RT Journal Article
SR Electronic
T1 Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 124354
DO 10.1101/124354
A1 Naoto Hayasaka
A1 Arisa Hirano
A1 Yuka Miyoshi
A1 Isao T. Tokuda
A1 Hikari Yoshitane
A1 Junichiro Matsuda
A1 Yoshitaka Fukada
YR 2017
UL http://biorxiv.org/content/early/2017/04/05/124354.abstract
AB Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism, as well as in skeletal development. In the course of investigating metabolic defects in the Sik3-deficient mice (Sik3−/−), we observed that circadian rhythmicity of the metabolisms was phase-delayed. Sik3−/− mice also displayed other abnormalities in circadian rhythms, including lengthening of the period, impaired entrainment to the light-dark cycle, phase variation in locomotor activities, and aberrant physiological rhythms. Ex vivo suprachiasmatic nucleus slices from Sik3−/− mice exhibited destabilized and desynchronized molecular rhythms among individual neurons. In cultured cells, Sik3-knockdown resulted in cycle-to-cycle fluctuations of the circadian periodicity. Expression levels of PER2, an essential clock protein, were elevated in Sik3-knockdown cells but down-regulated in Sik3-overexpressing cells, which could be ascribed to a phosphorylation-dependent decrease in PER2 protein stability. Collectively, our results indicate that SIK3 plays key roles in murine circadian rhythms by facilitating phosphorylation-dependent destabilization of PER2.