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Science 288 (5468): 1013-1019

Copyright © 2000 by the American Association for the Advancement of Science

Interacting Molecular Loops in the Mammalian Circadian Clock

Lauren P. Shearman, 1* Sathyanarayanan Sriram, 1* David R. Weaver, 1 Elizabeth S. Maywood, 2 In&etilde;s Chaves, 3 Binhai Zheng, 4 Kazuhiko Kume, 1 Cheng Chi Lee, 4 Gijsbertus T. J. van der , Horst, 3 Michael H. Hastings, 2 Steven M. Reppert 1dagger

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 of Clock/Clock mutant mice, homozygous Period2Brdm1 mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 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 and Cryptochrome cycles.

1 Laboratory of Developmental Chronobiology, MassGeneral Hospital for Children, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
2 Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
3 Medical Genetic Center, Department of Cell Biology and Genetics, Erasmus University, 3000 DR Rotterdam, Netherlands.
4 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: reppert{at}

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