Azzi Abdelhalim, Tao Zhipeng, Sun Yang, Erb Hannah, Guarino Carla, Wu Xu
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
iScience. 2023 Jul 20;26(8):107449. doi: 10.1016/j.isci.2023.107449. eCollection 2023 Aug 18.
Circadian clock controls daily behavior and physiology. The activity of various signaling pathways affects clock gene expression. Here, we show that the core circadian clock gene is a direct target of the Hippo pathway effector YAP. YAP binds to TEADs and occupies the proximal promoter regions of , positively regulating its transcription. Interestingly, we further identified that CRY1 acts in a feedback loop to fine-tune Hippo pathway activation by modulating the expression of and . Indeed, loss of CRY1 results in enhanced YAP activation. Consistently, we found that YAP levels and activity control clock gene expression and oscillation in synchronized cells. Furthermore, in breast cancer cells, CRY1 downregulation causes YAP/TAZ hyperactivation and enhanced DNA damage. Together, our findings provide a direct mechanistic link between the Hippo pathway and the circadian clock, where CRY1 and Hippo components form an orchestrated signaling network that influences cell growth and circadian rhythm.
昼夜节律时钟控制着日常行为和生理活动。各种信号通路的活性会影响时钟基因的表达。在此，我们表明核心昼夜节律时钟基因是Hippo信号通路效应因子YAP的直接靶标。YAP与TEADs结合并占据该基因近端启动子区域，正向调节其转录。有趣的是，我们进一步发现CRY1通过调节该基因及其他基因的表达，在一个反馈回路中发挥作用以微调Hippo信号通路的激活。确实，CRY1缺失会导致YAP激活增强。一致地，我们发现YAP的水平和活性控制着同步化细胞中时钟基因的表达和振荡。此外，在乳腺癌细胞中，CRY1下调会导致YAP/TAZ过度激活并增强DNA损伤。总之，我们的研究结果揭示了Hippo信号通路与昼夜节律时钟之间的直接机制联系，其中CRY1和Hippo信号通路组分形成了一个协调的信号网络，影响细胞生长和昼夜节律。
