Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics.
J Biol Rhythms
; 22(5): 375-86, 2007 Oct.
Article
em En
| MEDLINE
| ID: mdl-17876059
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Relógios Biológicos
/
Proteínas Nucleares
/
Ritmo Circadiano
/
Proteínas de Ciclo Celular
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Proteínas Contendo Repetições de beta-Transducina
/
Caseína Quinase 1 épsilon
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article