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Science 326 (5951): 437-440

Copyright © 2009 by the American Association for the Advancement of Science

AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation

Katja A. Lamia,1,* Uma M. Sachdeva,2,* Luciano DiTacchio,3 Elliot C. Williams,1 Jacqueline G. Alvarez,1,4 Daniel F. Egan,5 Debbie S. Vasquez,5 Henry Juguilon,1,4 Satchidananda Panda,3 Reuben J. Shaw,4,5 Craig B. Thompson,2,{dagger} Ronald M. Evans1,4,{dagger}

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.

1 Gene Expression Laboratory, the Salk Institute, La Jolla, CA 92037, USA.
2 Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
3 Regulatory Biology Laboratory, the Salk Institute, La Jolla, CA 92037, USA.
4 Howard Hughes Medical Institute, the Salk Institute, La Jolla, CA 92037, USA.
5 Molecular and Cellular Biology Laboratory, the Salk Institute, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: evans{at} (R.M.E.); craig{at} (C.B.T.)

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