Mitomycin C modulates the circadian oscillation of clock gene period 2 expression through attenuating the glucocorticoid signaling in mouse fibroblasts.
Mitomycin C modulates the circadian oscillation of clock gene period 2 expression through attenuating the glucocorticoid signaling in mouse fibroblasts.
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DOI：
10.1016/j.bbrc.2015.09.086
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发表时间：
2015-11
影响因子：
3.1
通讯作者：
Naoki Kusunose;Naoya Matsunaga;K. Kimoto;T. Akamine;Kengo Hamamura;S. Koyanagi;S. Ohdo;T. Kubota
中科院分区：
文献类型：
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作者：
Naoki Kusunose;Naoya Matsunaga;K. Kimoto;T. Akamine;Kengo Hamamura;S. Koyanagi;S. Ohdo;T. Kubota
时钟基因调节各种生理功能的昼夜节律。某些药物会减弱时钟基因的表达，导致节律紊乱。丝裂霉素 C (MMC) 通常与眼科手术结合使用，尤其是青光眼手术小梁切除术。本研究的目的是探讨MMC对MMC靶细胞成纤维细胞时钟基因表达的影响。 MMC处理后，小鼠成纤维细胞系NIH3T3细胞中Bmal1 mRNA水平显着降低，而Dbp、Per1和Rev-erbα mRNA水平显着升高。进行微阵列分析以探索负责 MMC 诱导的时钟基因表达改变的基因，并确定编码糖皮质激素受体 (GR) 的 Nr3c1 基因作为候选基因。 MMC 抑制 NIH3T3 细胞中 GR 配体地塞米松 (DEX) 对 Per1mRNA 的诱导。 MMC 还调节小鼠眼成纤维细胞中 DEX 驱动的 Per2::荧光素酶生物发光的昼夜节律振荡。我们的结果证明了 MMC 对 GR 信号传导和生物钟系统的先前未知的影响。目前的研究结果表明，MMC 联合小梁切除术可能会增加眼表局部昼夜节律紊乱的风险。
Clock gene regulates the circadian rhythm of various physiological functions. The expression of clock gene has been shown to be attenuated by certain drugs, resulting in a rhythm disorder. Mitomycin C (MMC) is often used in combination with ophthalmic surgery, especially in trabeculectomy, a glaucoma surgical procedure. The purpose of this study was to investigate the influence of MMC on clock gene expression in fibroblasts, the target cells of MMC. Following MMC treatment,Bmal1mRNA levels was significantly decreased, whereasDbp,Per1, andRev-erbαmRNA levels were significantly increased in the mouse fibroblast cell line NIH3T3 cells. Microarray analysis was performed to explore of the gene(s) responsible for MMC-induced alteration of clock gene expression, and identifiedNr3c1gene encoding glucocorticoid receptor (GR) as a candidate. MMC suppressed the induction ofPer1mRNA by dexamethasone (DEX), ligand of GR, in NIH3T3 cells. MMC also modulated the DEX-driven circadian oscillations of Per2::Luciferase bioluminescence in mouse-derived ocular fibroblasts. Our results demonstrate a previously unknown effect of MMC in GR signaling and the circadian clock system. The present findings suggest that MMC combined with trabeculectomy could increase the risk for a local circadian rhythm-disorder at the ocular surface.