gupta, A. E. W. Hendrickson, S. S. Yun, J. J. Han, P. A. Schneider, B. D. Koh, M. J. Stenson, L. E. Wellik, J. C. Shing, K. L. Peterson, et al. (2012)
Blood 119, 476-487
   Abstract »    Full Text »    PDF »
Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule.
L. Zhao, F. He, H. Liu, Y. Zhu, W. Tian, P. Gao, H. He, W. Yue, X. Lei, B. Ni, et al. (2012)
J. Biol. Chem. 287, 1054-1065
   Abstract »    Full Text »    PDF »
Mechanical stretch induces the apoptosis regulator PUMA in vascular smooth muscle cells.
W.-P. Cheng, B.-W. Wang, S.-C. Chen, H. Chang, and K.-G. Shyu (2012)
Cardiovasc Res 93, 181-189
   Abstract »    Full Text »    PDF »
Mechanisms of ER Stress-Induced Apoptosis in Atherosclerosis.
C. M. Scull and I. Tabas (2011)
Arterioscler Thromb Vasc Biol 31, 2792-2797
   Abstract »    Full Text »    PDF »
Deficiency of Pro-apoptotic Hrk Attenuates Programmed Cell Death in the Developing Murine Nervous System but Does Not Affect Bcl-x Deficiency-Induced Neuron Apoptosis.
A. P. Ghosh, J. D. Cape, B. J. Klocke, and K. A. Roth (2011)
Journal of Histochemistry & Cytochemistry 59, 976-983
   Abstract »    Full Text »    PDF »
Cutting Edge: Regulatory T Cells Do Not Mediate Suppression via Programmed Cell Death Pathways.
A. L. Szymczak-Workman, G. M. Delgoffe, D. R. Green, and D. A. A. Vignali (2011)
J. Immunol. 187, 4416-4420
   Abstract »    Full Text »    PDF »
The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1{alpha}.
C. Hetz, F. Martinon, D. Rodriguez, and L. H. Glimcher (2011)
Physiol Rev 91, 1219-1243
   Abstract »    Full Text »    PDF »
Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets.
E. C. Josefsson, C. James, K. J. Henley, M. A. Debrincat, K. L. Rogers, M. R. Dowling, M. J. White, E. A. Kruse, R. M. Lane, S. Ellis, et al. (2011)
J. Exp. Med. 208, 2017-2031
   Abstract »    Full Text »    PDF »
Bcl-2 Family Genetic Profiling Reveals Microenvironment-Specific Determinants of Chemotherapeutic Response.
J. R. Pritchard, L. A. Gilbert, C. E. Meacham, J. L. Ricks, H. Jiang, D. A. Lauffenburger, and M. T. Hemann (2011)
Cancer Res. 71, 5850-5858
   Abstract »    Full Text »    PDF »
Developmental Arrest of T Cells in Rpl22-Deficient Mice Is Dependent upon Multiple p53 Effectors.
J. E. Stadanlick, Z. Zhang, S.-Y. Lee, M. Hemann, M. Biery, M. O. Carleton, G. P. Zambetti, S. J. Anderson, T. Oravecz, and D. L. Wiest (2011)
J. Immunol. 187, 664-675
   Abstract »    Full Text »    PDF »
Transient binding of an activator BH3 domain to the Bak BH3-binding groove initiates Bak oligomerization.
H. Dai, A. Smith, X. W. Meng, P. A. Schneider, Y.-P. Pang, and S. H. Kaufmann (2011)
J. Cell Biol. 194, 39-48
   Abstract »    Full Text »    PDF »
Noxa/Bcl-2 Protein Interactions Contribute to Bortezomib Resistance in Human Lymphoid Cells.
A. J. Smith, H. Dai, C. Correia, R. Takahashi, S.-H. Lee, I. Schmitz, and S. H. Kaufmann (2011)
J. Biol. Chem. 286, 17682-17692
   Abstract »    Full Text »    PDF »
The Role of BH3-Only Proteins in Tumor Cell Development, Signaling, and Treatment.
R. Elkholi, K. V. Floros, and J. E. Chipuk (2011)
Genes & Cancer 2, 523-537
   Abstract »    Full Text »    PDF »
Opening the Cellular Poison Cabinet.
S. J. Martin (2010)
Science 330, 1330-1331
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882