A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis.
A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis.
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DOI：
10.1158/0008-5472.can-08-2473
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Hinds PW
中科院分区：
文献类型：
--
作者：
Hu MG;Deshpande A;Enos M;Mao D;Hinds EA;Hu GF;Chang R;Guo Z;Dose M;Mao C;Tsichlis PN;Gounari F;Hinds PW
CDK 6促进细胞周期进程，并在人类淋巴恶性肿瘤中过度表达。为了确定CDK 6在发育和肿瘤发生中的作用，我们产生并分析了敲除小鼠。Cdk 6缺陷型小鼠表现出明显的胸腺萎缩，这是由于在双阴性（DN）阶段增殖分数减少和伴随的过渡性阻滞。使用OP 9-DL 1系统来传递时间控制的Notch受体依赖性信号，我们表明CDK 6是Notch依赖性存活、增殖和分化所需的。此外，CDK 6缺陷小鼠对由Notch信号传导的下游靶点活性AKT诱导的淋巴瘤形成具有抗性。这些结果证明了CDK 6在Notch/AKT依赖性T细胞发育和肿瘤发生中的关键需求，并强烈支持CDK 6作为人类淋巴恶性肿瘤的特异性治疗靶点。
CDK6 promotes cell cycle progression and is over-expressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double negative (DN) stages. Using the OP9-DL1 system to deliver temporally controlled, Notch-receptor dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active AKT, a downstream target of Notch signaling. These results demonstrate a critical requirement for CDK6 in Notch/AKT-dependent T cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies.