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Identification of RACK1 and Protein Kinase C as Integral Components of the Mammalian Circadian Clock
Maria S. Robles,*,
Charles J. Weitz
At the core of the mammalian circadian clock is a negative feedbackloop in which the dimeric transcription factor CLOCK-BMAL1 drivesprocesses that in turn suppress its transcriptional activity.To gain insight into the mechanisms of circadian feedback, weanalyzed mouse protein complexes containing BMAL1. Receptorfor activated C kinase–1 (RACK1) and protein kinase C– (PKC) were recruited in a circadian manner into a nuclear BMAL1complex during the negative feedback phase of the cycle. Overexpressionof RACK1 and PKC suppressed CLOCK-BMAL1 transcriptional activity,and RACK1 stimulated phosphorylation of BMAL1 by PKC in vitro.Depletion of endogenous RACK1 or PKC from fibroblasts shortenedthe circadian period, demonstrating that both molecules functionin the clock oscillatory mechanism. Thus, the classical PKCsignaling pathway is not limited to relaying external stimulibut is rhythmically activated by internal processes, formingan integral part of the circadian feedback loop.
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
* These authors contributed equally to this work.
Present address: Proteomics and Signal Transduction, Max PlanckInstitute for Biochemistry, D-82152 Martinsried, Germany.