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Analysis of MEKK1 involved in cytoskeleton and cell migration.

分析参与细胞骨架和细胞迁移的MEKK1。

基本信息

批准号：
15570162
负责人：
YUJIRI Toshiaki
金额：
$ 2.3万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15570162/
关键词：
MEKK1 embryonic stem cells Bcr-Abl Cell Migration Calpain STAT3 FAK IRS1 Cell migration

项目摘要

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 I (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 LIE, 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.

BCR-ABL癌基因是慢性粒细胞性白血病的分子标志，起源于具有分化和自我更新能力的原始造血干细胞。其产物Bcr-Abl蛋白已被证明激活信号转导和转录激活因子3（STAT 3），并促进胚胎干细胞（ES）的自我更新，即使在缺乏白血病抑制因子（LIF）的情况下。MEK激酶I（MEKK 1）是一种196-kDa的丝裂原活化蛋白激酶（MAPK）激酶，参与Bcr-Abl信号转导。为了研究MEKK 1在Bcr-Abl诱导的干细胞转化中的作用，将p210 Bcr-Abl稳定转染到野生型（WT<p210>）和MEKK 1-/-（MEKK 1-/-<p210>）ES细胞中。Bcr-Abl增强ES转染细胞中MEKK 1的表达，就像它在其他Bcr-Abl转化细胞中一样。在不存在LIE的情况下，WT+<p210>细胞显示组成型STAT 3活化，并形成具有强碱性磷酸酶活性的圆形紧凑集落，这是未分化ES细胞的特征表型。相比之下，MEKK 1-/-γ<p210>细胞显示出比WT-γ细胞更低的STAT 3活性<p210>，并形成具有弱碱性磷酸酶活性的大的扁平集落，这是分化的ES细胞的表型。这些结果表明MEKK 1在Bcr-Abl诱导的STAT 3激活和ES细胞的LIF非依赖性自我更新能力中起关键作用，因此可能参与Bcr-Abl介导的干细胞白血病发生。