University of Oulu

Elitsa Y. Dimova, Mirza Jakupovic, Kateryna Kubaichuk, Daniela Mennerich, Tabughang Franklin Chi, Filippo Tamanini, Małgorzata Oklejewicz, Jens Hänig, Nadiya Byts, Kari A. Mäkelä, Karl-Heinz Herzig, Peppi Koivunen, Ines Chaves, Gijsbertus van der Horst, Thomas Kietzmann, The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α, iScience, Volume 13, 2019, Pages 284-304, ISSN 2589-0042,

The circadian clock protein CRY1 is a negative regulator of HIF-1α

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Author: Dimova, Elitsa Y.1; Jakupovic, Mirza2; Kubaichuk, Kateryna1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O. Box 3000, 90014 Oulu, Finland
2Department of Biochemistry, University of Kaiserslautern, 67663 Kaiserslautern, Germany
3Department of Molecular Genetics, Erasmus University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands
4Novartis Pharma GmbH, 97082 Würzburg, Germany
5Biocenter Oulu, Department of Physiology, University of Oulu, 90014 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 6.7 MB)
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Language: English
Published: Elsevier, 2019
Publish Date: 2019-10-25


The circadian clock and the hypoxia-signaling pathway are regulated by an integrated interplay of positive and negative feedback limbs that incorporate energy homeostasis and carcinogenesis. We show that the negative circadian regulator CRY1 is also a negative regulator of hypoxia-inducible factor (HIF). Mechanistically, CRY1 interacts with the basic-helix-loop-helix domain of HIF-1α via its tail region. Subsequently, CRY1 reduces HIF-1α half-life and binding of HIFs to target gene promoters. This appeared to be CRY1 specific because genetic disruption of CRY1, but not CRY2, affected the hypoxia response. Furthermore, CRY1 deficiency could induce cellular HIF levels, proliferation, and migration, which could be reversed by CRISPR/Cas9- or short hairpin RNA-mediated HIF knockout. Altogether, our study provides a mechanistic explanation for genetic association studies linking a disruption of the circadian clock with hypoxia-associated processes such as carcinogenesis.

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Series: iScience
ISSN: 2589-0042
ISSN-E: 2589-0042
ISSN-L: 2589-0042
Volume: 13
Pages: 284 - 304
DOI: 10.1016/j.isci.2019.02.027
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Funding: This work was supported by grants from the Finnish Academy of Science (SA 296027), Jane and Aatos Erkko Foundation, the Finnish Cancer Foundation, the Finnish Center of International Mobility (CIMO), Biocenter Oulu, and University of Oulu to T.K.
Academy of Finland Grant Number: 296027
Detailed Information: 296027 (Academy of Finland Funding decision)
Copyright information: © 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (