Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock

Yool Lee, Jiwon Lee, Ilmin Kwon, Yoshihiro Nakajima, Yoshihiro Ohmiya, Gi Hoon Son, Kun Ho Lee, Kyungjin Kim

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The transcription factor CLOCK-BMAL1 is a core component of the molecular clock machinery that drives circadian gene expression and physiology in mammals. Recently, we reported that this heterodimeric transcription factor functions as a signaling molecule in response to the resetting stimuli via the Ca 2+-dependent protein kinase C pathway. Here, we demonstrate that the CREB-binding protein (CBP) plays a key role in rapid activation of the CLOCK-BMAL1 heterodimer that leads to phase resetting of the circadian clock. Under physiological conditions, a bimolecular fluorescence complementation (BiFC) assay revealed that CLOCK and BMAL1 dimerize in the cytoplasm and subsequently translocate into the nucleus in response to serum stimuli (mean time duration was 29.2 minutes and mean velocity 0.7 μm/minute). Concomitantly, BMAL1 rapidly recruited CBP on Per1 promoter E-box, but not p300 (a functional analog of CBP), in the discrete nuclear foci. However, recruitment of CBP by cAMP/Ca2+ response element-binding (CREB) protein on CRE was not markedly increased upon delivery of the resetting stimuli. Furthermore, overexpression of CBP greatly potentiated the CLOCK-BMAL1-mediated Per1 transcription, and this effect was completely abolished by site-directed mutation of E-box elements, but not by the mutation of CRE in the Per1 promoter. Furthermore, molecular knockdown of CBP severely dampened circadian oscillation of clock gene expression triggered by the resetting stimuli. These findings suggest that CBP recruitment by BMAL1 mediates acute transactivation of CLOCK-BMAL1, thereby inducing immediate-early Per1 transcription and phase resetting of the circadian clock.

Original languageEnglish
Pages (from-to)3547-3557
Number of pages11
JournalJournal of Cell Science
Volume123
Issue number20
DOIs
Publication statusPublished - 2010 Oct 15
Externally publishedYes

Fingerprint

CREB-Binding Protein
Circadian Clocks
Transcription Factors
E-Box Elements
Gene Expression
Cyclic AMP Response Element-Binding Protein
Mutation
Response Elements
Protein Kinase C
Transcriptional Activation
Mammals
Carrier Proteins
Cytoplasm
Fluorescence
Serum

Keywords

  • BiFC
  • Bimolecular fluorescence complementation assay
  • BMAL1
  • CBP
  • Circadian clock
  • Phase resetting
  • PKC

ASJC Scopus subject areas

  • Cell Biology

Cite this

Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. / Lee, Yool; Lee, Jiwon; Kwon, Ilmin; Nakajima, Yoshihiro; Ohmiya, Yoshihiro; Son, Gi Hoon; Lee, Kun Ho; Kim, Kyungjin.

In: Journal of Cell Science, Vol. 123, No. 20, 15.10.2010, p. 3547-3557.

Research output: Contribution to journalArticle

Lee, Y, Lee, J, Kwon, I, Nakajima, Y, Ohmiya, Y, Son, GH, Lee, KH & Kim, K 2010, 'Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock', Journal of Cell Science, vol. 123, no. 20, pp. 3547-3557. https://doi.org/10.1242/jcs.070300
Lee, Yool ; Lee, Jiwon ; Kwon, Ilmin ; Nakajima, Yoshihiro ; Ohmiya, Yoshihiro ; Son, Gi Hoon ; Lee, Kun Ho ; Kim, Kyungjin. / Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. In: Journal of Cell Science. 2010 ; Vol. 123, No. 20. pp. 3547-3557.
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