A novel role of CKIP-1 in promoting megakaryocytic differentiation.
A novel role of CKIP-1 in promoting megakaryocytic differentiation.
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DOI：
10.18632/oncotarget.15619
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发表时间：
2017-05-02
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
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作者：
Fan J;Wang Y;Shen Y;Liu Q;Gao R;Qiu Y;Wang C;Zhang L
酪蛋白激酶2相互作用蛋白-1(CKIP-1)是一种已知的心肌细胞和巨噬细胞增殖的调节因子。在本研究中，我们发现CKIP-1参与巨核细胞分化过程。在K562细胞向巨核细胞分化的过程中，CKIP-1显著上调，而PMA通过下调转录因子GATA-1而诱导其上调。通过瞬时转染、寡核苷酸定向突变和染色质免疫沉淀实验，我们鉴定了GATA-1对CKIP-1的转录调控。CKIP-1过表达启动K562细胞自发巨核细胞分化事件。相反，CKIP-1在细胞系中的敲除抑制了巨核细胞的分化。在机制上，CKIP-1的过表达改变了转录因子的表达水平，这些转录因子已被证明在红细胞-巨核细胞分化中起关键作用，如Fli-1、c-Myb和c-Myc。体内分析证实，与野生型小鼠相比，CKIP-1−/−小鼠从骨髓中获得的CD41+细胞数量减少，血小板水平降低。这是首次有直接证据表明CKIP-1是一种新的巨核细胞分化调节因子。
Casein kinase 2-interacting protein-1 (CKIP-1) is a known regulator of cardiomyocytes and macrophage proliferation. In this study, we showed that CKIP-1 was involved in the process of megakaryocytic differentiation. During megakaryocytic differentiation of K562 cells, CKIP-1 was dramatically upregulated and this upregulation induced by PMA was mediated through downregulation of transcription factor GATA-1. By transient transfection, oligonucleotide-directed mutagenesis and chromatin immunoprecipitation assays, we identified the transcriptional regulation of CKIP-1 by GATA-1. Overexpression of CKIP-1 initiated events of spontaneous megakaryocytic differentiation in K562 cells. Conversely, knockdown of CKIP-1 in cell lines suppressed megakaryocytic differentiation. Mechanistically, overexpression of CKIP-1 changed the expression levels of transcription factors that have been shown to be critical in erythro-megakaryocytic differentiation such as Fli-1, c-Myb and c-Myc. In vivo analysis confirmed that CKIP-1−/− mice had decreased number of CD41+ cells harvested from bone marrow, and lower platelet levels when compared to wild-type littermates. This is the first direct evidence suggesting that CKIP-1 is a novel regulator of megakaryocytic differentiation.