A Role for Id2 in Regulating Photic Entrainment of the Mammalian Circadian System

Duffield, Giles E.; Watson, Nathan P.; Mantani, Akio; Peirson, Stuart N.; Robles-Murguia, Maricela; Loros, Jennifer J.; Israel, Mark A.; Dunlap, Jay C.

doi:10.1016/j.cub.2008.12.052

Cited by 53 publications

(147 citation statements)

References 35 publications

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“…3D) (46). The BMAL1 mutant could still interact with CLOCK through helix-loop-helix and PAS domains, but the resulting complex would not bind E-box motifs, and thus the BMAL1 mutant would act as a dominantnegative mutant (47,48). Overexpression of the BMAL1 mutant effectively disrupted circadian rhythms and lowered basal levels of bioluminescence, suggesting that transactivation of the endogenous Per2-luc gene had been compromised, as expected (Fig.…”

Section: Overexpression Of Clock-bmal1 Reduces Amplitudes But Does Nosupporting

confidence: 69%

Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms

Lee¹,

Chen²,

Lee³

et al. 2011

Journal of Biological Chemistry

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The mammalian circadian oscillator is primarily driven by an essential negative feedback loop comprising a positive component, the CLOCK-BMAL1 complex, and a negative component, the PER-CRY complex. Numerous studies suggest that feedback inhibition of CLOCK-BMAL1 is mediated by timedependent physical interaction with its direct target gene products PER and CRY, suggesting that the ratio between the negative and positive complexes must be important for the molecular oscillator and rhythm generation. We explored this idea by altering expression of clock components in fibroblasts derived from Per2Luc and Per mutant mice, a cell system extensively used to study in vivo clock mechanisms. Our data demonstrate that the stoichiometric relationship between clock components is critical for the robustness of circadian rhythms and provide insights into the mechanistic organization of the negative feedback loop. Our findings may explain why certain mutant mice or cells are arrhythmic, whereas others are rhythmic, and suggest that robustness of circadian rhythms can be increased even in wild-type cells by modulating the stoichiometry.Sleep/wake cycles and other mammalian circadian rhythms are synchronized with changes in the local environment, most notably light/dark cycles, through endogenous circadian clocks (1-5). A master clock is located in the suprachiasmatic nuclei in the anterior hypothalamus; this clock adjusts itself based on light/dark information and synchronizes peripheral clocks present in most tissues. The molecular composition and operating mechanism of the clocks are very similar, if not identical, among suprachiasmatic nuclei and peripheral tissues (6, 7).The cell-autonomous molecular clock consists of several interacting transcriptional/post-translational feedback loops (8, 9). However, as found in most organisms, including Neurospora, Drosophila, and mammals (1, 10 -12), one negative feedback loop seems to be the primary driver of clock function; this loop is composed of positive elements and negative elements. In mammalian clock cells, CLOCK (or NPAS2) and BMAL1 are the positive elements, and they form a heterodimer that activates transcription of the negative components PER and CRY, which then constitute an inhibitory complex. The inhibitory complex closes the negative feedback loop by inhibiting the positive complex (CLOCK-BMAL1) through direct physical interaction (3, 4, 13-18). Although CLOCK and BMAL1 are dynamically regulated at the posttranslational level in a circadian fashion (14, 19 -22), their oscillations in abundance do not seem to be required for clock function (15,23,24). However, oscillations of the negative complex are critical for the clock, and PER seems to be ratelimiting for the rhythmic formation of the complex (14, 15). Constitutive overexpression of PER leads to constitutively elevated levels of the negative complex and constitutive down-regulation of CLOCK-BMAL1-controlled genes (15).Although the precise mechanism of the inhibition by the negative complex is not known, the mode of...

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Section: Overexpression Of Clock-bmal1 Reduces Amplitudes But Does Nosupporting

confidence: 69%

Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms

Lee¹,

Chen²,

Lee³

et al. 2011

Journal of Biological Chemistry

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“…It is however possible, that (instead of homodimer interactions) the predicted helix-loop-helix region of mPER2 engages in heterodimeric interactions with other helix-loop-helix proteins. Like the ID (inhibitor of DNA binding) family of helix-loop-helix proteins, mPERs could thereby potentially compete with the formation of transcriptionally active and DNA-binding dimeric basic-HLH transcription factors (33,34).…”

Section: Discussionmentioning

confidence: 99%

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

Kucera

Schmalen

Hennig

et al. 2012

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

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The three PERIOD homologues mPER1, mPER2, and mPER3 constitute central components of the mammalian circadian clock. They contain two PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B), which mediate homo-and heterodimeric mPER-mPER interactions as well as interactions with transcription factors and kinases. Here we present crystal structures of PAS domain fragments of mPER1 and mPER3 and compare them with the previously reported mPER2 structure. The structures reveal homodimers, which are mediated by interactions of the PAS-B β-sheet surface including a highly conserved tryptophan (Trp448 mPER1 , Trp419 mPER2 , Trp359 mPER3 ). mPER1 homodimers are additionally stabilized by interactions between the PAS-A domains and mPER3 homodimers by an N-terminal region including a predicted helix-loop-helix motive. We have verified the existence of these homodimer interfaces in solution and inside cells using analytical gel filtration and luciferase complementation assays and quantified their contributions to homodimer stability by analytical ultracentrifugation. We also show by fluorescence recovery after photobleaching analyses that destabilization of the PAS-B/tryptophan dimer interface leads to a faster mobility of mPER2 containing complexes in human U2OS cells. Our study reveals structural and quantitative differences between the homodimeric interactions of the three mouse PERIOD homologues, which are likely to contribute to their distinct clock functions.circadian clock | PAS domains | PERIOD proteins | protein interactions

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“…Regulation of the ryanodine receptor appears to involve circadian clock proteins in vitro (38), providing evidence that the http://doc.rero.ch clock may regulate components of its own input pathway. Recently, a role of inhibitor of DNA binding (Id) genes in the regulation of photic entrainment of the mammalian clock has been proposed (39). In particular, Id2 can inhibit CLOCK:BMAL1 transactivation of Per1 and AVP (arginine-vasopressin) promoters in vitro.…”

Section: The Suprachiasmatic Nuclei: a Relay To Synchronize Physiologmentioning

confidence: 99%

The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks

Dibner¹,

Schibler

Albrecht

2010

Annu. Rev. Physiol.

2,029

1,771

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Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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A Role for Id2 in Regulating Photic Entrainment of the Mammalian Circadian System

Cited by 53 publications

References 35 publications

Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms

Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks

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