β-TrCP1-Mediated Degradation of PERIOD2 Is Essential for Circadian Dynamics

Reischl, Silke; Vanselow, Katja; Westermark, Pål O.; Thierfelder, Nadine; Maier, Bert; Herzel, Hanspeter; Kramer, Achim

doi:10.1177/0748730407303926

Cited by 164 publications

(123 citation statements)

References 38 publications

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“…Among the multiple molecular mechanisms that influence the period of circadian rhythms, a major role is played by those that control clock protein degradation (Liu et al 2000;Eide et al 2005;Gallego et al 2006;Busino et al 2007;Reischl et al 2007). Here we compared three minimal models proposed for circadian clocks, showed that they predict opposite profiles of period as a function of the clock protein degradation rate, and indicated how to reconcile these contradictory predictions.…”

Section: Discussionmentioning

confidence: 99%

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

Gérard

Gonze

Goldbeter

2009

Phil. Trans. R. Soc. A.

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Circadian rhythms, which occur spontaneously with a period of about 24 h in a variety of organisms, allow their adaptation to the periodic variations of the environment. These rhythms are generated by a genetic regulatory network involving a negative feedback loop on transcription. Mathematical models based on the negative autoregulation of gene expression by the protein product of a clock gene account for the occurrence of selfsustained circadian oscillations. These models differ by their degree of complexity and, hence, by the number of variables considered. Some of these models can be considered as minimal because they contain a reduced number of biochemical processes and variables capable of producing sustained oscillations. In three of these minimal models, the period of the oscillations significantly changes with the rate of degradation of the clock protein. However, depending on the model considered, the period increases, decreases or passes through a maximum as a function of the protein degradation rate. We clarify the bases for these markedly different results by bringing to light the roles of (i) protein phosphorylation, which is required for protein degradation, and (ii) the velocity and degree of saturation of mRNA and protein degradation. Changes in the parameter values of the more complex of the minimal models can produce the period profiles observed in the other two models. The analysis allows us to reconcile the contradictory predictions for the dependence of the period on the clock protein degradation rate in three minimal models used to describe circadian rhythms.

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Section: Discussionmentioning

confidence: 99%

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

Gérard

Gonze

Goldbeter

2009

Phil. Trans. R. Soc. A.

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“…PER2 and BMAL1 can be acetylated (by CLOCK [Doi et al 2006;Grimaldi et al 2009] and, probably, additional acetyltransferases) and deacetylated in a circadian fashion by the NAD þ -dependent deacetylase Sirtuin 1 (SIRT1) (Asher et al 2008;Nakahata et al 2008). Moreover, the degradation of PER (Reischl et al 2007) and CRY Godinho et al 2007;Siepka et al 2007) proteins is regulated by specific ubiquitin ligase complexes.…”

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confidence: 99%

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

Saini

Suter²,

Liani³

et al. 2011

Cold Spring Harbor Symposia on Quantitative Biology

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Mammalian physiology has to adapt to daily alternating periods during which animals either forage and feed or sleep and fast. The adaptation of physiology to these oscillations is controlled by a circadian timekeeping system, in which a master pacemaker in the suprachiasmatic nucleus (SCN) synchronizes slave clocks in peripheral organs. Because the temporal coordination of metabolism is a major purpose of clocks in many tissues, it is important that metabolic and circadian cycles are tightly coordinated. Recent studies have revealed a multitude of signaling components that possibly link metabolism to circadian gene expression. Owing to this redundancy, the implication of any single signaling pathway in the synchronization of peripheral oscillators cannot be assessed by determining the steady-state phase, but instead requires the monitoring of phase-shifting kinetics at a high temporal resolution.

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“…In contrast, increased CRY stability leads to longer periods, as shown by genetic mutations of FBXL3 (12, 13) and KL001, a small molecule inhibitor of . Because the scale and complexity of the circadian network complicate an intuitive understanding of these relationships, mathematical models have played important roles in understanding how these manipulations affect circadian period (9,15,18).Given that both CKI and FBXL3 pathways similarly regulate the stability of linked negative factors, it was thought that simultaneous perturbations to both pathways might lead to nonadditive Significance Maintaining robust circadian rhythms has been linked to longevity and metabolic health. Because these rhythms are disturbed by factors such as jet lag, shift work, and high-fat diets, there is interest in developing pharmacological control strategies to modulate circadian function.…”

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confidence: 99%

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confidence: 99%

Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock

John

Hirota

Kay

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Posttranslational regulation of clock proteins is an essential part of mammalian circadian rhythms, conferring sensitivity to metabolic state and offering promising targets for pharmacological control. Two such regulators, casein kinase 1 (CKI) and F-box and leucinerich repeat protein 3 (FBXL3), modulate the stability of closely linked core clock proteins period (PER) and cryptochrome (CRY), respectively. Inhibition of either CKI or FBXL3 leads to longer periods, and their effects are independent despite targeting proteins with similar roles in clock function. A mechanistic understanding of this independence, however, has remained elusive. Our analysis of cellular circadian clock gene reporters further differentiated between the actions of CKI and FBXL3 by revealing opposite amplitude responses from each manipulation. To understand the functional relationship between the CKI-PER and FBXL3-CRY pathways, we generated robust mechanistic predictions by applying a bootstrap uncertainty analysis to multiple mathematical circadian models. Our results indicate that CKI primarily regulates the accumulating phase of the PER-CRY repressive complex by controlling the nuclear import rate, whereas FBXL3 separately regulates the duration of transcriptional repression in the nucleus. Dynamic simulations confirmed that this spatiotemporal separation is able to reproduce the independence of the two regulators in period regulation, as well as their opposite amplitude effect. As a result, this study provides further insight into the molecular clock machinery responsible for maintaining robust circadian rhythms.identifiability analysis | gene regulation | sensitivity analysis C ircadian rhythms are autonomous, near-24-h oscillations that coordinate daily changes in physiology and metabolism. Because circadian and metabolic regulators are tightly integrated, circadian disruptions often manifest in metabolic disease (1). Recent efforts have therefore sought to gain a mechanistic understanding of these pathways, such that the metabolic burdens imposed by a 24-h society might be mitigated. Posttranslational regulators, which play key roles in connecting circadian and metabolic processes, serve as likely targets for future therapeutics, demonstrated by the wealth of available circadian-active small molecules (2, 3).Oscillations in circadian gene transcription are generated through a time-delayed transcription-translation negative-feedback loop. In mammals, transcription factors CLOCK and BMAL1 promote transcription of E box-containing genes Period (Per) and Cryptochrome (Cry) (Fig. 1A). PER and CRY protein products form heterodimers to accumulate in the nucleus, in which PER is stoichiometrically limiting (4), and subsequently close the negative feedback loop by inhibiting CLOCK-BMAL1-promoted gene expression. Although steady-state endpoint assays have shown the possibility of nuclear entry of CRY without PER (5-7), experiments from Per1 −/− Per2 −/− mice demonstrated that PER proteins are required for the timely nuclear accumulation of ...

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β-TrCP1-Mediated Degradation of PERIOD2 Is Essential for Circadian Dynamics

Cited by 164 publications

References 38 publications

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock

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