Authors: Lamia KA; Sachdeva UM; DiTacchio L; Williams EC; Alvarez JG; Egan DF; Vasquez DS; Juguilon H; Panda S; Shaw RJ; Thompson CB; Evans RM
Abstract: Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.
Keywords: AMP-Activated Protein Kinases/*metabolism; ARNTL Transcription Factors; Amino Acid Substitution; Aminoimidazole Carboxamide/analogs & derivatives/pharmacology; Animals; Basic Helix-Loop-Helix Transcription Factors/genetics; Cell Line; Cell Nucleus/metabolism; Cells, Cultured; Circadian Rhythm/*physiology; Cryptochromes; Culture Media; Flavoproteins/genetics/*metabolism; Food; Glucose/metabolism/pharmacology; Humans; Liver/*metabolism; Mice; Mutagenesis, Site-Directed; Mutant Proteins/metabolism; Phosphorylation; Promoter Regions, Genetic; Protein Stability; Recombinant Fusion Proteins/metabolism; Ribonucleotides/pharmacology; Signal Transduction
Journal: Science (New York, N.Y.) Volume: 326 Issue: 5951 Pages: 437-40 Date: Oct. 17, 2009 PMID: 19833968 |
Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science (New York, N.Y.) 326: 437-40.
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