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Cell. 2016 Jun 16;165(7):1644-1657. doi: 10.1016/j.cell.2016.05.012. Epub 2016 May 26.

Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation.

Author information

1
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2
Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan; PRESTO, Japan Science and Technology Agency, Nagoya 464-8601, Japan.
3
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, NSW 2006, Australia.
5
Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
6
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
7
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.

Abstract

Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV-ERBα, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7. By relieving REV-ERBα-dependent repression, FBXW7 provides an unrecognized mechanism for enhancing the amplitude of clock gene transcription. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of REV-ERBα is necessary for FBXW7 recognition. Moreover, targeted hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels. This CDK1-FBXW7 pathway controlling REV-ERBα repression defines an unexpected molecular mechanism for re-engaging the positive transcriptional arm of the clock, as well as a potential route to manipulate clock amplitude via small molecule CDK1 inhibition.

PMID:
27238018
PMCID:
PMC4912445
DOI:
10.1016/j.cell.2016.05.012
[Indexed for MEDLINE]
Free PMC Article

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