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

Oct 9, 2010Journal of cell science

CBP helps activate the CLOCK-BMAL1 complex to reset the body’s internal clock

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Abstract

Mean time for CLOCK and BMAL1 dimerization and nuclear translocation was 29.2 minutes.

CLOCK-BMAL1, a key transcription factor, is involved in circadian gene expression and responds to resetting stimuli.
CBP is essential for the rapid activation of CLOCK-BMAL1, leading to phase resetting of the circadian clock.
Under physiological conditions, CLOCK and BMAL1 dimerize in the cytoplasm and move to the nucleus at a velocity of 0.7 μm/minute.
CBP is recruited by BMAL1 on the Per1 promoter but not by p300 in response to stimuli.
Overexpression of CBP enhances CLOCK-BMAL1-mediated transcription of Per1, while mutation of E-box elements abolishes this effect.
Knockdown of CBP disrupts the circadian oscillation of clock gene expression triggered by resetting stimuli.

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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 Ca²+-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.

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