Ligand modulation of REV-ERBalpha function resets the peripheral circadian clock in a phasic manner.
Ligand modulation of REV-ERBalpha function resets the peripheral circadian clock in a phasic manner.
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DOI：
10.1242/jcs.035048
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发表时间：
2008-11-01
影响因子：
4
通讯作者：
Loudon A
中科院分区：
文献类型：
--
作者：
Meng QJ;McMaster A;Beesley S;Lu WQ;Gibbs J;Parks D;Collins J;Farrow S;Donn R;Ray D;Loudon A
核受体REV-ERBα是生物钟的关键负反馈调节剂。REV-ERBα与Bmal 1（Arntl）启动子的ROR元件结合并抑制Bmal 1转录。这种稳定的负回路对于昼夜节律起搏器的精确控制是重要的。在本研究中，我们鉴定了一种新的合成REV-ERBα配体，其增强核受体辅阻遏物（NCoR）向REV-ERBα的募集。为了探讨REV-ERBα在分子钟重置反应中的作用，我们首先建立了Rat-1成纤维细胞中REV-ERBα的节律性转录谱和表达水平。当在昼夜节律振荡的不同阶段应用于含有稳定转染的Bmal 1：：Luc或Per 2：：Luc的细胞模型时，REV-ERBα配体诱导了相位依赖性双向相移。当相位变化对时间作图时，显示出清晰的相位响应曲线，具有约为0.001的显著峰谷振幅。5小时当将化合物应用于转基因PER 2：：Luc小鼠的原代肺成纤维细胞和异位肺切片时，也观察到相位重置效应。因此，内源性配体（如血红素）对REV-ERBα功能的类似调节可能是时钟重置的重要机制。此外，我们确定了一种新的方法来产生相移的时钟。
The nuclear receptor REV-ERBα is a key negative-feedback regulator of the biological clock. REV-ERBα binds to ROR elements of the Bmal1 (Arntl) promoter and represses Bmal1 transcription. This stabilizing negative loop is important for precise control of the circadian pacemaker. In the present study, we identified a novel synthetic REV-ERBα ligand, which enhances the recruitment of nuclear receptor co-repressor (NCoR) to REV-ERBα. In order to explore REV-ERBα action on resetting responses of the molecular clock, we first established the rhythmic transcription profile and expression level of REV-ERBα in Rat-1 fibroblasts. When applied at different phases of the circadian oscillation to cell models containing stably transfected Bmal1::Luc or Per2::Luc, the REV-ERBα ligand induced phase-dependent bi-directional phase shifts. When the phase changes were plotted against time, a clear phase response curve was revealed, with a significant peak-to-trough amplitude of ca. 5 hours. The phase-resetting effect was also observed when the compound was applied to primary lung fibroblasts and ectopic lung slices from transgenic PER2::Luc mice. Therefore, similar regulation of REV-ERBα function by endogenous ligands, such as heme, is likely to be an important mechanism for clock resetting. In addition, we identify a new means to generate phasic shifts in the clock.
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影响因子：
5.3
作者：
Eide, EJ;Woolf, MF;Virshup, DM
通讯作者：
Virshup, DM
DOI：
10.1073/pnas.162342499
发表时间：
2002-12-10
影响因子：
11.1
作者：
Burgess-Beusse, B;Farrell, C;Felsenfeld, G
通讯作者：
Felsenfeld, G
影响因子：
64.5
作者：
Balsalobre, A;Damiola, F;Schibler, U
通讯作者：
Schibler, U
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U
影响因子：
2.9
作者：
Okamoto, K;Onai, K;Ishiura, M
通讯作者：
Ishiura, M