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J. Biol. Chem., Vol. 275, Issue 23, 17225-17228, June 9, 2000

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ACCELERATED PUBLICATION
Bcl-2 Inhibits a Fas-induced Conformational Change in the Bax N Terminus and Bax Mitochondrial Translocation^*

Kathleen M. Murphy^§, Uldis N. Streips, and Richard B. Lock^¶

From the  Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, 40292 and the ^¶ Children's Cancer Institute Australia for Medical Research, High St., Randwick, New South Wales 2031, Australia

Members of the Bcl-2 family of proteins control the cellular commitment to apoptosis, although their role in Fas-induced apoptosis is ill-defined. In this report we demonstrate that activation of the Fas receptor present on a human breast epithelial cell line resulted in a conformational change in the N terminus of the pro-apoptotic protein Bax. This conformational change appeared to occur in the cytosol and precede Bax translocation to the mitochondria. Overexpression of the anti-apoptotic protein Bcl-2 inhibited both the conformational change of Bax as well as its relocalization to the mitochondria. Bcl-2 overexpression did not, however, inhibit Fas-induced cleavage of both procaspase-8 and the pro-apoptotic protein Bid, indicating that Bcl-2 functions downstream of these events. These results suggest that the mechanism by which Bcl-2 inhibits Bax mitochondrial translocation and subsequent amplification of the apoptotic cascade is not by providing a physical barrier to Bax, but rather by inhibiting an upstream event necessary for Bax conformational change.

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