CKIepsilon/delta-dependent Phosphorylation is a Temperature-insensitive, Period-determining Process in the Mammalian Circadian Clock

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Oct 7

PMID 19805222

Citations 139

Authors

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 Sakaki

Joseph S Takahashi

Hiroki R Ueda

Affiliations

Soon will be listed here.

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.

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