Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
Neuron. 2013 Aug 21;79(4):712-24. doi: 10.1016/j.neuron.2013.06.026.
Protein synthesis is critical for circadian clock function, but little is known of how translational regulation controls the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor(+/-) mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock.
蛋白质合成对于生物钟功能至关重要，但对于翻译调控如何控制哺乳动物的主生物钟——视交叉上核（SCN），知之甚少。在这里，我们证明了关键的翻译抑制剂，真核翻译起始因子 4E 结合蛋白 1（4E-BP1），通过机械靶标雷帕霉素（mTOR）信号在 SCN 中进行节律性调节，并且优先抑制血管活性肠肽（VIP）mRNA 的翻译。Eif4ebp1（编码 4E-BP1 的基因）敲除（KO）导致 VIP 上调和 SCN 中分子节律的振幅更高。因此，4E-BP1 缺失小鼠对光/暗周期的重新同步更快，并且对持续光照的节律破坏作用更具抵抗力。相反，在 Mtor(+/-) 小鼠中，VIP 表达减少，对持续光照的易感性增加。这些结果揭示了 mTOR/4E-BP1 介导的翻译控制在调节主钟的同步和同步中的关键作用。
