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Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism

Title
Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism
Authors
Lee, J[Lee, Jiyeon]Lee, S[Lee, Seungbeom]Chung, S[Chung, Sooyoung]Park, N[Park, Noheon]Son, GH[Son, Gi Hoon]An, H[An, Hongchan]Jang, J[Jang, Jaebong]Chang, DJ[Chang, Dong-Jo]Suh, YG[Suh, Young-Ger]Kim, K[Kim, Kyungjin]
DGIST Authors
Lee, J[Lee, Jiyeon]; Kim, K[Kim, Kyungjin]
Issue Date
2016-01-15
Citation
Biochemical and Biophysical Research Communications, 469(3), 580-586
Type
Article
Article Type
Article
Keywords
3T3 Cell LineAnimalAnimal CellAnimalsARNTL Protein, MouseARNTL Transcription FactorsBioluminescenceBrain-Muscle-Arnt-Like Protein 1Circadian ClockCircadian ClocksCircadian RhythmCitrate SynthaseControlled StudyDNA Responsive ElementEnhancer RegionEnzyme ActivityFeedback SystemFeedback, PhysiologicalGene ExpressionGene Expression RegulationGeneticsGlycogen Synthase Kinase-3BetaHep G2 Cell LineMiceMouseNon-HumanNR1D1 Protein, MouseNuclear Receptor NR1D1Nuclear Receptor Subfamily 1, Group D, Member 1PER2 ProteinPhysiologyPriority JournalPromoter RegionPromoter Regions, GeneticProteinProtein ExpressionProtein FunctionProtein PhosphorylationResponse ElementsRev-Erb AlphaRev ProteinROR Response Element ProteinROR/REV-ERB-Response ElementSite Directed MutagenesisSmall MoleculeThyroid Hormone ReceptorTranscription Factor ARNTLUnclassified Drug
ISSN
0006-291X
Abstract
Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by an innate genetically determined time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, development of small molecule modulators targeting the core clock machinery has only recently been initiated. BMAL1, a core clock gene, is controlled by a ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock. Therefore, we aimed to identify a novel small molecule modulator that regulates Bmal1 gene expression in RORE-dependency, thereby influencing the molecular feedback loop of the circadian clock. For this purpose, we carried out a cell-based screen of more than 1000 drug-like compounds, using a luciferase reporter driven by the proximal region of the mouse Bmal1 promoter. One compound, designated KK-S6, repressed the RORE-dependent transcriptional activity of the mBmal1 promoter and reduced endogenous BMAL1 protein expression. More importantly, KK-S6 significantly altered the amplitude of circadian oscillations of Bmal1 and Per2 promoter activities in a dose-dependent manner, but barely affected the period length. KK-S6 effectively decreased mRNA expression of metabolic genes acting downstream of REV-ERBα, Pai-1 and Citrate synthase, that contain RORE cis-element in their promoter. KK-S6 likely acts in a RORE-dependent manner by reinforcing the REV-ERBα activity, though not by the same mechanism as known REV-ERB agonists. In conclusion, the present study demonstrates that KK-S6 functions as a novel modulator of the amplitude of molecular circadian rhythms by influencing RORE-mediated BMAL1 expression. © 2015 The Authors. Published by Elsevier Inc.
URI
http://hdl.handle.net/20.500.11750/2736
DOI
10.1016/j.bbrc.2015.12.030
Publisher
Academic Press Inc.
Files:
There are no files associated with this item.
Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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