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ß-TrCP1-Mediated Degradation of PERIOD2 Is Essential for Circadian Dynamics

Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

Katja Vanselow

Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

Pål O. Westermark

Institute for Theoretical Biology, Humboldt-University Berlin, Berlin, Germany

Nadine Thierfelder

Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

Bert Maier

Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

Hanspeter Herzel

Institute for Theoretical Biology, Humboldt-University Berlin, Berlin, Germany

Achim Kramer

Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany, achim.kramer{at}charite.de

Regulated degradation of circadian clock proteins is a crucial step for rhythm generation per se but also for establishing a normal circadian period. Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (ß-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous ß-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of ß-TrCP interaction-deficient PER2 variants—but not wild-type PER2—results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity. Mathematical modeling conceptualizes the authors' findings and suggests that loss of sustained rhythmicity in cells with eliminated ß-TrCP-mediated PER2 degradation is due to excessive nuclear repression, a prediction they verified experimentally.

Key Words: ß-TrCP • PERIOD2 • protein degradation • F-box protein • CKI • mathematical modeling

Journal of Biological Rhythms, Vol. 22, No. 5, 375-386 (2007)
DOI: 10.1177/0748730407303926


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