MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-κB activation

• Published in: Oncogene Vol. 22; no. 49; pp. 7774 - 7780
• Main Authors: NAWATA, Ryouhei, YUJIRI, Toshiaki, NAKAMURA, Yukinori, ARIYOSHI, Koichi, TAKAHASHI, Toru, SATO, Yutaka, OKA, Yoshitomo, TANIZAWA, Yukio
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 30.10.2003; Nature Publishing Group
• Subjects: Abl gene; Abl protein; Apoptosis; Bcr gene; BCR protein; Biological and medical sciences; c-Jun protein; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chronic myeloid leukemia; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Fusion protein; Gene expression; Genetic transformation; JNK protein; Kinases; Leukemia; Leukemogenesis; MEK kinase; MEK kinase 1; MEKK1 protein; Molecular and cellular biology; Myeloid leukemia; NF-κB protein; Oncogenes; Protein-tyrosine kinase; Signal transduction; Transcription factors; Transformed cells; MEK kinase 1; Enzyme; Kinase; Transferases; NF-KB; Bcr-Abl; Activation; Onc gene; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206901

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.