A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival
| Autor: | Nilesh Chitnis, Kent Armeson, Constantinos Koumenis, Gerald Wertheim, Yiwen Bu, J. Alan Diehl, Akihiro Yoshida, Chi V. Dang, Amanda R. Oran, Feven Tameire, Davide Ruggero, Serge Y. Fuchs, Victoria J. Gennaro, Brian J. Altman, Steven B. McMahon |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine endocrine system Light Signal Transduction Cell Survival Photoperiod Circadian clock CLOCK Proteins Bone Neoplasms Mice Transgenic Biology Article Mice eIF-2 Kinase 03 medical and health sciences Cell Line Tumor Circadian Clocks microRNA Animals Humans Circadian rhythm RNA Small Interfering B-Lymphocytes Osteosarcoma Osteoblasts Cell growth Endoplasmic reticulum ARNTL Transcription Factors Cell Biology Hedgehog signaling pathway 3. Good health Cell biology Gene Expression Regulation Neoplastic Mice Inbred C57BL MicroRNAs 030104 developmental biology Unfolded Protein Response Unfolded protein response Heterografts Signal transduction |
| Zdroj: | Nature Cell Biology. 20:104-115 |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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