MEK kinase 1 is essential for Bcr-Abl-induced STAT3 and self-renewal activity in embryonic stem cells.
BCR-ABL oncogene, the molecular hallmark of chronic myelogenous leukemia, arises in a primitive hematopoietic stem cell that has the capacity for both differentiation and self-renewal. Its product, Bcr-Abl protein, has been shown to activate signal transducers and activators of transcription 3 (STAT3) and to promote self-renewal in embryonic stem (ES) cells, even in the absence of leukemia inhibitory factor (LIF). MEK kinase 1 (MEKK1) is a 196-kDa mitogen-activated protein kinase (MAPK) kinase kinase involved in Bcr-Abl signal transduction. To investigate the role of MEKK1 in Bcr-Abl-induced transformation of stem cells, p210 Bcr-Abl was stably transfected into wild-type (WT(p210)) and MEKK1-/- (MEKK1-/-(p210)) ES cells. Bcr-Abl enhanced MEKK1 expression in ES transfectants, as it does in other Bcr-Abl-transformed cells. In the absence of LIF, WT(p210) cells showed constitutive STAT3 activation and formed rounded, compact colonies having strong alkaline phosphatase activity, a characteristic phenotype of undifferentiated ES cells. MEKK1-/-(p210) cells, by contrast, showed less STAT3 activity than WT(p210) cells and formed large, flattened colonies having weak alkaline phosphatase activity, a phenotype of differentiated ES cells. These results indicate that MEKK1 plays a key role in Bcr-Abl-induced STAT3 activation and in ES cells' capacity for LIF-independent self-renewal, and may thus be involved in Bcr-Abl-mediated leukemogenesis in stem cells.
Nakamura
Yukinori
Y
Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
Yujiri
Toshiaki
T
Nawata
Ryouhei
R
Tagami
Kozo
K
Tanizawa
Yukio
Y
D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016313:Genes, abl; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D010641:Phenotype; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016315:Proto-Oncogene Proteins c-abl; D048728:MAP Kinase Kinase Kinase 1