Tumor suppression by the mammalian Period genes
Tumor suppression by the mammalian Period genes
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DOI：
10.1007/s10552-005-9003-8
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发表时间：
2006-05-01
影响因子：
2.3
通讯作者：
Lee, CC
中科院分区：
文献类型：
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作者：
Lee, CC
Period（Per）基因是哺乳动物关键的昼夜节律调节因子。小鼠Per（mPer）基因在视交叉上核和外周组织中的表达具有昼夜模式。基因切除mPER 1和mPER 2功能导致小鼠基于跑轮活动的昼夜节律控制完全丧失。此外，这些动物还表现出明显的过早衰老和肿瘤和增生表型的显著增加。当受到γ-辐射的攻击时，mPer 2缺陷小鼠通过快速毛发变灰来响应，在胸腺细胞中缺乏p53介导的凋亡，并且具有稳健的肿瘤发生。我们的研究表明，生物钟功能在体内细胞周期、DNA损伤反应和肿瘤抑制中起着重要作用。在mPer 2突变小鼠中，参与细胞周期调控和肿瘤抑制的基因（如c-Myc、细胞周期蛋白D1、细胞周期蛋白A、Mdm-2和Gadd 45 α）的时间表达失调。此外，遗传学研究表明，细胞周期和生长控制的许多关键调节因子也是重要的生物钟调节因子，证实了生物钟功能在生物体内稳态中的关键作用。最近对人类乳腺癌和子宫内膜癌的研究表明，PERIOD蛋白的丢失和失调在肿瘤细胞中是常见的。
The Period (Per) genes are key circadian rhythm regulators in mammals. Expression of the mouse Per (mPer) genes have diurnal pattern in the suprachiamstic nuclei and in peripheral tissues. Genetic ablation mPER1 and mPER2 function results in a complete loss of circadian rhythm control based on wheel running activity in mice. In addition, these animals also display apparent premature aging and significant increase in neoplastic and hyperplastic phenotypes. When challenged by gamma-radiation, mPer2 deficient mice response by rapid hair graying, are deficient in p53-mediated apoptosis in thymocytes and have robust tumor occurrences. Our studies have demonstrated that the circadian clock function is very important for cell cycle, DNA damage response and tumor suppression in vivo. Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2 and Gadd45 alpha is deregulated in mPer2 mutant mice. In addition, genetic studies have demonstrated that many key regulators of cell cycle and growth control are also important circadian clock regulators confirming the critical role of circadian function in organismal homeostasis. Recently studies of human breast and endometrial cancers revealed that the loss and deregulation of PERIOD proteins is common in the tumor cells.