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CIPC is a mammalian circadian clock protein without invertebrate homologues

Nature Cell Biology volume 9, pages 268–275 (2007)Cite this article

Abstract

At the core of the mammalian circadian clock is a feedback loop in which the heterodimeric transcription factor CLOCK–Brain, Muscle Arnt-like-1 (BMAL1) drives expression of its negative regulators, periods (PERs) and cryptochromes (CRYs). Here, we provide evidence that CLOCK-Interacting Protein, Circadian (CIPC) is an additional negative-feedback regulator of the circadian clock. CIPC exhibits circadian regulation in multiple tissues, and it is a potent and specific inhibitor of CLOCK–BMAL1 activity that functions independently of CRYs. CIPC–CLOCK protein complexes are present in vivo, and depletion of endogenous CIPC shortens the circadian period length. CIPC is unrelated to known proteins and has no recognizable homologues outside vertebrates. Our results suggest that negative feedback in the mammalian circadian clock is divided into distinct pathways, and that the addition of new genes has contributed to the complexity of vertebrate clocks.

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Figure 1: Characterization of CIPC interaction with CLOCK.
Figure 2: Circadian rhythms of Cipc mRNA and protein expression in multiple peripheral tissues.
Figure 3: CIPC inhibits CLOCK–BMAL1 transcriptional activity in mammalian cells in a manner that is distinguishable from CRY proteins.
Figure 4: Colocalization of CIPC and CLOCK in liver-cell nuclei.
Figure 5: Presence of CIPC–CLOCK protein complexes in vivo.
Figure 6: Depletion of endogenous CIPC shortens the circadian period of mammalian cells.

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Acknowledgements

We thank Choogon Lee for advice on immunoprecipitation and D. Knutti and K.-F. Storch for helpful comments on the manuscript. This work was supported by the National Institutes of Health (NIH; R01-MH59943; C.J.W.), by a Dana-Mahoney Fellowship from the Dana Foundation (W.-N.Z.), and by the Deutsche Forschungsgemeinschaft and the 6th Framework Project EUCLOCK (A.K.).

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Author notes

  1. Nikolay Malinin

    Present address: Current address: Department of Immunology, University of Toronto, Toronto, 1 King's College Circle, Ontario, M5S 1A8, Canada.,

  2. Fu-Chia Yang

    Present address: Current address: Dana Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.,

  3. David Staknis

    Present address: Current address: Global Prior Art, Inc., 21 Milk St., Boston, MA 02109, USA.,

  4. Nicholas Gekakis

    Present address: Current address: The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.,

Authors and Affiliations

  1. Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, 02115, MA, USA

    Wen-Ning Zhao, Nikolay Malinin, Fu-Chia Yang, David Staknis, Nicholas Gekakis & Charles J. Weitz

  2. Laboratory of Chronobiology, Institute of Medical Immunology, Schumann Str. 20−21. Charité-Universitaetsmedizin-Berlin, Berlin, 10098, Germany

    Bert Maier, Silke Reischl & Achim Kramer

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Supplementary figures S1, S2, S3, S4, S5, Supplementary Notes and Supplementary Methods (PDF 631 kb)

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Zhao, WN., Malinin, N., Yang, FC. et al. CIPC is a mammalian circadian clock protein without invertebrate homologues. Nat Cell Biol 9, 268–275 (2007). https://doi.org/10.1038/ncb1539

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