CRY2 and FBXL3 Cooperatively Degrade c-MYC

Huber, Anne-Laure; Papp, Stephanie J.; Chan, Alanna B.; Henriksson, Emma; Jordan, Sabine D.; Kriebs, Anna; Nguyen, Madelena; Wallace, Martina; Li, Zhizhong; Metallo, Christian M.; Lamia, Katja

doi:10.1016/j.molcel.2016.10.012

Cited by 163 publications

(187 citation statements)

References 80 publications

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“…Since CRY1 and CRY2 modulate several transcription factors (Huber et al, 2016; Lamia et al, 2011; Zhang et al, 2010) and we are studying mice in which they have been deleted in all tissues, we examined several possible contributions to the enhanced exercise performance in CRY-deficient animals. Glycogen is a major source of carbohydrate-derived energy during exercise and we measured increased glycogen content in both skeletal muscle and liver of CRY dKO mice compared to wildtype littermates (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

et al. 2017

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SUMMARY Cellular metabolite balance and mitochondrial function are under circadian control, but the pathways connecting the molecular clock to these functions are unclear. Peroxisome proliferator activated receptor delta (PPARδ) enables preferential utilization of lipids as fuel during exercise and is a major driver of exercise endurance. We show here that the circadian repressors CRY1 and CRY2 function as co-repressors for PPARδ. Cry1−/−;Cry2−/− myotubes and muscles exhibit elevated expression of PPARδ target genes, particularly in the context of exercise. Notably, CRY1/2 seem to repress a distinct subset of PPARδ target genes in muscle compared to the co-repressor NCOR1. In vivo, genetic disruption of Cry1 and Cry2 enhances sprint exercise performance in mice. Collectively, our data demonstrate that CRY1 and CRY2 modulate exercise physiology by altering the activity of several transcription factors, including CLOCK/BMAL1 and PPARδ and thereby alter energy storage and substrate selection for energy production.

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Section: Resultsmentioning

confidence: 99%

CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

et al. 2017

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“…Lactate is transported across cell membranes by monocarboxylate transporters (MCTs) (Hertz and Dienel, 2005), many of which undergo strong circadian oscillations of expression in mouse liver (Figs. 2E and 2F, (Koike et al, 2012)) and fibroblasts (Huber et al, 2016). In addition to the daily rhythm in metformin-induced acute blood glucose reduction, we observed unexpected severe toxicity of metformin at night, which could be reversed by providing supplemental glucose and heating pads to maintain glycemic and thermal homeostasis.…”

Section: Discussionmentioning

confidence: 99%

The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin

et al. 2017

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Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Though it is a relatively safe and effective drug, clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic usage of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms impact the biological responses to metformin in a complex manner.

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“…The cancer suppressive role of CRY2 was also evaluated by Huber et al, whose mechanistic data indicated that CRY2 and FBXL3 cooperatively destabilized c-MYC (a critical oncoprotein for cancer cell proliferation), and disruption of Cry2 may contribute to elevated c-MYC and higher cancer susceptibility in shift-workers and animals. 54 However, Chun et al…”

Section: Stabilization Of Per and Cry Have Distinct Effects On Cancermentioning

confidence: 99%

Oncogenic and Circadian Effects of Small Molecules Directly and Indirectly Targeting the Core Circadian Clock

Lin

Robertson

Bisbee³

et al. 2019

Preprint

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Circadian rhythms are essential for controlling the cell cycle, cellular proliferation, and apoptosis, and hence, are tightly linked to cell fate. Disruption of circadian rhythms has been shown to trigger various pathological developments, including cancer. Several recent studies have used a variety of small molecules to affect circadian oscillations, however, their concomitant cellular effects were not assessed. Here, we use five molecules, grouped into direct versus indirect effectors of the circadian clock, to modulate periods in a human osteosarcoma cell line (U2OS), and determined their influences on cellular behaviors, including motility and colony formation. Luciferase reporters, whose expression were driven via Bmal1and Per2-promoters (positive and negative protein components of the core clock), were used to facilitate the visualization and quantitative analysis of circadian oscillations. We show that all molecules significantly increase or decrease the circadian periods of Bmal1 and Per2 in a dosedependent manner, but period length does not correlate with the extent of cell migration or proliferation. We observed that only molecules that affected circadian oscillations to a greater extent showed significant influence on cell functions (e.g. motility and colony formation).Because it is important to consider the likelihood of biological effects resulting from noncircadian targets, we also provide a thorough discussion of potential modes of action. Future studies should employ additional compounds that directly target circadian proteins and/or have different circadian effects, and evaluation in other cancer models to determine whether results obtained here remain consistent. proteins aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL/BMAL1) and circadian locomotor output cycles kaput (CLOCK) heterodimerize in the morning and bind to the E-box promoter, which initiates the expression of Period (Per) and Cryptochrome (Cry). PER and CRY accumulate in the evening and form a heterodimer, which translocates back into the nucleus and inhibits Bmal1 and Clock activity. 18 As a result, the core circadian machinery oscillates with a period of approximately 24 h. In cell culture, intrinsic and self-sustained circadian clocks are persistent even in the absence of external time cues. 19 To synchronize clocks in cultured cells, treatments of high concentration serum 20 or chemical reagents (e.g. dexamethasone 21 or forskolin 22 ) are frequently used. Circadian rhythmicity is tightly associated with post-translational modifications of clock proteins. 23 Phosphorylation of most clock proteins occurs in a rhythmic manner; thus, alteration of clock protein phosphorylation can result in changes to circadian periods. 24 Genetic manipulations of the post-translational regulators of clock proteins have been shown to affect circadian functions and periodicity. 24-25 However, conventional genetic approaches also result in fatality, pleiotropy, and functional redundancy. Alternatively, chemical modulation of these...

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CRY2 and FBXL3 Cooperatively Degrade c-MYC

Cited by 163 publications

References 80 publications

CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin

Oncogenic and Circadian Effects of Small Molecules Directly and Indirectly Targeting the Core Circadian Clock

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