Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 337 (6098): 1094-1097

Copyright © 2012 by the American Association for the Advancement of Science

Identification of Small Molecule Activators of Cryptochrome

Tsuyoshi Hirota,1,7 Jae Wook Lee,2 Peter C. St. John,3 Mariko Sawa,1 Keiko Iwaisako,4 Takako Noguchi,5 Pagkapol Y. Pongsawakul,1 Tim Sonntag,1 David K. Welsh,5,6 David A. Brenner,4 Francis J. Doyle, III,3 Peter G. Schultz,2,* Steve A. Kay1,7,*

Abstract: Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate clock function might offer therapeutic approaches to such diseases, only a few compounds have been identified that selectively target core clock proteins. From an unbiased cell-based circadian phenotypic screen, we identified KL001, a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation of CRY, resulting in lengthening of the circadian period. In combination with mathematical modeling, our studies using KL001 revealed that CRY1 and CRY2 share a similar functional role in the period regulation. Furthermore, KL001-mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes. KL001 thus provides a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes.

1 Division of Biological Sciences and Center for Chronobiology, University of California San Diego, La Jolla, CA 92093, USA.
2 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
3 Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
4 Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
5 Department of Psychiatry and Center for Chronobiology, University of California San Diego, La Jolla, CA 92093, USA.
6 Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
7 San Diego Center for Systems Biology, University of California San Diego, La Jolla, CA 92093, USA.

* To whom correspondence should be addressed. E-mail: skay{at}ucsd.edu (S.A.K.); schultz{at}scripps.edu (P.G.S.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Nuclear receptors rock around the clock.
X. Zhao, H. Cho, R. T. Yu, A. R. Atkins, M. Downes, and R. M. Evans (2014)
EMBO Rep.
   Abstract »    Full Text »    PDF »
Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock.
P. C. St. John, T. Hirota, S. A. Kay, and F. J. Doyle III (2014)
PNAS 111, 2040-2045
   Abstract »    Full Text »    PDF »
Variants in glucose- and circadian rhythm-related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial.
K. Mirzaei, M. Xu, Q. Qi, L. de Jonge, G. A. Bray, F. Sacks, and L. Qi (2014)
Am J Clin Nutr 99, 392-399
   Abstract »    Full Text »    PDF »
Circadian Regulation of Lipid Mobilization in White Adipose Tissues.
A. Shostak, J. Meyer-Kovac, and H. Oster (2013)
Diabetes 62, 2195-2203
   Abstract »    Full Text »    PDF »
Mechanism of the circadian clock in physiology.
J. Richards and M. L. Gumz (2013)
Am J Physiol Regulatory Integrative Comp Physiol 304, R1053-R1064
   Abstract »    Full Text »    PDF »
Genetic redundancy strengthens the circadian clock leading to a narrow entrainment range.
A. Erzberger, G. Hampp, A. E. Granada, U. Albrecht, and H. Herzel (2013)
J R Soc Interface 10, 20130221
   Abstract »    Full Text »    PDF »
Distinct and Separable Roles for Endogenous CRY1 and CRY2 within the Circadian Molecular Clockwork of the Suprachiasmatic Nucleus, as Revealed by the Fbxl3Afh Mutation.
S. N. Anand, E. S. Maywood, J. E. Chesham, G. Joynson, G. T. Banks, M. H. Hastings, and P. M. Nolan (2013)
J. Neurosci. 33, 7145-7153
   Abstract »    Full Text »    PDF »
Cry1-/- Circadian Rhythmicity Depends on SCN Intercellular Coupling.
J. A. Evans, H. Pan, A. C. Liu, and D. K. Welsh (2012)
J Biol Rhythms 27, 443-452
   Abstract »    Full Text »    PDF »
Circadian Surprise--It's Not All About Transcription.
C. J. Doherty and S. A. Kay (2012)
Science 338, 338-340
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882