Journal article
Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock
Journal of cell science, Vol.123(20), pp.3547-3557
10/15/2010
PMID: 20930143
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 mu m/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/Ca(2+) 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.
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Details
- Title
- Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock
- Creators
- Yool Lee - Washington State University, Biomedical Sciences, Department ofJiwon Lee - Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South KoreaIlmin Kwon - Seoul National UniversityYoshihiro Nakajima - National Institute of Advanced Industrial Science and TechnologyYoshihiro Ohmiya - National Institute of Advanced Industrial Science and TechnologyGi Hoon Son - Seoul National UniversityKun Ho Lee - Chosun UniversityKyungjin Kim - Daegu Gyeongbuk Institute of Science and Technology
- Publication Details
- Journal of cell science, Vol.123(20), pp.3547-3557
- Academic Unit
- Elson S. Floyd College of Medicine
- Publisher
- COMPANY OF BIOLOGISTS LTD
- Number of pages
- 11
- Grant note
- 2009-0070022 / National Research Foundation of Korea Korea Ministry of Education, Science and Technology (MEST); Ministry of Education, Science & Technology (MEST), Republic of Korea 21590266 / Grants-in-Aid for Scientific Research; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research (KAKENHI) BioImaging Research Center at GIST
- Identifiers
- 99901132534901842
- Language
- English
- Resource Type
- Journal article