Different Roles of Negative and Positive Components of the Circadian Clock in Oncogene-induced Neoplastic Transformation
Different Roles of Negative and Positive Components of the Circadian Clock in Oncogene-induced Neoplastic Transformation
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DOI：
10.1074/jbc.m115.706481
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发表时间：
2016-05-13
影响因子：
4.8
通讯作者：
Ohdo, Shigehiro
中科院分区：
文献类型：
--
作者：
Katamune, Chiharu;Koyanagi, Satoru;Ohdo, Shigehiro
在哺乳动物中，生理功能中的昼夜节律是由负调节子和正调节子组成的转录-翻译反馈环驱动的分子振荡器产生的。这种生物钟机制的破坏被认为会增加癌症发展的风险，但生物钟的每个组成部分对肿瘤发生的潜在贡献很少被探索。本文报道了昼夜节律反馈环的负性和正性转录调控因子在癌基因诱导的肿瘤转化中的不同作用。从缺乏负性生物钟调节因子Period 2（Per 2）或Cryptochrome 12（Cry 12）的动物制备的小鼠胚胎成纤维细胞易于通过H-ras（V12）和SV 40大T抗原（SV 40 LT）的共表达诱导转化。相反，从缺乏正生物钟调节因子Bmal 1或Clock的小鼠制备的小鼠胚胎成纤维细胞显示出对癌基因诱导的转化的抗性。在Per 2突变体和Cry 1/2缺失细胞中，癌基因的引入诱导了ATF 4的表达，ATF 4是细胞衰老相关蛋白p16 INK 4a和p19 ARF的有效阻遏物。升高的ATF 4水平足以抑制这些蛋白质的表达并驱动致癌转化。相反，在Bmal 1-null和Clock突变体细胞中，癌基因导入不诱导ATF 4的表达，这允许p16 INK 4a和p19 ARF的组成型表达触发细胞衰老。虽然基因消融的负或正的生物钟转录调节导致生理功能的节奏中断，我们的研究结果定义了他们的不同贡献肿瘤细胞转化。
In mammals, circadian rhythms in physiological function are generated by a molecular oscillator driven by transcriptional-translational feedback loop consisting of negative and positive regulators. Disruption of this circadian clock machinery is thought to increase the risk of cancer development, but the potential contributions of each component of circadian clock to oncogenesis have been little explored. Here we reported that negative and positive transcriptional regulators of circadian feedback loop had different roles in oncogene-induced neoplastic transformation. Mouse embryonic fibroblasts prepared from animals deficient in negative circadian clock regulators, Period2 (Per2) or Cryptochrome1/2 (Cry1/2), were prone to transformation induced by co-expression of H-ras(V12) and SV40 large T antigen (SV40LT). In contrast, mouse embryonic fibroblasts prepared from mice deficient in positive circadian clock regulators, Bmal1 or Clock, showed resistance to oncogene-induced transformation. In Per2 mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, in Bmal1-null and Clock mutant cells, the expression of ATF4 was not induced by oncogene introduction, which allowed constitutive expression of p16INK4a and p19ARF triggering cellular senescence. Although genetic ablation of either negative or positive transcriptional regulators of the circadian clock leads to disrupted rhythms in physiological functions, our findings define their different contributions to neoplastic cellular transformation.