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Vol. 63, Issue 2, 276-282, February 2003
Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts (S.K., D.R., D.K.); Lovelace Respiratory Research
Institute, Albuquerque, New Mexico (N.M., S.S.)
Normal aerobic metabolism is associated with the production of
reactive oxygen species (ROS) and, consequently, the induction of
apoptosis and necrosis. The cell death response to oxidative stress is
thought to contribute to aging, neurological degeneration, and other
disorders. ROS-induced apoptosis and necrosis involves activation of
the cytoplasmic c-Abl tyrosine kinase and thereby signaling to
mitochondria. Herein, we show that STI571, an inhibitor of Bcr-Abl in
chronic myelogenous leukemia, blocks activation of c-Abl in the
response of mouse embryo fibroblasts and human U-937 myeloid leukemia
cells to hydrogen peroxide (H2O2).
Immunofluorescence microscopy and subcellular fractionation studies
demonstrate that STI571 decreases H2O2-induced
targeting of c-Abl to mitochondria in the two cell types by 59 to 85%.
The results also show that STI571 attenuates
H2O2-induced loss of the mitochondrial
transmembrane potential. In concert with these effects, STI571 inhibits
the death response to H2O2 exposure by 40 to
80% depending on the cell type. These findings indicate that
inhibition of c-Abl signaling by STI571 attenuates mitochondrial
dysfunction and cell death in the cellular response to oxidative stress.
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