Abstract
Bcr-Abl tyrosine kinase, a chimeric oncoprotein responsible for chronic myelogenous leukemia, constitutively activates several signal transduction pathways that stimulate cell proliferation and prevent apoptosis in hematopoietic cells. The antiapoptotic function of Bcr-Abl is necessary for hematopoietic transformation, and also contributes to leukemogenesis. Herein, we show for the first time that cell transformation induced by Bcr-Abl leads to increased expression and kinase activity of MEK kinase 1 (MEKK1), which acts upstream of the c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and NF-κB signaling pathways. Inhibition of MEKK1 activity using a dominant-negative MEKK1 mutant (MEKK1km) diminished the ability of Bcr-Abl to protect cells from genotoxin-induced apoptosis, but had no effect on the proliferation of Bcr-Abl-transformed cells. Expression of MEKK1km also reduced NF-κB activation, and inhibited antiapoptotic c-IAP1 and c-IAP2 mRNA expression in response to the genotoxin. By contrast, neither JNK nor ERK activation was affected. These results indicate that MEKK1 is a downstream target of Bcr-Abl, and that the antiapoptotic effect of Bcr-Abl in chronic myelogenous leukemia cells is mediated via the MEKK1-NF-κB pathway.
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Acknowledgements
We thank Drs Owen N Witte and Gary L Johnson for their generous gifts of plasmids. We also thank Ms Yukari Kora for technical assistance. This work was supported by research fellowships from the Japan Society for the Promotion of Science for Young Scientists and from The Nakajima Foundation (to TY).
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Nawata, R., Yujiri, T., Nakamura, Y. et al. MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-κB activation. Oncogene 22, 7774–7780 (2003). https://doi.org/10.1038/sj.onc.1206901
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DOI: https://doi.org/10.1038/sj.onc.1206901
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