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

PNAS 97 (6): 2597-2602

Copyright © 2000 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins

Hong Zhang*, Qunli Xu*, Stanislaw Krajewski, Maryla Krajewska, Zhihua Xie, Sally Fuess, Shinichi Kitada, Krzysztof Pawlowski, Adam Godzik, and John C. Reed{dagger}

Program on Apoptosis and Cell Death Regulation, The Burnham Institute, La Jolla, CA 92037

Accepted for publication December 27, 1999.

Received for publication October 26, 1999.

Abstract: Two major pathways for induction of apoptosis have been identified—intrinsic and extrinsic. The extrinsic pathway is represented by tumor necrosis factor family receptors, which utilize protein interaction modules known as death domains and death effector domains (DEDs) to assemble receptor signaling complexes that recruit and activate certain caspase-family cell death proteases, namely procaspases-8 and -10. The intrinsic pathway for apoptosis involves the participation of mitochondria, which release caspase-activating proteins. Bcl-2 family proteins govern this mitochondria-dependent apoptosis pathway, with proteins such as Bax functioning as inducers and proteins such as Bcl-2 and Bcl-XL serving as suppressors of cell death. An apoptosis regulator, BAR, was identified by using a yeast-based screen for inhibitors of Bax-induced cell death. The BAR protein contains a SAM domain, which is required for its interactions with Bcl-2 and Bcl-XL and for suppression of Bax-induced cell death in both mammalian cells and yeast. In addition, BAR contains a DED-like domain responsible for its interaction with DED-containing procaspases and suppression of Fas-induced apoptosis. Furthermore, BAR can bridge procaspase-8 and Bcl-2 into a protein complex. The BAR protein is anchored in intracellular membranes where Bcl-2 resides. BAR therefore may represent a scaffold protein capable of bridging two major apoptosis pathways.


* H.Z. and Q.X. contributed equally to this work.

{dagger} To whom reprint requests should be addressed at: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail: jreed{at}burnham-inst.org.

