c-Jun N-terminal kinase mediates AML1-ETO protein-induced connexin-43 expression
c-Jun N-terminal kinase mediates AML1-ETO protein-induced connexin-43 expression
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c-Jun N 末端激酶介导 AML1-ETO 蛋白诱导的 connexin-43 表达
DOI：
10.1016/j.bbrc.2007.03.009
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发表时间：
2007-05-04
影响因子：
3.1
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
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作者：
Gao, Feng-Hou;Wang, Qiong;Chen, Guo-Qiang
AML 1-ETO融合蛋白是白血病相关染色体易位t（8;2 1）的产物，可上调缝隙连接蛋白家族成员Cx43的表达。然而，其机制仍不清楚。通过生物信息学分析，我们发现在Cx43基因上游的5 '-侧翼区存在两个与AML 1结合的共有序列和两个激活蛋白（AP）I位点。电泳迁移率改变实验表明，AML 1-ETO可直接与这两个AML 1结合位点结合，而荧光素酶报告基因实验表明，AML 1-ETO蛋白诱导Cx43的过程中，AML 1结合位点并不是必需的。相反，AP 1位点在此事件中发挥了重要作用。结果表明，AML 1-ETO在U937细胞中的过表达激活了c-Jun N-末端激酶（JNK），而其特异性抑制剂SP 600125有效地阻断了AML 1-ETO诱导的Cx43表达，提示JNK信号通路参与了AML 1-ETO诱导的Cx43表达。这些结果将为了解AML 1-ETO相关白血病发生的机制提供新的见解。(c)2007年爱思唯尔公司All rights reserved.
AML1-ETO fusion protein, a product of leukemia-related chromosomal translocation t(8;2 1), was reported to upregulate expression of connexin-43 (Cx43), a member of gap junction-constituted connexin family. However, its mechanism(s) remains unclear. By bioinformatic analysis, here we showed that there are two putative AML1-binding consensus sequences followed by two activated protein (AP) I sites in the 5 '-flanking region upstream to Cx43 gene. AML1-ETO could directly bind to these two AML1-binding sites in electrophoretic mobility shift assay, but luciferase reporter assay revealed that the AML1 binding sites were not indispensable for Cx43 induction by AML1-ETO protein. Conversely, AP1 sites exerted an important role in this event. In agreement, AML1-ETO overexpression in leukemic U937 cells activated c-Jun N-terminal kinase (JNK), while its specific inhibitor SP600125 effectively abrogated AML1-ETO-induced Cx43 expression, indicating that JNK signaling pathway contributes to AML1-ETO induced Cx43 expression. These results would shed new insights for understanding mechanisms of AML1-ETO-associated leukemogenesis. (c) 2007 Elsevier Inc. All rights reserved.