title: The mammalian circadian clock protein period counteracts cryptochrome in phosphorylation dynamics of circadian locomotor output cycles kaput (CLOCK).
abstract: The circadian transcription factor CLOCK exhibits a circadian oscillation in its phosphorylation levels. Although it remains unclear whether this phosphorylation contributes to circadian rhythm generation, it has been suggested to be involved in transcriptional activity, intracellular localization, and degradative turnover of CLOCK. Here, we obtained direct evidence that CLOCK phosphorylation may be essential for autonomous circadian oscillation in clock gene expression. Importantly, we found that the circadian transcriptional repressors Cryptochrome (CRY) and Period (PER) showed an opposite effect on CLOCK phosphorylation; CRY impaired BMAL1-dependent CLOCK phosphorylation, whereas PER protected the phosphorylation against CRY. Interestingly, unlike PER1 and PER2, PER3 did not exert a protective action, which correlates with the phenotypic differences among mice lacking the Per genes. Further studies on the regulatory mechanism of CLOCK phosphorylation would thus lead to elucidation of the mechanism of CRY-mediated transcriptional repression and an understanding of the true role of PER in the negative feedback system.
authors.affiliation: Research Institute for Time Studies, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8511, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Matsumura
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Department of Mechanical Engineering, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Japan, and.
authors.forename: Isao
authors.initials: I
authors.lastname: Tokuda
authors.affiliation: Research Institute for Time Studies, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8511, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsuo
authors.affiliation: Research Institute for Time Studies, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8511, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
authors.affiliation: Research Institute for Time Studies, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8511, Japan,. Electronic address: akashima@yamaguchi-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Akashi
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D056926:CLOCK Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D056931:Cryptochromes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D041681:NIH 3T3 Cells; D009991:Oscillometry; D056950:Period Circadian Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D056931:Cryptochromes; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C512645:Per3 protein, mouse; D056950:Period Circadian Proteins; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: Circadian Clock; Circadian Rhythm; Clock Gene; Gene Expression; Phosphorylation