Role of the CLOCK protein in the mammalian circadian mechanism

N Gekakis, D Staknis, HB Nguyen, FC Davis… - Science, 1998 - science.org
N Gekakis, D Staknis, HB Nguyen, FC Davis, LD Wilsbacher, DP King, JS Takahashi
Science, 1998science.org
The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and
is related to transcription factors that act as heterodimers. Potential partners of CLOCK were
isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1
at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated
transcription from E-box elements, a type of transcription factor–binding site, found adjacent
to the mouse per1 gene and from an identical E-box known to be important for per gene …
The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor–binding site, found adjacent to the mouseper1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.
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