The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress
The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress
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DOI：
10.1111/j.1349-7006.2011.01884.x
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发表时间：
2011-05-01
期刊：
影响因子：
5.7
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
--
作者：
Ishizawa, Jo;Kuninaka, Shinji;Saya, Hideyuki
各种关键的细胞周期组分，尤其是G 0/G1调节剂，不仅对细胞增殖而且对细胞分化具有影响。Cdh 1是维持后期促进复合物/环体活性的共激活因子之一，在有丝分裂期起着至关重要的作用，但最近被鉴定为G 0/G1调节因子，这表明Cdh 1在细胞分化中的作用。在这里，我们产生了Cdh 1条件基因陷阱小鼠检查Cdh 1功能的成年组织克服Cdh 1纯合子基因陷阱小鼠的胚胎致死性。我们专注于造血系统，发现Cdh 1缺陷小鼠表现出成熟谱系祖细胞的普遍减少和短期造血干细胞的显着增加。在Cdh 1下调后不久，这种现象通过照射变得明显，表明Cdh 1通过保护细胞免受遗传毒性应激来调节造血干细胞和成熟谱系祖细胞的池大小。我们还发现辐射诱导的G2/M检查点在Cdh 1缺陷的BM细胞中是有缺陷的，导致干/祖细胞的损失。这是第一份揭示Cdh 1在成人造血中的功能并显示Cdh 1在体内G2/M检查点调节中的作用的报告。（Cancer Sci 2011; 102：967-974）。
Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo. (Cancer Sci 2011; 102: 967-974).