| First Author | Hayasaka N | Year | 2017 |
| Journal | Elife | Volume | 6 |
| PubMed ID | 29227248 | Mgi Jnum | J:254967 |
| Mgi Id | MGI:6111003 | Doi | 10.7554/eLife.24779 |
| Citation | Hayasaka N, et al. (2017) Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein. Elife 6:e24779 |
| abstractText | Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism. In the course of investigating metabolic defects in Sik3-deficient mice (Sik3(-/-)), we observed that circadian rhythmicity of the metabolisms was phase-delayed. Sik3(-/-) mice also exhibited other circadian abnormalities, 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 abnormal bioluminescence rhythms. Expression levels of PER2, a clock protein, were elevated in Sik3-knockdown cells but down-regulated in Sik3-overexpressing cells, which could be attributed to a phosphorylation-dependent decrease in PER2 protein stability. This was further confirmed by PER2 accumulation in the Sik3(-/-) fibroblasts and liver. Collectively, SIK3 plays key roles in circadian rhythms by facilitating phosphorylation-dependent PER2 destabilization, either directly or indirectly. |
