The unfolded protein response (UPR) is a stress-activated signalling pathway that regulates cell proliferation, metabolism and survival. The circadian clock coordinates metabolism and signal transduction with light/dark cycles. We explore how UPR signalling interfaces with the circadian clock. UPR activation induces a 10 h phase shift in circadian oscillations through induction of miR-211, a PERK-inducible microRNA that transiently suppresses both Bmal1 and Clock, core circadian regulators. Molecular investigation reveals that miR-211 directly regulates Bmal1 and Clock via distinct mechanisms. Suppression of Bmal1 and Clock has the anticipated impact on expression of select circadian genes, but we also find that repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation to stresses that disrupt endoplasmic reticulum homeostasis. Our data demonstrate that c-Myc-dependent activation of the UPR inhibits Bmal1 in Burkitt's lymphoma, thereby suppressing both circadian oscillation and ongoing protein synthesis to facilitate tumour progression.

中文翻译：

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PERK-miR-211轴抑制昼夜节律调节器和蛋白质合成，从而促进癌细胞的存活。

展开的蛋白质反应（UPR）是一种应力激活的信号传导途径，可调节细胞增殖，代谢和存活。昼夜节律时钟以光/暗周期协调新陈代谢和信号转导。我们探讨了UPR信号与生物钟的接口。UPR激活通过miR-211的诱导在昼夜节律振荡中发生10 h相移，miR-211是PERK诱导的microRNA，可瞬时抑制Bmal1和Clock，这是昼夜节律的调节剂。分子研究表明，miR-211通过不同的机制直接调节Bmal1和Clock。Bmal1和Clock的抑制对某些昼夜节律基因的表达具有预期的影响，但是我们还发现，抑制Bmal1对于UPR依赖性蛋白合成的抑制和细胞适应破坏内质网稳态的应力必不可少。我们的数据表明，UPR的c-Myc依赖性激活抑制了伯基特淋巴瘤中的Bmal1，从而抑制了昼夜节律振荡和正在进行的蛋白质合成，从而促进了肿瘤的进展。