Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis
Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis
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DOI：
10.4161/cc.7.9.5886
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发表时间：
2008-05-01
期刊：
影响因子：
4.3
通讯作者：
Nikitin, Alexander Yu
中科院分区：
文献类型：
--
作者：
Antoch, Marina P.;Gorbacheva, Victoria Y.;Nikitin, Alexander Yu
哺乳动物的昼夜节律系统涉及各种生物过程的调节，包括涉及遗传毒性应激反应和肿瘤抑制的生物过程。在这里，我们报告说，在昼夜节律转录因子时钟（时钟/时钟突变小鼠）的功能缺陷的小鼠不显示肿瘤形成的倾向，无论是在他们的正常寿命或受到γ射线的挑战。这种表型与Clock突变小鼠淋巴组织中的高凋亡率和低增殖率一致，并且得到许多凋亡和细胞周期相关基因的基因表达谱以及CLOCK下调细胞生长抑制的支持。与此同时，Clock突变小鼠通过加速其衰老程序对低剂量辐射做出反应，并发展出与Bmal 1缺陷小鼠相似的表型。总之，我们的研究结果表明，生物钟的破坏与衰老和癌症的生物学后果的二分法。他们还强调了衰老、致癌和生物钟机制的各个组成部分之间存在着复杂的相互联系。
The mammalian circadian system has been implicated in the regulation of various biological processes including those involved in genotoxic stress responses and tumor suppression. Here we report that mice with the functional deficiency in circadian transcription factor CLOCK (Clock/Clock mutant mice) do not display predisposition to tumor formation both during their normal lifespan or when challenged by gamma-radiation. This phenotype is consistent with high apoptotic and low proliferation rate in lymphoid tissues of Clock mutant mice and is supported by the gene expression profiling of a number of apoptosis and cell cycle-related genes, as well as by growth inhibition of cells with CLOCK downregulation. At the same time, Clock mutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice. Taken together, our results demonstrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to ageing and cancer. They also highlight the existence of a complex interconnection between ageing, carcinogenesis and individual components of the circadian clock machinery.