This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chang, B. S.
Right arrow Articles by Thompson, C. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chang, B. S.
Right arrow Articles by Thompson, C. B.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 1999, p. 6673-6681, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The BH3 Domain of Bcl-xS Is Required for Inhibition of the Antiapoptotic Function of Bcl-xL

Brian S. Chang,1,2 Ameeta Kelekar,1,3 Marian H. Harris,1,4,dagger John E. Harlan,5 Stephen W. Fesik,5 and Craig B. Thompson1,2,3,4,*

Gwen Knapp Center for Lupus and Immunology Research,1 Department of Medicine,2 Howard Hughes Medical Institute,3 and Department of Molecular Genetics and Cell Biology,4 The University of Chicago, Chicago, Illinois 60637, and Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 606645

Received 8 December 1998/Returned for modification 23 February 1999/Accepted 6 July 1999

bcl-x is a member of the bcl-2 family of genes. The major protein product, Bcl-xL, is a 233-amino-acid protein which has antiapoptotic properties. In contrast, one of the alternatively spliced transcripts of the bcl-x gene codes for the protein Bcl-xS, which lacks 63 amino acids present in Bcl-xL and has proapoptotic activity. Unlike other proapoptotic Bcl-2 family members, such as Bax and Bak, Bcl-xS does not seem to induce cell death in the absence of an additional death signal. However, Bcl-xS does interfere with the ability of Bcl-xL to antagonize Bax-induced death in transiently transfected 293 cells. Mutational analysis of Bcl-xS was conducted to identify the domains necessary to mediate its proapoptotic phenotype. Deletion mutants of Bcl-xS which still contained an intact BH3 domain retained the ability to inhibit survival through antagonism of Bcl-xL. Bcl-xS was able to form heterodimers with Bcl-xL in mammalian cells, and its ability to inhibit survival correlated with the ability to heterodimerize with Bcl-xL. Deletion mutants of Bax and Bcl-2, which lacked BH1 and BH2 domains but contained a BH3 domain, were able to antagonize the survival effect conferred by Bcl-xL. The results suggest that BH3 domains from both pro- and antiapoptotic Bcl-2 family members, while lacking an intrinsic ability to promote programmed cell death, can be potent inhibitors of Bcl-xL survival function.

* Corresponding author. Present address: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104. Phone: (215) 746-5534. Fax: (215) 746-5511. E-mail: craig{at}mail.med.upenn.edu.

dagger Present address: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104.

Molecular and Cellular Biology, October 1999, p. 6673-6681, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Revil, T., Toutant, J., Shkreta, L., Garneau, D., Cloutier, P., Chabot, B. (2007). Protein Kinase C-Dependent Control of Bcl-x Alternative Splicing. Mol. Cell. Biol. 27: 8431-8441 [Abstract] [Full Text]  
  • Kroemer, G., Galluzzi, L., Brenner, C. (2007). Mitochondrial Membrane Permeabilization in Cell Death. Physiol. Rev. 87: 99-163 [Abstract] [Full Text]  
  • Braun, T., Dar, S., Vorobiov, D., Lindenboim, L., Dascal, N., Stein, R. (2003). Expression of Bcl-xS in Xenopus Oocytes Induces BH3-Dependent and Caspase-Dependent Cytochrome c Release and Apoptosis. Mol Cancer Res 1: 186-194 [Abstract] [Full Text]  
  • Fridman, J. S., Benedict, M. A., Maybaum, J. (1999). bcl-Xs-induced Cell Death in 3T3 Cells Does Not Require or Induce Caspase Activation. Cancer Res. 59: 5999-6004 [Abstract] [Full Text]  
  • Sevilla, L., Zaldumbide, A., Carlotti, F., Dayem, M. A., Pognonec, P., Boulukos, K. E. (2001). Bcl-xL Expression Correlates with Primary Macrophage Differentiation, Activation of Functional Competence, and Survival and Results from Synergistic Transcriptional Activation by Ets2 and PU.1. J. Biol. Chem. 276: 17800-17807 [Abstract] [Full Text]  
  • Sun, Y.-F., Yu, L.-Y., Saarma, M., Timmusk, T., Arumae, U. (2001). Neuron-specific Bcl-2 Homology 3 Domain-only Splice Variant of Bak Is Anti-apoptotic in Neurons, but Pro-apoptotic in Non-neuronal Cells. J. Biol. Chem. 276: 16240-16247 [Abstract] [Full Text]  
  • Plas, D. R., Talapatra, S., Edinger, A. L., Rathmell, J. C., Thompson, C. B. (2001). Akt and Bcl-xL Promote Growth Factor-independent Survival through Distinct Effects on Mitochondrial Physiology. J. Biol. Chem. 276: 12041-12048 [Abstract] [Full Text]  
  • Bae, J., Leo, C. P., Hsu, S. Y., Hsueh, A. J. W. (2000). MCL-1S, a Splicing Variant of the Antiapoptotic BCL-2 Family Member MCL-1, Encodes a Proapoptotic Protein Possessing Only the BH3 Domain. J. Biol. Chem. 275: 25255-25261 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»