Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics.
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 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-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 beta-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 beta-TrCP-mediated PER2 degradation is due to excessive nuclear repression, a prediction they verified experimentally.
Reischl
Silke
S
Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, 10115 Berlin, Germany.
Vanselow
Katja
K
Westermark
Pål O
PO
Thierfelder
Nadine
N
Maier
Bert
B
Herzel
Hanspeter
H
Kramer
Achim
A
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000502:physiology*; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D010641:Phenotype; D010766:Phosphorylation; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000502:physiology*
C471644:BTRC protein, human; C471643:Btrc protein, mouse; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D044844:beta-Transducin Repeat-Containing Proteins; D048149:Casein Kinase 1 epsilon