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Fig. 1. Interlocked feedback loop model for Drosophila and mouse circadian
oscillators. (A) Drosophila. The per/tim loop (left) and
dClk loop (right) are shown. The model is based on data from
peripheral oscillators. dCLK-CYC heterodimers activate per and
tim transcription, and PER and TIM monomers accumulate in the
cytoplasm and form heterodimers. PER-TIM then enters the nucleus, binds
dCLK-CYC and inhibits the activation of per and tim, thus
completing the per/tim feedback loop. dCLK-CYC dimers inhibit
dClk transcription either directly (1a/1b) or indirectly via
activation of a dClk repressor (2). Repression might occur through
protein-DNA interaction (1a/2a) or protein-protein interaction (1b/2b).
Repression of dClk is relieved when PER-TIM binds to dCLK-CYC, thus
preventing this negative-feedback, and ensuring that per/tim and
dClk mRNA transcripts cycle in anti-phase. Light input occurs through
CRY, ultimately leading to the degradation of TIM. CRY can bind to TIM and
PER, but whether CRY translocates to the nucleus with the PER-TIM dimer is not
known. dClk repressor, gene that represses dClk
transcription; dClk REPRESSOR, protein that represses dClk
transcription; dClk ACTIVATOR, protein that activates dClk
transcription. (B) Mouse. The mPer/mCry loop (left) and
Bmal1 loop (right) are shown. The model is based on data from the SCN
(black and green lines) and peripheral tissues (black, red and blue lines).
mCLK-BMAL1 dimers activate mPer1, mPer2, mCry1 and mCry2
transcription, which is followed by the accumulation of mPERs and mCRYs in the
cytoplasm. The mPERs bind to mCRYs and translocate to the nucleus. mCRYs
and/or mPER2 then bind and inhibit mCLK-BMAL1, completing the
mPer/mCry negative-feedback loop. Repression of Bmal1
transcription in peripheral tissues is mCLK-BMAL1 dependent. mCLK-BMAL1 might
repress Bmal1 either directly through protein-DNA (1a) or
protein-protein (1b) interaction, or indirectly by activating a Bmal1
repressor (2). The Bmal1 REPRESSOR may operate via protein-DNA
(2a) or protein-protein (2b) interaction. Repression would then be relieved by
mPER-mCRY-mediated inhibition of mCLK-BMAL1. In the SCN, mPER2 might
co-activate Bmal1 by binding the Bmal1 ACTIVATOR (3a) or the
Bmal1 REPRESSOR (3b). The figure is primarily based on in vivo data,
since it is becoming increasingly evident that the interpretation of cell
culture experiments is complicated by the presence of endogenous clock
components (either expressed naturally or resulting from experimental
manipulation). Bmal1 repressor, gene that represses Bmal1
transcription; Bmal1 REPRESSOR, protein that represses Bmal1
transcription; Bmal1 ACTIVATOR, protein that activates Bmal1
transcription.
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