Communicated by Erkki Ruoslahti, The Burnham Institute, La Jolla, CA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Hydrogen Peroxide Enhances Radiation-induced Apoptosis and Inhibition of Melanoma Cell Proliferation.
Y. FANG, B. J. MOORE, Q. BAI, K. M. COOK, E. J. HERRICK, and M. B. NICHOLL (2013)
Anticancer Res 33, 1799-1807
   Abstract »    Full Text »    PDF »
The Protein Factor-arrest 11 (Far11) Is Essential for the Toxicity of Human Caspase-10 in Yeast and Participates in the Regulation of Autophagy and the DNA Damage Signaling.
P. Lisa-Santamaria, A. Jimenez, and J. L. Revuelta (2012)
J. Biol. Chem. 287, 29636-29647
   Abstract »    Full Text »    PDF »
Bifunctional Apoptosis Regulator (BAR), an Endoplasmic Reticulum (ER)-associated E3 Ubiquitin Ligase, Modulates BI-1 Protein Stability and Function in ER Stress.
J. Rong, L. Chen, J. I. Toth, M. Tcherpakov, M. D. Petroski, and J. C. Reed (2011)
J. Biol. Chem. 286, 1453-1463
   Abstract »    Full Text »    PDF »
The Caspase-8 Dimerization/Dissociation Balance Is a Highly Potent Regulator of Caspase-8, -3, -6 Signaling.
M. L. Wurstle, M. A. Laussmann, and M. Rehm (2010)
J. Biol. Chem. 285, 33209-33218
   Abstract »    Full Text »    PDF »
Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis.
Y. Fang, S. Yu, J. S. Ellis, T. Sharav, and H. Braley-Mullen (2010)
J. Leukoc. Biol. 87, 1019-1028
   Abstract »    Full Text »    PDF »
The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-{alpha} motif domain in thymic selection and T-cell activation.
S. Shen, J. Lau, M. Zhu, J. Zou, D. Fuller, Q.-j. Li, and W. Zhang (2009)
Blood 114, 74-84
   Abstract »    Full Text »    PDF »
Good news for mice with heart attacks: preventing acute myocardial injury by inhibiting apoptosis.
G. A. MacGowan (2009)
Cardiovasc Res 81, 1-2
   Full Text »    PDF »
Over-expression of a modified bifunctional apoptosis regulator protects against cardiac injury and doxorubicin-induced cardiotoxicity in transgenic mice.
C. C. Chua, J. Gao, Y.-S. Ho, X. Xu, I-C. Kuo, K.-Y. Chua, H. Wang, R. C. Hamdy, J. C. Reed, and B. H.L. Chua (2009)
Cardiovasc Res 81, 20-27
   Abstract »    Full Text »    PDF »
Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.
F. Gonzalvez, Z. T. Schug, R. H. Houtkooper, E. D. MacKenzie, D. G. Brooks, R. J.A. Wanders, P. X. Petit, F. M. Vaz, and E. Gottlieb (2008)
J. Cell Biol. 183, 681-696
   Abstract »    Full Text »    PDF »
BI-1 Regulates Endoplasmic Reticulum Ca2+ Homeostasis Downstream of Bcl-2 Family Proteins.
C. Xu, W. Xu, A. E. Palmer, and J. C. Reed (2008)
J. Biol. Chem. 283, 11477-11484
   Abstract »    Full Text »    PDF »
Kruppel-Like Zinc Finger Protein Glis2 Is Essential for the Maintenance of Normal Renal Functions.
Y.-S. Kim, H. S. Kang, R. Herbert, J. Y. Beak, J. B. Collins, S. F. Grissom, and A. M. Jetten (2008)
Mol. Cell. Biol. 28, 2358-2367
   Abstract »    Full Text »    PDF »
Key Note Lecture: Toward a Mechanistic Taxonomy for Cell Death Programs.
D. E. Bredesen (2007)
Stroke 38, 652-660
   Abstract »    Full Text »    PDF »
Human cellular protein VRK2 interacts specifically with Epstein-Barr virus BHRF1, a homologue of Bcl-2, and enhances cell survival..
L.-Y. Li, M.-Y. Liu, H.-M. Shih, C.-H. Tsai, and J.-Y. Chen (2006)
J. Gen. Virol. 87, 2869-2878
   Abstract »    Full Text »    PDF »
Missense Mutation in Sterile {alpha} Motif of Novel Protein SamCystin is Associated with Polycystic Kidney Disease in (cy/+) Rat.
J. H. Brown, M.-T. Bihoreau, S. Hoffmann, B. Kranzlin, I. Tychinskaya, N. Obermuller, D. Podlich, S. N. Boehn, P. J. Kaisaki, N. Megel, et al. (2005)
J. Am. Soc. Nephrol. 16, 3517-3526
   Abstract »    Full Text »    PDF »
Structural Organization of a Sex-comb-on-midleg/Polyhomeotic Copolymer.
C. A. Kim, M. R. Sawaya, D. Cascio, W. Kim, and J. U. Bowie (2005)
J. Biol. Chem. 280, 27769-27775
   Abstract »    Full Text »    PDF »
Mapping of Familial Thoracic Aortic Aneurysm/Dissection With Patent Ductus Arteriosus to 16p12.2-p13.13.
P. K. Van Kien, F. Mathieu, L. Zhu, A. Lalande, C. Betard, M. Lathrop, F. Brunotte, J.-E. Wolf, and X. Jeunemaitre (2005)
Circulation 112, 200-206
   Abstract »    Full Text »    PDF »
The Many Faces of SAM.
F. Qiao and J. U. Bowie (2005)
Sci. STKE 2005, re7
   Abstract »    Full Text »    PDF »
Mammalian Prion Protein Suppresses Bax-induced Cell Death in Yeast.
A. Li and D. A. Harris (2005)
J. Biol. Chem. 280, 17430-17434
   Abstract »    Full Text »    PDF »
Bistability Analyses of a Caspase Activation Model for Receptor-induced Apoptosis.
T. Eissing, H. Conzelmann, E. D. Gilles, F. Allgower, E. Bullinger, and P. Scheurich (2004)
J. Biol. Chem. 279, 36892-36897
   Abstract »    Full Text »    PDF »
The Domains of Apoptosis: A Genomics Perspective.
J. C. Reed, K. S. Doctor, and A. Godzik (2004)
