The circadian clock protein CRY1 is a negative regulator of HIF-1α
Dimova, Elitsa Y.; Jakupovic, Mirza; Kubaichuk, Kateryna; Mennerich, Daniela; Chi, Tabughang Franklin; Tamanini, Filippo; Oklejewicz, Małgorzata; Hänig, Jens; Byts, Nadiya; Mäkelä, Kari A.; Herzig, Karl-Heinz; Koivunen, Peppi; Chaves, Ines; van der Horst, Gijsbertus; Kietzmann, Thomas (2019-03-29)
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, https://doi.org/10.1016/j.isci.2019.02.027
© 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://creativecommons.org/licenses/by-nc-nd/4.0/
https://urn.fi/URN:NBN:fi-fe2019102534721
Tiivistelmä
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 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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