TY - JOUR
T1 - CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock
AU - Isojima, Yasushi
AU - Nakajima, Masato
AU - Ukai, Hideki
AU - Fujishima, Hiroshi
AU - Yamada, Rikuhiro G.
AU - Masumoto, Koh Hei
AU - Kiuchi, Reiko
AU - Ishida, Mayumi
AU - Ukai-Tadenuma, Maki
AU - Minami, Yoichi
AU - Kito, Ryotaku
AU - Nakao, Kazuki
AU - Kishimoto, Wataru
AU - Yoo, Seung Hee
AU - Shimomura, Kazuhiro
AU - Takao, Toshifumi
AU - Takano, Atsuko
AU - Kojima, Toshio
AU - Nagai, Katsuya
AU - Sakaki, Yoshiyuki
AU - Takahashi, Joseph S.
AU - Ueda, Hiroki R.
PY - 2009/9/15
Y1 - 2009/9/15
N2 - 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.
AB - 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.
KW - Chemical biological approach
KW - Temperature compensation
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U2 - 10.1073/pnas.0908733106
DO - 10.1073/pnas.0908733106
M3 - Article
C2 - 19805222
AN - SCOPUS:70349452319
SN - 0027-8424
VL - 106
SP - 15744
EP - 15749
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -