The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein lnteraction
The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein lnteraction
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DOI：
10.1074/jbc.m607613200
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发表时间：
2007-03-02
影响因子：
4.8
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
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作者：
Dahl, Richard;Iyer, Sangeeta R.;Simon, M. Celeste
缺乏锌指转录抑制蛋白 GFI-1 的小鼠呈中性粒细胞减少症。这些小鼠产生异常的未成熟骨髓细胞，表现出巨噬细胞和粒细胞的特征。此外，Gfi-1(-/-) 小鼠非常容易受到细菌感染。有趣的是，Gfi-1(-/-) 骨髓细胞过度表达 PU 的靶基因。 I 转录因子，例如巨噬细胞集落刺激因子受体和 PU.1 本身。因此，我们确定了 GFI-1 是否调节 PU.1 的转录活性。我们的数据表明 GFI-1 与 PU.1 发生物理相互作用，抑制 PU.1 依赖性转录。这种抑制具有重要的功能，因为 GFI-1 可以阻断 PU.1 诱导的多能造血祖细胞系的巨噬细胞分化。原代小鼠造血祖细胞中 GFI-1 的逆转录病毒表达增加了粒细胞分化，但以巨噬细胞分化为代价。我们将 Gfi-1(+/-) 和 PU.1(+/-) 小鼠杂交，观察到 PU.I 位点的杂合性部分挽救了 Gfi-1(-/-) 混合骨髓谱系表型，但未能恢复粒细胞分化。我们的数据表明，GFI-1 抑制 PUA 活性，并且 Gfi-1(-/-) 骨髓细胞中缺乏这种抑制导致了观察到的混合谱系表型。
Mice lacking the zinc finger transcriptional repressor protein GFI-1 are neutropenic. These mice generate abnormal immature myeloid cells exhibiting characteristics of both macrophages and granulocytes. Furthermore, Gfi-1(-/-) mice are highly susceptible to bacterial infection. Interestingly, Gfi-1(-/-) myeloid cells overexpress target genes of the PU. I transcription factor such as the macrophage colony-stimulating factor receptor and PU.1 itself. We therefore determined whether GFI-1 modulates the transcriptional activity of PU.1. Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. Retroviral expression of GFI-1 in primary murine hematopoietic progenitors increased granulocyte differentiation at the expense of macrophage differentiation. We interbred Gfi-1(+/-) and PU.1(+/-) mice and observed that heterozygosity at the PU.I locus partially rescued the Gfi-1(-/-) mixed myeloid lineage phenotype, but failed to restore granulocyte differentiation. Our data demonstrate that GFI-1 represses PUA activity and that lack of this repression in Gfi-1(-/-) myeloid cells contributes to the observed mixed lineage phenotype.