Sci. STKE 2004, re9
   Abstract »    Full Text »    PDF »
p63: molecular complexity in development and cancer.
M. D. Westfall and J. A. Pietenpol (2004)
Carcinogenesis 25, 857-864
   Abstract »    Full Text »    PDF »
Apoptosis Repressor with Caspase Recruitment Domain Protects against Cell Death by Interfering with Bax Activation.
A. B. Gustafsson, J. G. Tsai, S. E. Logue, M. T. Crow, and R. A. Gottlieb (2004)
J. Biol. Chem. 279, 21233-21238
   Abstract »    Full Text »    PDF »
Renal epithelial gene expression profile and bismuth-induced resistance against cisplatin nephrotoxicity.
B. T Leussink, H. J Baelde, T. M B.-v. den Berg, E. de Heer, G. B van der Voet, A. Slikkerveer, J. A Bruijn, and F. A de Wolff (2003)
Human and Experimental Toxicology 22, 535-540
   Abstract »    PDF »
PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis.
C. Gao, W. Sun, M. Christofidou-Solomidou, M. Sawada, D. K. Newman, C. Bergom, S. M. Albelda, S. Matsuyama, and P. J. Newman (2003)
Blood 102, 169-179
   Abstract »    Full Text »    PDF »
Oligomerization-dependent Association of the SAM Domains from Schizosaccharomyces pombe Byr2 and Ste4.
R. Ramachander, C. A. Kim, M. L. Phillips, C. D. Mackereth, C. D. Thanos, L. P. McIntosh, and J. U. Bowie (2002)
J. Biol. Chem. 277, 39585-39593
   Abstract »    Full Text »    PDF »
Cytoplasmic {micro} Heavy Chain Confers Sensitivity to Dexamethasone-induced Apoptosis in Early B-lineage Acute Lymphoblastic Leukemia.
J. M. Kim, J. Fang, S. Rheingold, R. Aplenc, R. Wasserman, and S. A. Grupp (2002)
Cancer Res. 62, 4212-4216
   Abstract »    Full Text »    PDF »
Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin.
H.-W. Wang, T. V. Sharp, A. Koumi, G. Koentges, and C. Boshoff (2002)
EMBO J. 21, 2602-2615
   Abstract »    Full Text »    PDF »
Identification and Characterization of DEDD2, a Death Effector Domain-containing Protein.
W. Roth, F. Stenner-Liewen, K. Pawlowski, A. Godzik, and J. C. Reed (2002)
J. Biol. Chem. 277, 7501-7508
   Abstract »    Full Text »    PDF »
Inactivation of Caspase-8 on Mitochondria of Bcl-xL-expressing MCF7-Fas Cells. ROLE FOR THE BIFUNCTIONAL APOPTOSIS REGULATOR PROTEIN.
A. H. Stegh, B. C. Barnhart, J. Volkland, A. Algeciras-Schimnich, N. Ke, J. C. Reed, and M. E. Peter (2002)
J. Biol. Chem. 277, 4351-4360
   Abstract »    Full Text »    PDF »
Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view.
A. D. Schimmer, D. W. Hedley, L. Z. Penn, and M. D. Minden (2001)
Blood 98, 3541-3553
   Full Text »    PDF »
Cellular stress response and apoptosis in cancer therapy.
I. Herr and K.-M. Debatin (2001)
Blood 98, 2603-2614
   Abstract »    Full Text »    PDF »
Fas-mediated Apoptosis in Neuroblastoma Requires Mitochondrial Activation and Is Inhibited by FLICE Inhibitor Protein and bcl-2.
V. Poulaki, N. Mitsiades, M. E. Romero, and M. Tsokos (2001)
Cancer Res. 61, 4864-4872
   Abstract »    Full Text »    PDF »
Apoptosis in sepsis: a new target for therapeutic exploration.
C. OBERHOLZER, A. OBERHOLZER, M. CLARE-SALZLER, and L. L. MOLDAWER (2001)
FASEB J 15, 879-892
   Abstract »    Full Text »    PDF »
Huntingtin Interacting Protein 1 Induces Apoptosis via a Novel Caspase-dependent Death Effector Domain.
A. S. Hackam, A. S. Yassa, R. Singaraja, M. Metzler, C.-A. Gutekunst, L. Gan, S. Warby, C. L. Wellington, J. Vaillancourt, N. Chen, et al. (2000)
J. Biol. Chem. 275, 41299-41308
   Abstract »    Full Text »    PDF »
Identification of the Cytolinker Plectin as a Major Early In Vivo Substrate for Caspase 8 during CD95- and Tumor Necrosis Factor Receptor-Mediated Apoptosis.
A. H. Stegh, H. Herrmann, S. Lampel, D. Weisenberger, K. Andra, M. Seper, G. Wiche, P. H. Krammer, and M. E. Peter (2000)
Mol. Cell. Biol. 20, 5665-5679
   Abstract »    Full Text »    PDF »
Bcl-G, a Novel Pro-apoptotic Member of the Bcl-2 Family.
B. Guo, A. Godzik, and J. C. Reed (2001)
J. Biol. Chem. 276, 2780-2785
   Abstract »    Full Text »    PDF »
Apoptosis-resistant Mitochondria in T Cells Selected for Resistance to Fas Signaling.
G.-Q. Wang, B. R. Gastman, E. Wieckowski, L. A. Goldstein, A. Rabinovitz, X.-M. Yin, and H. Rabinowich (2001)
J. Biol. Chem. 276, 3610-3619
   Abstract »    Full Text »    PDF »
Huntingtin interacting protein 1 (HIP-1) induces apoptosis via a novel caspase-dependent death effector domain.
A. S. Hackam, A. S. Yassa, R. Singaraja, M. Metzler, C.-A. Gutekunst, L. Gan, S. Warby, C. L. Wellington, J. Vaillancourt, N. Chen, et al. (2000)
J. Biol. Chem.
   Abstract »
The Cellular Protein PRA1 Modulates the Anti-apoptotic Activity of Epstein-Barr Virus BHRF1, a Homologue of Bcl-2, through Direct Interaction.
L.-Y. Li, H.-M. Shih, M.-Y. Liu, and J.-Y. Chen (2001)
J. Biol. Chem. 276, 27354-27362
   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