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首页> 外文期刊>Molecular and Cellular Biology >Point Mutations in Two EVI1 Zn Fingers Abolish EVI1-GATA1 Interaction and Allow Erythroid Differentiation of Murine Bone Marrow Cells
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Point Mutations in Two EVI1 Zn Fingers Abolish EVI1-GATA1 Interaction and Allow Erythroid Differentiation of Murine Bone Marrow Cells

机译：两个EVI1锌指中的点突变消除了EVI1-GATA1的相互作用，并允许鼠骨髓细胞的类红细胞分化

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EVI1 is an aggressive nuclear oncoprotein deregulated by recurring chromosomal abnormalities in myelodysplastic syndrome (MDS). The expression of the corresponding gene is a very poor prognostic marker for MDS patients and is associated with severe defects of the erythroid lineage. We have recently shown that the constitutive expression of EVI1 in murine bone marrow results in a fatal disease with features characteristic of MDS, including anemia, dyserythropoiesis, and dysmegakaryopoiesis. These lineages are regulated by the DNA-binding transcription factor GATA1. EVI1 has two zinc finger domains containing seven motifs at the N terminus and three motifs at the C terminus. Supported by results of assays utilizing synthetic DNA promoters, it was earlier proposed that erythroid-lineage repression by EVI1 is based on the ability of this protein to compete with GATA1 for DNA-binding sites, resulting in repression of gene activation by GATA1. Here, however, we show that EVI1 is unable to bind to classic GATA1 sites. To understand the mechanism utilized by EVI1 to repress erythropoiesis, we used a combination of biochemical assays, mutation analyses, and in vitro bone marrow differentiation. The results indicate that EVI1 interacts directly with the GATA1 protein rather than the DNA sequence. We further show that this protein-protein interaction blocks efficient recognition or binding to DNA by GATA1. Point mutations that disrupt the geometry of two zinc fingers of EVI1 abolish the protein-protein interaction, leading to normal erythroid differentiation of normal murine bone marrow in vitro.
机译：EVI1是一种侵袭性核癌蛋白，可通过骨髓增生异常综合征（MDS）的染色体异常复发而失控。对于MDS患者，相应基因的表达是非常差的预后标记，并且与红系谱系的严重缺陷有关。我们最近显示，鼠骨髓中EVI1的组成型表达可导致致命性疾病，其具有MDS的特征，包括贫血，促红细胞生成和肌核异常。这些谱系受DNA结合转录因子GATA1调控。 EVI1具有两个锌指结构域，在N端包含七个基序，在C端包含三个基序。在利用合成DNA启动子的分析结果的支持下，较早时有人提出EVI1抑制类胡萝卜素谱系是基于该蛋白质与GATA1竞争DNA结合位点的能力，从而导致GATA1抑制基因激活。但是，在这里，我们显示EVI1无法绑定到经典GATA1站点。为了了解EVI1抑制红细胞生成的机制，我们使用了生化分析，突变分析和体外骨髓分化的组合。结果表明，EVI1直接与GATA1蛋白相互作用而不是与DNA序列相互作用。我们进一步表明，这种蛋白质-蛋白质相互作用阻止了GATA1对DNA的有效识别或结合。点突变破坏了EVI1的两个锌指的几何结构，从而消除了蛋白质之间的相互作用，从而导致了正常鼠骨髓在体外的正常红系分化。

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