CDK6 kinase activity is required for thymocyte development
CDK6 kinase activity is required for thymocyte development
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DOI：
10.1182/blood-2010-08-300517
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发表时间：
2011-06-09
期刊：
影响因子：
20.3
通讯作者：
Hinds, Philip W.
中科院分区：
文献类型：
--
作者：
Hu, Miaofen G.;Deshpande, Amit;Hinds, Philip W.
细胞周期蛋白依赖性激酶-6（CDK 6）是胸腺细胞发育和肿瘤发生所必需的。为了从机制上剖析CDK 6在胸腺细胞发育中的作用，我们产生并分析了突变敲入小鼠，发现表达激酶死亡的Cdk 6等位基因（Cdk 6（K43 M））的小鼠胸腺细胞和造血干细胞和祖细胞（Lin（-）Sca-1（+）c-Kit（+）[LSK]）明显减少。相反，表达INK 4不敏感、过度活跃的Cdk 6（R31 C）等位基因的小鼠在LSK和胸腺细胞中表现出过度增殖。然而，这至少部分地被增加的细胞凋亡抵消，这可能在没有其他遗传事件的情况下限制祖细胞和胸腺细胞的扩增。我们的机制研究表明，CDK 6激酶活性有助于Notch信号传导，因为失活的CDK 6激酶破坏了Notch依赖的生存，增殖和LSK的分化，伴随着Notch靶基因表达的改变，如CD 25的大量上调。此外，Cdk 6（K43 M）小鼠中CD 25的敲除挽救了在年轻小鼠中观察到的大多数缺陷。这些结果说明CDK 6激酶活性在胸腺细胞发育中的重要作用，其部分通过调节Notch靶基因表达来起作用。CDK 6作为Notch下游介质的这种作用鉴定了CDK 6激酶活性作为人类淋巴恶性肿瘤的潜在治疗靶点。（血。2011;117（23）：6120-6131）
Cyclin-dependent kinase-6 (CDK6) is required for early thymocyte development and tumorigenesis. To mechanistically dissect the role of CDK6 in thymocyte development, we generated and analyzed mutant knock-in mice and found that mice expressing a kinase-dead Cdk6 allele (Cdk6(K43M)) had a pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells (Lin(-)Sca-1(+)c-Kit(+) [LSK]). In contrast, mice expressing the INK4-insensitive, hyperactive Cdk6(R31C) allele displayed excess proliferation in LSK and thymocytes. However, this is countered at least in part by increased apoptosis, which may limit progenitor and thymocyte expansion in the absence of other genetic events. Our mechanistic studies demonstrate that CDK6 kinase activity contributes to Notch signaling because inactive CDK6 kinase disrupts Notch-dependent survival, proliferation, and differentiation of LSK, with concomitant alteration of Notch target gene expression, such as massive up-regulation of CD25. Further, knockout of CD25 in Cdk6(K43M) mice rescued most defects observed in young mice. These results illustrate an important role for CDK6 kinase activity in thymocyte development that operates partially through modulating Notch target gene expression. This role of CDK6 as a downstream mediator of Notch identifies CDK6 kinase activity as a potential therapeutic target in human lymphoid malignancies. (Blood. 2011;117(23):6120-6131)