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PMID:19833968

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Citation

Lamia, KA, Sachdeva, UM, DiTacchio, L, Williams, EC, Alvarez, JG, Egan, DF, Vasquez, DS, Juguilon, H, Panda, S, Shaw, RJ, Thompson, CB and Evans, RM (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326:437-40

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.

Links

PubMed PMC2819106 Online version:10.1126/science.1172156

Keywords

AMP-Activated Protein Kinases/metabolism; ARNTL Transcription Factors; Amino Acid Substitution; Aminoimidazole Carboxamide/analogs & derivatives; Aminoimidazole Carboxamide/pharmacology; Animals; Basic Helix-Loop-Helix Transcription Factors/genetics; Cell Line; Cell Nucleus/metabolism; Cells, Cultured; Circadian Rhythm/physiology; Cryptochromes; Culture Media; Flavoproteins/genetics; Flavoproteins/metabolism; Food; Glucose/metabolism; Glucose/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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CRY1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8BRK8

F

Seeded From UniProt

complete

MOUSE:CRY1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q5EG47

F

Seeded From UniProt

complete

MOUSE:CRY1

involved_in

GO:0042752: regulation of circadian rhythm

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AAPK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P97784

F

Seeded From UniProt

complete

MOUSE:AAPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P97784

F

Seeded From UniProt

complete

MOUSE:AAPK2

enables

GO:0004679: AMP-activated protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:AAPK2

involved_in

GO:0042752: regulation of circadian rhythm

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AAPK1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AAPK1

enables

GO:0004679: AMP-activated protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:AAPK1

involved_in

GO:0042752: regulation of circadian rhythm

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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