Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors
Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors
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DOI：
10.1038/onc.2014.364
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发表时间：
2014-11
期刊：
影响因子：
8
通讯作者：
V. Tomiatti;R. Istvanffy;E. Pietschmann;Susanne Kratzat;Alexander Hoellein;Leticia Quintanilla-Fend;N. Bubnoff;Christian Peschel;R. Oostendorp;Ulrich Keller
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文献类型：
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作者：
V. Tomiatti;R. Istvanffy;E. Pietschmann;Susanne Kratzat;Alexander Hoellein;Leticia Quintanilla-Fend;N. Bubnoff;Christian Peschel;R. Oostendorp;Ulrich Keller
细胞周期蛋白依赖性激酶亚基1（Cks 1）是Skp 1-Cullin 1-Skp 2（SCF Skp 2）泛素连接酶的关键限速组分，其控制细胞周期抑制剂丰度。细胞周期蛋白依赖性激酶（Cdk）抑制剂（CKIs）调节造血干细胞（HSC）的自我更新、细胞毒性应激后的再生和肿瘤细胞增殖。因此，我们研究了Cks 1在HSC和一种原型干细胞疾病慢性粒细胞白血病（CML）中的作用。Cks 1转录本在Lin− Sca-1+ Kit+（LSK）HSC中高度表达，并且丢失导致SCF Skp 2/Cks 1底物p21、p27、p57和p130的积累，特别是在CD 150 + LSK细胞中。这种积累与Cks 1 −/− HSC的增殖和积累减少、应激后再生较慢和HSC静止期延长有关。在造血祖细胞（HPC）水平，Cks 1的损失对细胞凋亡敏感。在慢性粒细胞白血病，Cks 1的表达增加，治疗与Abl激酶抑制剂，伊马替尼，减少Cks 1的表达。此外，我们发现Cks 1是Bcr-Abl诱导的非依赖于腺嘌呤的克隆活性的关键。总之，我们的研究提出了一种新的功能，Cks 1在维持HSC/HPC稳态，并表明，Cks 1是一个可能的目标，在治疗的SCF Skp 2/Cks 1复合物，控制CKI丰度和癌细胞增殖。
Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCF Skp2) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin− Sca-1+ Kit+(LSK) HSC, and the loss resulted in accumulation of the SCF Skp2/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1−/− HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr–Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCF Skp2/Cks1 complex that controls CKI abundance and cancer cell proliferation.