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

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 a...

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Published in:	Nature cell biology Vol. 20; no. 1; pp. 104 - 115
Main Authors:	Bu, Yiwen, Yoshida, Akihiro, Chitnis, Nilesh, Altman, Brian J., Tameire, Feven, Oran, Amanda, Gennaro, Victoria, Armeson, Kent E., McMahon, Steven B., Wertheim, Gerald B., Dang, Chi V., Ruggero, Davide, Koumenis, Constantinos, Fuchs, Serge Y., Diehl, J. Alan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.01.2018 Nature Publishing Group
Subjects:	631/337/384/331 631/67/395 631/80/105 631/80/474/1768 Activation Animals ARNTL Transcription Factors - antagonists & inhibitors ARNTL Transcription Factors - genetics ARNTL Transcription Factors - metabolism B-Lymphocytes - metabolism B-Lymphocytes - pathology Biomedical and Life Sciences BMAL1 protein Bone Neoplasms - genetics Bone Neoplasms - metabolism Bone Neoplasms - pathology c-Myc protein Cancer Cancer cells Cancer Research Cell Biology Cell Line, Tumor Cell proliferation Cell Survival Cellular signal transduction Circadian Clocks - genetics Circadian rhythm Circadian rhythms CLOCK Proteins - antagonists & inhibitors CLOCK Proteins - genetics CLOCK Proteins - metabolism Developmental Biology eIF-2 Kinase - genetics eIF-2 Kinase - metabolism Endoplasmic reticulum Gene expression Gene Expression Regulation, Neoplastic Genes Heterografts Homeostasis Humans Interfaces Life Sciences Light Signal Transduction Lymphoma Lymphomas Male Metabolism Mice Mice, Inbred C57BL Mice, Transgenic MicroRNA MicroRNAs - genetics MicroRNAs - metabolism miRNA Myc protein Oscillations Osteoblasts - metabolism Osteoblasts - pathology Osteosarcoma - genetics Osteosarcoma - metabolism Osteosarcoma - pathology Photoperiod Protein biosynthesis Protein folding Protein synthesis Proteins Regulators Ribonucleic acid RNA RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Signal transduction Signaling Stem Cells Survival Tumors Unfolded Protein Response
ISSN:	1465-7392, 1476-4679, 1476-4679
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Summary:	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. PERK regulates tumour cell survival. Bu et al. show that the unfolded protein response protein PERK induces miR-211 repression of the circadian factor Bmal1 to regulate protein synthesis and stress responses, contributing to tumour progression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-017-0006-y