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Biochemistry and Biophysics |
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
The role of the mitochondrial permeability transition (MPT) in the killing of HeLa cells by staurosporine (STR) was assessed with the use of bongkrekic acid (BK), an inhibitor of the MPT. BK prevented cell killing as well as biochemical manifestations of the MPT: (a) the loss of the mitochondrial membrane potential (
m); (b) the release of cytochrome c from the intramembranous space to the cytosol; and (c) the release of malate dehydrogenase from the mitochondrial matrix. Stable transfectants that overexpressed Akt were also resistant to cell killing and did not develop an MPT. STR inhibited the phosphorylation of Bad, whereas Bad phosphorylation was preserved in cells that overexpress Akt. In wild-type HeLa cells treated with STR, the content of Bax in the cytosol decreased as that in the mitochondria increased, a result that was again prevented by overexpression of Akt. Bid accumulation in the mitochondria with STR was not affected by overexpression of Akt. The pan-caspase inhibitor Z-Val-Ala-Val-Asp(OMe) fluoromethylketone prevented cell killing but not induction of the MPT. The data document the central role of the MPT in the killing of HeLa cells by STR. The data are consistent with the hypothesis that induction of the MPT is a consequence of the movement of Bax to the mitochondria. Phosphorylation of Bad prevents Bax translocation. Caspases participate in the events related to cell killing that occur subsequent to induction of the MPT.
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