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The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α

43 Pages Posted: 6 Mar 2019 Sneak Peek Status: Published

See all articles by Elitsa Y. Dimova

Elitsa Y. Dimova

University of Oulu - Faculty of Biochemistry and Molecular Medicine

Mirza Jakupovic

University of Kaiserslautern - Biochemistry

Kateryna Kubaichuk

University of Oulu - Faculty of Biochemistry and Molecular Medicine

Daniela Mennerich

University of Oulu - Faculty of Biochemistry and Molecular Medicine

Tabughang Franklin Chi

University of Oulu - Faculty of Biochemistry and Molecular Medicine

Filippo Tamanini

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Małgorzata Oklejewicz

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Jens Hänig

Novartis Pharma GmbH

Nadiya Byts

University of Oulu - Faculty of Biochemistry and Molecular Medicine

Kari A. Mäkelä

University of Oulu - Department of Physiology

Karl-Heinz Herzig

University of Oulu - Department of Physiology

Peppi Koivunen

University of Oulu - Faculty of Biochemistry and Molecular Medicine

Ines Chaves

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Gijsbertus Van der Horst

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Thomas Kietzmann

University of Oulu - Faculty of Biochemistry and Molecular Medicine

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Abstract

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 hypoxiainducible factor (HIF). Mechanistically, CRY1 interacts with the basic helixloop-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 since genetic disruption of CRY1 but not CRY2 affected the hypoxia response. Further, CRY1-deficiency could induce cellular HIF levels, proliferation and migration, which could be reversed by CRISPR/Cas9 or shRNA mediated HIF knock-out. 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.

Suggested Citation

Dimova, Elitsa Y. and Jakupovic, Mirza and Kubaichuk, Kateryna and Mennerich, Daniela and Chi, Tabughang Franklin and Tamanini, Filippo and Oklejewicz, Małgorzata and Hänig, Jens and Byts, Nadiya and Mäkelä, Kari A. and Herzig, Karl-Heinz and Koivunen, Peppi and Chaves, Ines and Van der Horst, Gijsbertus and Kietzmann, Thomas, The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α (2018). Available at SSRN: https://ssrn.com/abstract=3188393 or http://dx.doi.org/10.2139/ssrn.3188393
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Elitsa Y. Dimova (Contact Author)

University of Oulu - Faculty of Biochemistry and Molecular Medicine ( email )

P.O. Box 3000
Oulu, 90014
Finland

Mirza Jakupovic

University of Kaiserslautern - Biochemistry

Kaiserslautern
Germany

Kateryna Kubaichuk

University of Oulu - Faculty of Biochemistry and Molecular Medicine

P.O. Box 3000
Oulu, 90014
Finland

Daniela Mennerich

University of Oulu - Faculty of Biochemistry and Molecular Medicine

P.O. Box 3000
Oulu, 90014
Finland

Tabughang Franklin Chi

University of Oulu - Faculty of Biochemistry and Molecular Medicine

P.O. Box 3000
Oulu, 90014
Finland

Filippo Tamanini

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Rotterdam
Netherlands

Małgorzata Oklejewicz

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Rotterdam
Netherlands

Jens Hänig

Novartis Pharma GmbH

Würzburg
Germany

Nadiya Byts

University of Oulu - Faculty of Biochemistry and Molecular Medicine

P.O. Box 3000
Oulu, 90014
Finland

Kari A. Mäkelä

University of Oulu - Department of Physiology

Oulu
Finland

Karl-Heinz Herzig

University of Oulu - Department of Physiology ( email )

Oulu
Finland

Peppi Koivunen

University of Oulu - Faculty of Biochemistry and Molecular Medicine

P.O. Box 3000
Oulu, 90014
Finland

Ines Chaves

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Rotterdam
Netherlands

Gijsbertus Van der Horst

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Rotterdam
Netherlands

Thomas Kietzmann

University of Oulu - Faculty of Biochemistry and Molecular Medicine ( email )

P.O. Box 3000
Oulu, 90014
Finland

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