title: Bcl-2 inhibits a Fas-induced conformational change in the Bax N terminus and Bax mitochondrial translocation.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Murphy
authors.forename: U N
authors.initials: UN
authors.lastname: Streips
authors.forename: R B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D017209:Apoptosis; D001940:Breast; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000502:physiology*
chemical_list: C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor