p57KiP2 and p27Kip1 Cooperate to Maintain Hematopoietic Stem Cell Quiescence through Interactions with Hsc70
p57KiP2 and p27Kip1 Cooperate to Maintain Hematopoietic Stem Cell Quiescence through Interactions with Hsc70
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DOI：
10.1016/j.stem.2011.07.003
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发表时间：
2011-09-02
期刊：
影响因子：
23.9
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Zou, Peng;Yoshihara, Hiroki;Suda, Toshio
细胞周期调控因子在造血干细胞（HSC）休眠和增殖之间的平衡中起着关键作用。在这项研究中，我们报告说，细胞周期进入正常进行的HSC空细胞周期蛋白依赖性激酶（CDK）抑制剂p57由于补偿上调p27。然而，p57和p27缺失的HSC更具增殖性，并且在移植中具有降低的植入能力。我们发现热休克同源蛋白70（Hsc 70）与p57和p27相互作用，Hsc 70的亚细胞定位对维持HSC细胞周期动力学至关重要。在HSC中p57和p27的组合缺陷导致Hsc 70/细胞周期蛋白D1复合物的核输入，伴随Rb磷酸化，并引起维持HSC静止的严重缺陷。综上所述，这些数据表明，调控细胞质定位的Hsc 70/细胞周期蛋白D1复合物的p57和p27是一个关键的细胞内机制，在控制HSC休眠。
Cell cycle regulators play critical roles in the balance between hematopoietic stem cell (HSC) dormancy and proliferation. In this study, we report that cell cycle entry proceeded normally in HSCs null for cyclin-dependent kinase (CDK) inhibitor p57 due to compensatory upregulation of p27. HSCs null for both p57 and p27, however, were more proliferative and had reduced capacity to engraft in transplantation. We found that heat shock cognate protein 70 (Hsc70) interacts with both p57 and p27 and that the subcellular localization of Hsc70 was critical to maintain HSC cell cycle kinetics. Combined deficiency of p57 and p27 in HSCs resulted in nuclear import of an Hsc70/cyclin D1 complex, concomitant with Rb phosphorylation, and elicited severe defects in maintaining HSC quiescence. Taken together, these data suggest that regulation of cytoplasmic localization of Hsc70/cyclin D1 complex by p57 and p27 is a key intracellular mechanism in controlling HSC dormancy.