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Nat Cell Biol. 2018 Jan;20(1):104-115. doi: 10.1038/s41556-017-0006-y. Epub 2017 Dec 11.

A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival.

Author information

1
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
2
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
3
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
5
Department of Public Health Sciences and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
6
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Departments of Urology and Cellular and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
8
Department of Biomedical Sciences, School of Veterinary Medicine, Philadelphia, PA, USA.
9
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. diehl@musc.edu.

Abstract

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.

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