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

Dimova, Elitsa Y.; Jakupovic, Mirza; Kubaichuk, Kateryna; Mennerich, Daniela; Franklin, Tabughang; Tamanini, Filippo; Oklejewicz, Małgorzata; Hänig, Jens; Byts, Nadiya; Mäkelä, Kari; Herzig, Karl‐Heinz; Koivunen, Peppi; Chaves, Inês; Horst, Gijsbertus T. J. van der; Kietzmann, Thomas

doi:10.1016/j.isci.2019.02.027

Cited by 52 publications

(51 citation statements)

References 79 publications

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“…Similarly, HIF-1α cooperates with BMAL1/MOP3 and CLOCK to regulate gene expression in a cell line of mouse neuroblastoma [24]. On the other hand, the negative circadian regulator CRY1, but not CRY2, reduces HIF-1α half-life and affects the hypoxia response in mice [25]. Our data reinforce the hypothesis that a crosstalk between hypoxia and circadian signaling pathways exist in a HIF-1α dependent fashion [26].…”

Section: Discussionsupporting

confidence: 82%

Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

López‐Cano

Gutiérrez-Carrasquilla

Barbé

et al. 2020

JCM

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Limited reports exist on the relationships between regulation of oxygen homeostasis and circadian clock genes in type 2 diabetes. We examined whether the expression of Hypoxia-Inducible Factor-1α (HIF-1α) and HIF-2α relates to changes in the expression of clock genes (Period homolog proteins (PER)1, PER2, PER3, Retinoid-related orphan receptor alpha (RORA), Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), Circadian locomotor output cycles kaput (CLOCK), and Cryptochrome proteins (CRY) 1 and CRY2) in patients with type 2 diabetes. A total of 129 subjects were evaluated in this cross-sectional study (48% with diabetes). The gene expression was measured by polymerase chain reaction. The lactate and pyruvate levels were used as surrogate of the hypoxia induced anaerobic glycolysis activity. Patients with diabetes showed an increased plasma concentration of both lactate (2102.1 ± 688.2 vs. 1730.4 ± 694.4 uM/L, p = 0.013) and pyruvate (61.9 ± 25.6 vs. 50.3 ± 23.1 uM/L, p = 0.026) in comparison to controls. However, this finding was accompanied by a blunted HIF-1α expression (1.1 (0.2 to 5.0) vs. 1.7 (0.4 to 9.2) arbitrary units (AU), p ≤ 0.001). Patients with diabetes also showed a significant reduction of all assessed clock genes’ expression. Univariate analysis showed that HIF-1α and almost all clock genes were significantly and negatively correlated with HbA1c concentration. In addition, positive correlations between HIF-1α and the clock genes were observed. The stepwise multivariate regression analysis showed that HbA1c and clock genes independently predicted the expression of HIF-1α. Type 2 diabetes modifies the expression of HIF-1α and clock genes, which correlates with the degree of metabolic control.

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Section: Discussionsupporting

confidence: 82%

Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

López‐Cano

Gutiérrez-Carrasquilla

Barbé

et al. 2020

JCM

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“…The expression of a key HIF protein, HIF1α, is under circadian rhythm control. CRY1 reduces HIF-1α half-life and HIF binding to target gene promoters and abrogation of CRY1/2 stabilized HIF1α in response to hypoxia [90] while PER2 activates HIF-1α and facilitates its recruitment to promoter regions of its downstream genes. HIF-1α activation by PER2 was related to keeping the asparagine residue at position 803 of HIF-1α (HIF-1α N803) unhydroxylated by hypoxic stimulation in the absence of changes in HIF-1α protein levels [91].…”

Section: Disrupted Hif Activation and Epo Productionmentioning

confidence: 99%

Chronodisruption: A Poorly Recognized Feature of CKD

Carriazo

Ramos

Sanz

et al. 2020

Toxins

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Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic.

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“…Furthermore, there is an E-box in the promoter of the HIF1A gene, indicating that CLOCK/BMAL1 can induce expression of HIF1A [73]. CRY1 can bind directly to the HIF-1α protein in mice, which dampens HIF-1 expression of target genes [80]. This means that during periods of high CRY1 expression, the maximal HIF-1α hypoxic response can be dampened, though still present.…”

Section: Role Of Hypoxia and Circadian Rhythm In Radioresistance Of Hggsmentioning

confidence: 99%

“…This means that during periods of high CRY1 expression, the maximal HIF-1α hypoxic response can be dampened, though still present. During periods of low CRY1, HIF activity increases, which leads to cellular proliferation and migration in some circumstances [80]. Furthermore, PER2 has been found to bind to HIF-1α, which increases HIF-1 activity, and has the opposite effect of CRY2 [81].…”

Section: Role Of Hypoxia and Circadian Rhythm In Radioresistance Of Hggsmentioning

confidence: 99%

Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas

Shen

Cook

Gee

et al. 2020

J Exp Clin Cancer Res

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Radiotherapy is the cornerstone of treatment of high-grade gliomas (HGGs). It eradicates tumor cells by inducing oxidative stress and subsequent DNA damage. Unfortunately, almost all HGGs recur locally within several months secondary to radioresistance with intricate molecular mechanisms. Therefore, unravelling specific underlying mechanisms of radioresistance is critical to elucidating novel strategies to improve the radiosensitivity of tumor cells, and enhance the efficacy of radiotherapy. This review addresses our current understanding of how hypoxia and the hypoxia-inducible factor 1 (HIF-1) signaling pathway have a profound impact on the response of HGGs to radiotherapy. In addition, intriguing links between hypoxic signaling, circadian rhythms and cell metabolism have been recently discovered, which may provide insights into our fundamental understanding of radioresistance. Cellular pathways involved in the hypoxic response, DNA repair and metabolism can fluctuate over 24-h periods due to circadian regulation. These oscillatory patterns may have consequences for tumor radioresistance. Timing radiotherapy for specific times of the day (chronoradiotherapy) could be beneficial in patients with HGGs and will be discussed.

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

Cited by 52 publications

References 79 publications

Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

Chronodisruption: A Poorly Recognized Feature of CKD

Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas

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