Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPα interaction
Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPα interaction
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DOI：
10.1038/sj.emboj.7601675
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发表时间：
2007-05-02
期刊：
影响因子：
11.4
通讯作者：
Nerlov, C.
中科院分区：
文献类型：
--
作者：
Fujimoto, T.;Anderson, K.;Nerlov, C.
细胞周期机制和转录因子之间的相互作用在协调终末分化和增殖停滞中起着核心作用。我们在这里表明，细胞周期蛋白依赖性激酶6（Cdk 6）是专门在增殖的造血祖细胞表达，Cdk 6抑制转录激活Runx 1，但不是C/ EBP α或PU。1. Cdk 6通过与Runx 1的runt结构域结合，干扰Runx 1 DNA结合和Runx 1-C/ EBPa相互作用来抑制Runx 1活性。在体外和体内，cdk 6表达增加髓系祖细胞增殖，抑制髓系特异性基因表达和终末分化。Cdk 6的这些作用不需要Cdk 6激酶活性。Cdk 6介导的抑制粒细胞分化可以逆转过量Runx 1，与Runx 1是Cdk 6的主要目标一致。我们建议，Cdk 6下调髓系祖细胞释放Runx 1 Cdk 6抑制，从而允许终端分化。由于Runx转录因子在造血、神经元和成骨谱系中发挥着重要作用，这种新的非经典Cdk 6功能可能控制多种组织和细胞类型的终末分化。
Interactions between the cell cycle machinery and transcription factors play a central role in coordinating terminal differentiation and proliferation arrest. We here show that cyclin-dependent kinase 6 (Cdk6) is specifically expressed in proliferating hematopoietic progenitor cells, and that Cdk6 inhibits transcriptional activation by Runx1, but not C/ EBP alpha or PU. 1. Cdk6 inhibits Runx1 activity by binding to the runt domain of Runx1, interfering with Runx1 DNA binding and Runx1-C/ EBPa interaction. Cdk6 expression increased myeloid progenitor proliferation, and inhibited myeloid lineage-specific gene expression and terminal differentiation in vitro and in vivo. These effects of Cdk6 did not require Cdk6 kinase activity. Cdk6-mediated inhibition of granulocytic differentiation could be reversed by excess Runx1, consistent with Runx1 being the major target for Cdk6. We propose that Cdk6 downregulation in myeloid progenitors releases Runx1 from Cdk6 inhibition, thereby allowing terminal differentiation. Since Runx transcription factors play central roles in hematopoietic, neuronal and osteogenic lineages, this novel, noncanonical Cdk6 function may control terminal differentiation in multiple tissues and cell types.