Genes to cells : devoted to molecular & cellular mechanismsJan 31, 2004

Daily clock controls BMAL1 movement and modification between nucleus and cytoplasm in cultured cells

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

A significant time lag between Bmal1 transcription and the cytoplasmic/nuclear accumulation of BMAL1 was observed.

Nuclear accumulation of BMAL1 coincided with the peak of Per1 transcription and matched the nuclear accumulation of CLOCK.
BMAL1 showed a pattern of gradual phosphorylation and dephosphorylation in the nucleus, while cytoplasmic BMAL1 remained unphosphorylated.
In CRY-deficient fibroblasts, both cytoplasmic and nuclear BMAL1 were found only in hyperphosphorylated forms, indicating disrupted nucleocytoplasmic shuttling.
The study suggests that the timing of BMAL1's nuclear entry and its phosphorylation states are crucial for the stability of the circadian clock.

Simplified

BACKGROUND: Recent discoveries of clock proteins have unveiled an important part of the mammalian circadian clock mechanism. However, the molecular clockwork that cause these fundamental feedback loops to stably oscillate with a approximately 24 h-periodicity remain unclear.

RESULTS: Serum-shocked fibroblasts were used as a cellular clock model. Circadian changes in the subcellular localization and phosphorylation of BMAL1 protein in these cells were assessed by immunocytochemistry and immunoblotting. A significant time lag between Bmal1 transcription and the cytoplasmic/nuclear accumulation of BMAL1 was observed. After its nuclear accumulation, BMAL1 accumulated in the cytoplasm again, mainly by nucleoexport, before the increase of Bmal1 transcripts. Nuclear accumulation of BMAL1 matched nuclear accumulation of CLOCK and the peak of Per1 transcription. Nuclear BMAL1 was gradually phosphorylated and then dephosphorylated in a temporally regulated manner, although cytoplasmic BMAL1 was not. In serum-shocked mCry1/mCry2 (CRY)-deficient fibroblasts, which lack a functional clock, both the cytoplasmic and nuclear BMAL1 were only present as hyperphosphorylated forms and their circadian nucleocytoplasmic shuttling was absent.

CONCLUSIONS: We propose that the nucleocytoplasmic shuttling and phosphorylation states of BMAL1 are regulated by circadian clock, and that this temporally regulated and time-delayed nuclear entry of BMAL1 is important in the maintenance of a stably oscillating clock.

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Daily clock controls BMAL1 movement and modification between nucleus and cytoplasm in cultured cells

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