Molecular and Cellular Biology, October 1999, p. 6673-6681, Vol. 19, No. 10
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Copyright © 1999, American Society for Microbiology. All rights reserved.

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