title: CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock.
abstract: 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 Iepsilon (CKIepsilon) or CKIdelta phosphorylation of the PER2 protein. Manipulation of CKIepsilon/delta-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 CKIepsilon/delta-dependent phosphorylation, was temperature-insensitive in living clock cells, yet sensitive to chemical perturbations. This temperature-insensitivity was preserved in the CKIepsilon/delta-dependent phosphorylation of a synthetic peptide in vitro. Thus, CKIepsilon/delta-dependent phosphorylation is likely a temperature-insensitive period-determining process in the mammalian circadian clock.
authors.affiliation: Comparative Systems Biology Team, Genomic Science Center, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Isojima
authors.forename: Masato
authors.initials: M
authors.lastname: Nakajima
authors.forename: Hideki
authors.initials: H
authors.lastname: Ukai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujishima
authors.forename: Rikuhiro G
authors.initials: RG
authors.lastname: Yamada
authors.forename: Koh-hei
authors.initials: KH
authors.lastname: Masumoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Kiuchi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishida
authors.forename: Maki
authors.initials: M
authors.lastname: Ukai-Tadenuma
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Minami
authors.forename: Ryotaku
authors.initials: R
authors.lastname: Kito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.forename: Wataru
authors.initials: W
authors.lastname: Kishimoto
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takao
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takano
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagai
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakaki
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.forename: Hiroki R
authors.initials: HR
authors.lastname: Ueda
mesh_terms: D000818:Animals; D005075:Biological Evolution; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000458:Cyanobacteria / Q000235:genetics / Q000502:physiology; D006801:Humans; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014157:Transcription Factors; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta