Research Article

Interacting Molecular Loops in the Mammalian Circadian Clock

Science  12 May 2000:
Vol. 288, Issue 5468, pp. 1013-1019
DOI: 10.1126/science.288.5468.1013

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Abstract

We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis ofClock/Clock mutant mice, homozygousPeriod2Brdm1 mutants, andCryptochrome-deficient mice reveals substantially alteredBmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period andCryptochrome cycles.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed. E-mail: reppert{at}helix.mgh.harvard.edu

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