Aryl hydrocarbon receptor activation attenuates Per1 gene induction and influences circadian clock resetting.
Aryl hydrocarbon receptor activation attenuates Per1 gene induction and influences circadian clock resetting.
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DOI：
10.1093/toxsci/kfs345
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发表时间：
2013-01
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通讯作者：
Canxin Xu;Chun Wang;Stacey L Krager;K. Bottum;S. Tischkau
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作者：
Canxin Xu;Chun Wang;Stacey L Krager;K. Bottum;S. Tischkau
生物钟的光刺激调节是一种重要的适应性生理反应，它能使行为与太阳时间保持同步。我们之前的研究表明，芳香烃受体（AhR）激动剂2,3,7,8 - 四氯二苯并 - p - 二恶英会减弱夜间早期光诱导的相位重置。然而，其抑制机制仍不清楚。在这项研究中，我们发现另一种强效的AhR激动剂 - β - 萘黄酮（BNF）显著降低了野生型（WT）小鼠光诱导的相移，而AhR基因敲除小鼠对光的反应增强且不受BNF影响。从机制上讲，BNF阻断了WT小鼠视交叉上核和肝脏中Per1转录本的光诱导，并且BNF阻断了Hepa - 1c1c7（c7）细胞中福司柯林（FSK）诱导的Per1转录本。一个E - 盒诱饵不影响BNF对c7细胞中FSK诱导的Per1转录本的抑制。与缺乏功能性AhR活性的细胞（c12）相比，在表达高水平AhR的细胞（c7）中，对福司柯林与佛波醇12 - 十四酸酯13 - 乙酸酯联合作用下的Per1启动子活性的环磷腺苷酸反应元件（CRE）依赖性诱导受到抑制。此外，BNF对FSK诱导的Per1的抑制作用依赖于JNK的磷酸化。总之，这些结果表明，AhR激活通过激活JNK、对Per1启动子中CRE的负调控以及对Per1的抑制来抑制光诱导的相位重置。
Light-stimulated adjustment of the circadian clock is an important adaptive physiological response that allows maintenance of behavioral synchrony with solar time. Our previous studies indicate that the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin attenuates light-induced phase resetting in early night. However, the mechanism of inhibition remains unclear. In this study, we showed that another potent AhR agonist-β-naphthoflavone (BNF)-significantly decreased light-induced phase shifts in wild-type (WT) mice, whereas AhR knockout mice had an enhanced response to light that was unaffected by BNF. Mechanistically, BNF blocked light induction of the Per1 transcript in suprachiasmatic nucleus and liver in WT mice, and BNF blocked forskolin (FSK)-induced Per1 transcripts in Hepa-1c1c7 (c7) cells. An E-box decoy did not affect BNF inhibition of FSK-induced Per1 transcripts in c7 cells. cAMP-response element (CRE)-dependent induction of Per1 promoter activity in response to FSK in combination with phorbol 12-tetradecanoate 13-acetate was suppressed in cells that expressed high levels of AhR (c7) compared with cells lacking functional AhR activity (c12). In addition, the inhibitory effect of BNF on FSK-induced Per1 was dependent on phosphorylation of JNK. Together, these results suggest that AhR activation inhibits light-induced phase resetting through the activation of JNK, negative regulation of CREs in the Per1 promoter, and suppression of Per1.