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-kappaB 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-kappaB 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-kappaB pathway.
