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Sleep and Biological Rhythms

開催日 2014/9/12
時間 9:00 - 10:00
会場 Room H(304)
Chairperson(s) 八木田 和弘 / Kazuhiro Yagita (京都府立医科大学大学院医学研究科統合生理学 / Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Japan)
人見 健文 / Takefumi Hitomi (京都大学大学院 医学研究科 臨床病態検査学講座 / Department of Clinical Laboratory Medicine, Kyoto University, Graduate school of Medecine, Japan)

Salt-inducible kinase 3 regulates circadian clocks in mice by destabilization of PER2 protein

  • O2-H-1-1
  • 早坂 直人 / Naoto Hayasaka:1,2,3 三好 由夏 / Yuka Miyoshi:3 平野 有紗 / Arisa Hirano:4 徳田 功 / Isao T. Tokuda:5 深田 吉孝 / Yoshitaka Fukada:4 
  • 1:山口大学院医・機能神経解剖 / Dept Funct Anatomy, Yamaguchi Univ Med School, Yamaguchi, Japan 2:JSTさきがけ / PRESTO, JST, Saitama, Japan 3:近畿大医解剖 / Dept Anatomy, Kinki Univ, Osaka, Japan 4:東京大院理生物化学 / Dept Biophysics Biochem, Univ of Tokyo, Tokyo, Japan 5:立命大理工機械工学 / Dept Mechanical Engineering, Ritsumeikan Univ, Shiga, Japan 

Salt-inducible kinase 3 (SIK3), a Ser/Thr kinase belonging to the AMP-activated protein kinase (AMPK) family, plays a crucial role in various metabolisms as well as in skeletal development. SIK3 is abundantly expressed in various organs/tissues including the brain. It remains elusive, however, how SIK3 regulates functions of the central nervous system. Behavioral and physiological analyses of Sik3-deficient mice (Sik3-/-) demonstrated severe abnormalities in circadian rhythms, such as lengthened period, impaired entrainment to light/dark cycle in behavior, significant phase-delay in locomotor activity, and other physiological rhythms. These phenotypes contrast to those observed in tau, a gain-of-function mutation in casein kinase 1 epsilon (CKIε). Remarkably, ex vivo SCN explant cultures from Sik3-/-; Per2-luciferase+/+ mice showed desynchronization of Per2-luc rhythms among individual SCN cells. In addition, the mouse embryonic fibroblast (MEF) and astrocyte cell lines isolated from Sik3-/- mice exhibited circadian rhythms with an average period shorter than that of the controls. Expression levels of PER2, an essential clock protein, were elevated in Sik3-knockdown cells, whereas reduced in Sik3-overexpressed cells. These effects were due to phosphorylation-dependent alterations in PER2 protein stability, which were observed with and without CKI inhibitors. Our results suggest that SIK3 regulates circadian pacemakers as well as circadian input and output pathways by phosphorylation-dependent, but CKIε-independent destabilization of PER2.

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