title: Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation.
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.
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan; PRESTO, Japan Science and Technology Agency, Nagoya 464-8601, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirota
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Cho
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ling-Wa
authors.initials: LW
authors.lastname: Chong
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Lamia
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Sihao
authors.initials: S
authors.lastname: Liu
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ester
authors.initials: E
authors.lastname: Banayo
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: 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.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Kay
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D057906:Circadian Clocks; D002940:Circadian Rhythm; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D055786:Gene Knockout Techniques; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; C064353:NR1D1 protein, human; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D044767:Ubiquitin-Protein Ligases; D016203:CDC2 Protein Kinase