期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 32, 页码 24273-24278出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M002094200
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资金
- NCI NIH HHS [CA75348-03] Funding Source: Medline
- NIDDK NIH HHS [DK50654] Funding Source: Medline
The BCR/ABL oncogene causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and myeloid cells, It is shown here that transformation of the hematopoietic cell lines Ba/F3, 32Dcl3, and M07e with BCR/ABL results in an increase in reactive oxygen species (ROS) compared with quiescent, untransformed cells. The increase in ROS was directly due to BCR/ABL because it was blocked by the ABL-specific tyrosine kinase inhibitor STI571, Oxidative stress through ROS is believed to have many biochemical effects, including the potential ability to inhibit protein-tyrosine phosphatases (PTPases), To understand the significance of increased production of ROS, a model system was established in which hydrogen peroxide (H2O2) was added to untransformed cells to mimic the increase in ROS induced constitutively by BCR/ABL. H2O2 substantially reduced total cellular PTPase activity to a degree approximately equivalent to that of pervanadate, a well known PTPase inhibitor. Further, stimulation of untransformed cells with H2O2 or pervanadate increased tyrosine phosphorylation of each of the most prominent known substrates of BCR/ABL, including c-ABL, c-CBL, SHC, and SHP-2. Treatment of the BCR/ABL-expressing cell line MO7/p210 with the reducing agents pyrrolidine dithiocarbamate or N-acetylcysteine reduced the accumulation of ROS and also decreased tyrosine phosphorylation of cellular proteins. Further, treatment of M07e cells with H2O2 or pervanadate increased the tyrosine kinase activity of c-ABL, Drugs that alter ROS metabolism or reactivate PTPases may antagonize BCR/ABL transformation.
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