cAMP-response Element (CRE)-mediated Transcription by Activating Transcription Factor-4 (ATF4) Is Essential for Circadian Expression of the Period2 Gene
cAMP-response Element (CRE)-mediated Transcription by Activating Transcription Factor-4 (ATF4) Is Essential for Circadian Expression of the Period2 Gene
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DOI：
10.1074/jbc.m111.258970
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发表时间：
2011-09-16
影响因子：
4.8
通讯作者：
Ohdo, Shigehiro
中科院分区：
文献类型：
--
作者：
Koyanagi, Satoru;Hamdan, Ahmed M.;Ohdo, Shigehiro
转录激活因子（ATF）/cAMP反应元件（CRE）结合（CREB）蛋白依赖于cAMP刺激诱导CRE介导的基因转录。cAMP依赖性信号传导以昼夜节律方式振荡，这又维持昼夜节律钟的核心振荡机制。在这里，我们表明，在ATF/CREB家族蛋白，ATF 4是必不可少的周期2（Per 2）基因，昼夜节律钟的关键组成部分的昼夜表达。Atf 4基因的转录受生物钟的核心成分调控，其表达在小鼠组织以及胚胎成纤维细胞中表现出昼夜节律振荡。ATF 4以昼夜节律的时间依赖性方式与Per 2启动子的CRE结合，并周期性地激活Per 2基因的转录。因此，Per 2表达的振荡在从Atf 4-null小鼠制备的胚胎细胞中减弱。此外，ATF 4的缺失也破坏了其他时钟基因表达的节奏。这些结果表明，ATF 4是负责维持CRE-mediated基因表达的昼夜节律振荡的组分，并且还构成了连接cAMP依赖性信号传导与昼夜节律钟的分子连接。
Activating transcription factor (ATF)/cAMP-response element (CRE)-binding (CREB) proteins induce the CRE-mediated gene transcription depending on the cAMP stimulation. cAMP-dependent signaling oscillates in a circadian manner, which in turn also sustains core oscillation machinery of the circadian clock. Here, we show that among the ATF/CREB family proteins, ATF4 is essential for the circadian expression of the Period2 (Per2) gene, a key component of the circadian clock. Transcription of the Atf4 gene was regulated by core components of the circadian clock, and its expression exhibited circadian oscillation in mouse tissues as well as embryonic fibroblasts. ATF4 bound to the CRE of the Per2 promoter in a circadian time-dependent manner and periodically activated the transcription of the Per2 gene. Consequently, the oscillation of the Per2 expression was attenuated in embryonic cells prepared from Atf4-null mice. Furthermore, the loss of ATF4 also disrupted the rhythms in the expression of other clock genes. These results suggest that ATF4 is a component responsible for sustaining circadian oscillation of CRE-mediated gene expression and also constitute a molecular link connecting cAMP-dependent signaling to the circadian clock.