Circadian Amplitude Regulation via FBXW7-targeted REV-ERBα Degradation
| Autor: | Michael Downes, Xuan Zhao, Xuemei Han, Christopher Liddle, Ronald M. Evans, Ling-Wa Chong, Katja A. Lamia, Han Cho, Tsuyoshi Hirota, Ruth T. Yu, Annette R. Atkins, Ester Banayo, Sihao Liu, John R. Yates, Steve A. Kay |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
F-Box-WD Repeat-Containing Protein 7 Ubiquitin-Protein Ligases Circadian clock Cell Cycle Proteins Biology F-box protein General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Gene Knockout Techniques Mice Ubiquitin Transcription (biology) Cell Line Tumor Circadian Clocks CDC2 Protein Kinase Animals Humans Circadian rhythm Phosphorylation Psychological repression Cyclin-dependent kinase 1 F-Box Proteins Lipid Metabolism Cell biology Circadian Rhythm CLOCK 030104 developmental biology Biochemistry Liver Nuclear Receptor Subfamily 1 Group D Member 1 biology.protein Transcriptome Protein Processing Post-Translational |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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