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Journal of Biochemistry Advance Access originally published online on September 8, 2008
Journal of Biochemistry 2008 144(5):609-618; doi:10.1093/jb/mvn112
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© 2008 The Japanese Biochemical Society

The Role of β-TrCP1 and β-TrCP2 in Circadian Rhythm Generation by Mediating Degradation of Clock Protein PER2

Kanae Ohsaki1, Katsutaka Oishi1, Yuko Kozono1, Keiko Nakayama2, Keiichi I. Nakayama3 and Norio Ishida1,4,*

1Clock Cell Biology Research Group, Advanced Industrial Science and Technology, Ibaraki; 2Department of Functional Genomics, Graduate School of Medicine & School of Medicine, Tohoku University, Sendai; 3Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka; and 4Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan

*To whom correspondence should be addressed. Tel: +81-29-861-6053, Fax: +81-29-861-9499, E-mail: n.ishida{at}aist.go.jp

Received June 6, 2008; Accepted August 14, 2008


  Abstract

The mammalian circadian clock proteins undergo a daily cycle of accumulation followed by phosphorylation and degradation. The mechanism by which clock proteins undergo degradation has not been fully understood. Circadian clock protein PERIOD2 (PER2) is shown to be the potential target of F-box protein β-TrCP1, a component of ubiquitin E3 ligase. Here, we show that β-TrCP2 as well as β-TrCP1 target PER2 protein in vitro. We also identified β-TrCP binding site (m2) of PER2 being recognized by both β-TrCP1 and β-TrCP2. Luciferase–PER2 fusion system revealed that m2 site was responsible for the stability of PER2. The role of β-TrCP1 and β-TrCP2 in circadian rhythm generation was analysed by real-time reporter assay revealing that siRNA-mediated suppressions of β-TrCP1 and/or β-TrCP2 attenuate circadian oscillations in NIH3T3 cell. β-TrCP1-deficient mice, however, showed normal period length, light-induced phase-shift response in behaviour and normal expression of PER2, suggesting that β-TrCP1 is dispensable for the central clock in the suprachiasmatic nucleus. Our study indicates that β-TrCP1 and β-TrCP2 were involved in the cell autonomous circadian rhythm generation in culture cells, although the role of β-TrCP2 in the central clock in the suprachiasmatic nucleus remains to be elucidated.

Key Words: β-TrCP, circadian rhythm, F-box protein, knockout mouse, ubiquitin E3 ligase


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