IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line
IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line
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DOI：
10.1038/sj.onc.1202796
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发表时间：
1999-07-22
期刊：
影响因子：
8
通讯作者：
Gouilleux, F
中科院分区：
文献类型：
--
作者：
Dumon, S;Santos, SCR;Gouilleux, F
细胞因子对Jak/STAT通路的激活已显示出调节造血细胞的分化、增殖或凋亡。在Stat蛋白中，STAT 5被广泛的细胞因子激活。为了研究STAT 5在造血细胞中的作用，我们在IL-3依赖性骨髓来源的Ba/F3细胞系中稳定表达STAT 5的显性阴性形式（STAT 5A Delta 749）。发现表达STAT 5A Delta 749的Ba/F3细胞在IL-3撤除后比亲本或对照Ba/F3细胞对细胞凋亡更敏感。对细胞死亡调节因子Bcl-2和Bcl-x的表达的分析显示，表达STAT 5A Delta 749的Ba/F3细胞中Bcl-x的水平低于对照细胞。在这些细胞中，IL-3对Bcl-x表达的蛋白质和mRNA水平调节受到损害，而对Bcl-2表达的调节不受影响。我们进一步证明了Bcl-x基因启动子含有一个与STAT 5结合的近端STAT共有序列。在Ba/F3细胞中观察到STAT 5对Bcl-x基因启动子报告构建体的反式激活。在STAT结合位点引入突变消除了这种反式激活。这些数据表明Bcl-x可能是STAT 5的靶基因。它们还支持STAT 5参与造血细胞存活。
Activation of the Jak/STAT pathway by cytokines has been shown to regulate differentiation, proliferation or apoptosis in hematopoeitic cells. Among the Stat proteins, STAT5 is activated by a broad range of cytokines. In order to study the role of STAT5 in hematopoietic cells, we stably expressed a dominant negative form of STAT5 (STAT5A Delta 749) in the IL-3 dependent bone marrow derived Ba/F3 cell line. Ba/F3 cells expressing STAT5A Delta 749 were found to be more sensitive to apoptosis than parental or control Ba/F3 cells after IL-3 withdrawal. Analysis of the expression of the cell death regulators, Bcl-2 and Bcl-x, revealed that the level of Bcl-x was lower in Ba/F3 cells expressing STAT5A Delta 749 than in control cells. IL-3 regulation of Bcl-x expression at protein and mRNA levels was impaired in these cells while that of Bcl-2 expression was unaffected. We further demonstrated that the Bcl-x gene promoter contained a proximal STAT consensus sequence that bound STAT5. Transactivation of a Bcl-x gene promoter reporter construct by STAT5 was observed in Ba/F3 cells. Introduction of a mutation in the STAT binding site abolished this transactivation. These data indicate that Bcl-x is probably a STAT5 target gene. They also support the involvement of STAT5 in hematopoietic cell survival.