MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-κB activation
MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-κB activation
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DOI：
10.1038/sj.onc.1206901
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发表时间：
2003-10-30
期刊：
影响因子：
8
通讯作者：
Tanizawa, Y
中科院分区：
文献类型：
--
作者：
Nawata, R;Yujiri, T;Tanizawa, Y
Bcr-Abl酪氨酸激酶是一种负责慢性髓性白血病的嵌合癌蛋白，在造血细胞中组成性地激活几种刺激细胞增殖和防止细胞凋亡的信号转导途径。Bcr-Abl的抗凋亡功能是造血转化所必需的，也有助于白血病的发生。在此，我们首次发现Bcr-Abl诱导的细胞转化导致MEK激酶1 （MEKK1）的表达和激酶活性增加，MEKK1作用于c-Jun n末端激酶（JNK）、细胞外信号调节激酶（ERK）和NF-kappaB信号通路的上游。使用MEKK1显性阴性突变体（MEKK1km）抑制MEKK1活性会降低Bcr-Abl保护细胞免受基因毒素诱导的凋亡的能力，但对Bcr-Abl转化细胞的增殖没有影响。MEKK1km的表达也降低了NF-kappaB的激活，抑制了抗凋亡细胞c-IAP1和c-IAP2 mRNA的表达。相比之下，JNK和ERK的激活均未受到影响。这些结果表明，MEKK1是Bcr-Abl的下游靶点，Bcr-Abl在慢性髓性白血病细胞中的抗凋亡作用是通过MEKK1- nf - kappab途径介导的。
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.