CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Yasushi Isojima, Masato Nakajima, Hideki Ukai, Hiroshi Fujishima, Rikuhiro G. Yamada, Koh Hei Masumoto, Reiko Kiuchi, Mayumi Ishida, Maki Ukai-Tadenuma, Yoichi Minami, Ryotaku Kito, Kazuki Nakao, Wataru Kishimoto, Seung Hee Yoo, Kazuhiro Shimomura, Toshifumi Takao, Atsuko Takano, Toshio Kojima, Katsuya Nagai, Yoshiyuki SakakiJoseph S. Takahashi, Hiroki R. Ueda

Research output: Contribution to journalArticle

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A striking feature of the circadian clock is its flexible yet robust response to various environmental conditions. To analyze the biochemical processes underlying this flexible-yet-robust characteristic, we examined the effects of 1,260 pharmacologically active compounds in mouse and human clock cell lines. Compounds that markedly (>10 s.d.) lengthened the period in both cell lines, also lengthened it in central clock tissues and peripheral clock cells. Most compounds inhibited casein kinase Iε (CKIε) or CKIδ phosphorylation of the PER2 protein. Manipulation of CKIε/δ-dependent phosphorylation by these compounds lengthened the period of the mammalian clock from circadian (24 h) to circabidian (48 h), revealing its high sensitivity to chemical perturbation. The degradation rate of PER2, which is regulated by CKIε/δ-dependent phosphorylation, was temperature-insensitive in living clock cells, yet sensitive to chemical perturbations. This temperature-insensitivity was preserved in the CKIε/δ-dependent phosphorylation of a synthetic peptide in vitro. Thus, CKIε/δ- dependent phosphorylation is likely a temperature-insensitive period-determining process in the mammalian circadian clock.

Original languageEnglish (US)
Pages (from-to)15744-15749
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
Publication statusPublished - Sep 15 2009



  • Chemical biological approach
  • Temperature compensation

ASJC Scopus subject areas

  • General

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