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Papers In Press, published online ahead of print March 30, 2006
Dept. of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199
Corresponding Author: chamberstimothyc{at}uams.edu
To gain a broader insight into the role of Bcl-2 proteins in apoptosis induced after mitotic arrest, we investigated the subcellular location, oligomeric structure, and protein interactions of Bax, Bcl-2 and Bcl-xL in vinblastine-treated KB-3 cells. Vinblastine induced the translocation of Bax from the cytosol to the mitochondria which was accompanied by conformational activation and oligomerization of Bax. Bcl-2 was located in the mitochondria and underwent multisite phosphorylation after vinblastine treatment and was strictly monomeric under all conditions. In contrast, in control cells, Bcl-xL existed in both monomeric (30 kDa) and oligomeric (150 kDa) forms. Treatment with agents that induced Bcl-xL phosphorylation (microtubule inhibitors) caused loss of the 150 kDa form, but this species was unaffected by apoptotic stimuli that did not stimulate phosphorylation. Vinblastine also promoted Bax activation and Bax oligomerization in HCT116 colon cancer cells. Both wild-type and Bax-deficient HCT116 cells expressed the 150 kDa form of Bcl-xL which was depleted similarly in both cell lines upon vinblastine treatment. Co-immunoprecipitation studies revealed that in untreated KB-3 cells inactive cytosolic Bax interacted with Bcl-xL, whereas in vinblastine-treated cells activated mitochondrial Bax did not interact with Bcl-xL. Interaction of Bcl-2 with Bax was not observed under any condition. Overexpression of Bcl-xL inhibited vinblastine-induced Bax activation and Bax dimerization, and in parallel inhibited apoptosis. The results indicate that vinblastine-induced apoptosis requires translocation, activation and oligomerization of Bax, and is associated with specific changes in the oligomeric properties of Bcl-xL which occur independently of Bax.
J. Biol. Chem, 10.1074/jbc.M512586200
Submitted on November 23, 2005
Accepted on March 30, 2006
Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members
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