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首页> 外文期刊>Molecular and Cellular Biology >Direct Protein Interactions Are Responsible for Ikaros-GATA and Ikaros-Cdk9 Cooperativeness in Hematopoietic Cells
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Direct Protein Interactions Are Responsible for Ikaros-GATA and Ikaros-Cdk9 Cooperativeness in Hematopoietic Cells

机译：直接蛋白相互作用是造血细胞中Ikaros-GATA和Ikaros-Cdk9合作的负责任。

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摘要

Ikaros (Ik) is a critical regulator of hematopoietic gene expression. Here, we established that the Ik interactions with GATA transcription factors and cyclin-dependent kinase 9 (Cdk9), a component of the positive transcription elongation factor b (P-TEFb), are required for transcriptional activation of Ik target genes. A detailed dissection of Ik-GATA and Ik-Cdk9 protein interactions indicated that the C-terminal zinc finger domain of Ik interacts directly with the C-terminal zinc fingers of GATA1, GATA2, and GATA3, whereas the N-terminal zinc finger domain of Ik is required for interaction with the kinase and T-loop domains of Cdk9. The relevance of these interactions was demonstrated in vivo in COS-7 and primary hematopoietic cells, in which Ik facilitated Cdk9 and GATA protein recruitment to gene promoters and transcriptional activation. Moreover, the oncogenic isoform Ik6 did not efficiently interact with Cdk9 or GATA proteins in vivo and perturbed Cdk9/P-TEFb recruitment to Ik target genes, thereby affecting transcription elongation. Finally, characterization of a novel nuclear Ik isoform revealed that Ik exon 6 is dispensable for interactions with Mi2 and GATA proteins but is essential for the Cdk9 interaction. Thus, Ik is central to the Ik-GATA-Cdk9 regulatory network, which is broadly utilized for gene regulation in hematopoietic cells.
机译：Ikaros（Ik）是造血基因表达的关键调节剂。在这里，我们确定Ik目标基因的转录激活需要与GATA转录因子和细胞周期蛋白依赖性激酶9（Cdk9）（正转录延伸因子b（P-TEFb）的组成部分）进行Ik相互作用。 Ik-GATA和Ik-Cdk9蛋白相互作用的详细解剖表明，Ik的C末端锌指结构域与GATA1，GATA2和GATA3的C末端锌指结构域直接相互作用，而Nk的N末端锌指结构域与Cdk9的激酶和T环结构域相互作用需要Ik。这些相互作用的相关性在COS-7和原代造血细胞中得到了体内证实，其中Ik促进Cdk9和GATA蛋白募集到基因启动子和转录激活。此外，致癌同工型Ik6无法有效地与Cdk9或GATA蛋白在体内相互作用，并扰乱了Cdk9 / P-TEFb募集至Ik目标基因，从而影响了转录延伸。最后，新型核Ik同工型的表征表明Ik外显子6对于与Mi2和GATA蛋白的相互作用是必不可少的，但对Cdk9相互作用却必不可少。因此，Ik是Ik-GATA-Cdk9调控网络的核心，该网络广泛用于造血细胞的基因调控。

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