胸腺细胞发育和肿瘤发生过程中细胞周期蛋白依赖性激酶6的需求。
A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis.
作者信息
Hu Miaofen G, Deshpande Amit, Enos Miriam, Mao Daqin, Hinds Elisabeth A, Hu Guo-fu, Chang Rui, Guo Zhuyan, Dose Marei, Mao Changchuin, Tsichlis Philip N, Gounari Fotini, Hinds Philip W
机构信息
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
出版信息
Cancer Res. 2009 Feb 1;69(3):810-8. doi: 10.1158/0008-5472.CAN-08-2473. Epub 2009 Jan 20.
Abstract
Cyclin-dependent kinase 6 (CDK6) promotes cell cycle progression and is overexpressed 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 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 show 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.
摘要
细胞周期蛋白依赖性激酶6（CDK6）促进细胞周期进程，且在人类淋巴恶性肿瘤中过表达。为了确定CDK6在发育和肿瘤发生中的作用，我们构建并分析了基因敲除小鼠。Cdk6基因缺失的小鼠表现出明显的胸腺萎缩，这是由于双阴性阶段增殖比例降低以及随之而来的过渡阻滞所致。利用OP9-DL1系统传递时间可控的Notch受体依赖性信号，我们发现CDK6是Notch依赖性存活、增殖和分化所必需的。此外，Cdk6基因缺失的小鼠对由Notch信号的下游靶点活性Akt诱导的淋巴瘤发生具有抗性。这些结果表明CDK6在Notch/Akt依赖性T细胞发育和肿瘤发生中至关重要，有力地支持了CDK6作为人类淋巴恶性肿瘤的一个特异性治疗靶点。
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