MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-kappaB activation.
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.
Nawata
Ryouhei
R
Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
Yujiri
Toshiaki
T
Nakamura
Yukinori
Y
Ariyoshi
Koichi
K
Takahashi
Toru
T
Sato
Yutaka
Y
Oka
Yoshitomo
Y
Tanizawa
Yukio
Y
D000818:Animals; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001483:Base Sequence; D002460:Cell Line; D016313:Genes, abl / Q000502:physiology*; D051034:Inhibitor of Apoptosis Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044767:Ubiquitin-Protein Ligases
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse