Mitogen-Activated Protein Kinase Is a Functional Component of the Autonomous Circadian System in the Suprachiasmatic Nucleus

Akashi, Makoto; Hayasaka, Noboru; Yamazaki, Shin; Node, Koichi

doi:10.1523/jneurosci.3410-07.2008

Cited by 48 publications

(46 citation statements)

References 24 publications

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“…It is tempting to speculate that the circadian phenotype of the PHLPP1-null mice described here could be parallel to the function of PHLPP1 in memory formation. This intriguing possibility is supported by the fact that PKC and MAPKs are important for circadian function (22,23) and that PHLPP1 itself oscillates in the SCN (11). Our findings support a scenario in which PHLPP1 may operate in controlling the consolidation of circadian periodicity after resetting.…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps PHLPP1 may also regulate the phosphorylation state of some circadian regulators, including CLOCK and PER2, the phosphorylation of which has been shown to be critical for normal circadian function (31,32). Furthermore, PKC and MAPK, (PHLPP1-regulated kinases) have been shown to be important for clock resetting (22,23). Future studies will establish whether PHLPP1 physiologically dephosphorylates any components of the clock machinery.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock

Masubuchi

Gao

O’Neill

et al. 2010

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

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The pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) differentially attenuates Akt, PKC, and ERK1/2 signaling, thereby controlling the duration and amplitude of responses evoked by these kinases. PHLPP1 is expressed in the mammalian central clock, the suprachiasmatic nucleus, where it oscillates in a circadian fashion. To explore the role of PHLPP1 in vivo, we have generated mice with a targeted deletion of the PHLPP1 gene. Here we show that PHLPP1-null mice, although displaying normal circadian rhythmicity, have a drastically impaired capacity to stabilize the circadian period after light-induced resetting, producing a large phase shift after light resetting. Our findings reveal that PHLPP1 exerts a previously unappreciated role in circadian control, governing the consolidation of circadian periodicity after resetting.Per | period | after-effect | suprachiasmatic nucleus | phase shift E ssential properties of the mammalian circadian clock are a self-sustained oscillation under constant conditions and the dynamic resetting induced by light. These properties of the clock are necessary for humans and other mammals where they control cyclical activities as disparate as the sleep/wake cycle, metabolism, and cardiac function (1-3). The fine tuning of the endogenous clock by exogenous cues (zeitgebers) can be especially apparent when one travels across time zones or is transferred to a night shift working schedule (4). Circadian rhythms in mammals are driven by the central pacemaker, which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus (5). Light administration during the subjective night activates neurons of the retino-hypothalamic tract that target the SCN, and thereby resets behavioral rhythmicity. If mice are exposed to a light stimulus in the early night the clock delays, whereas it advances if light is given at late night (5, 6), underscoring the adaptability of the clock to changing lighting environment. Although there have been remarkable advances in deciphering the molecular organization of the circadian clock (1, 7), understanding of the molecular pathways involved in light-induced clock resetting is still incomplete (5).PHLPP1 and PHLPP2 (pleckstrin homology domain leucinerich repeats protein phosphatases 1 and 2) are Ser/Thr protein phosphatases that have been implicated in the regulation of various signaling pathways. These phosphatases negatively regulate Akt and protein kinase C (PKC) by direct dephosphorylation (8-10). In addition, a splice variant isoform of PHLPP1 (PHLPP1β, also known as suprachiasmatic nucleus circadian oscillatory protein, SCOP, see ref. 11) has been implicated in cognitive processes and its degradation appears to be required for long-term memory formation (12). PHLPP1 is thought to be involved in long-term memory formation by inhibiting ERK1/2 via direct binding to and inhibition of K-Ras, a small GTPase operating upstream of ERK1/2 (13). Interestingly, PHLPP1 (SCOP) is expressed in a circadian manner in the SCN, peaking in the sub...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock

Masubuchi

Gao

O’Neill

et al. 2010

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

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“…Interestingly, it has been reported that circadian activation of ERK is autonomously regulated in the suprachiasmatic nuclei (SCN), the central circadian pacemaker in mammals. 22,23) This finding, together with our previous observation that ERK mediates light-induction of zCry1a expression, 11) suggests that ERK signaling cascade could also contribute to the transcriptional regulation of zCry1a gene in DD conditions. In order to address this, we first tested the temporal pattern of ERK phosphorylation in zebrafish cultured cells.…”

Section: Fig 3 Effects Of Zclock3-deltac On Transcription Of Zcry1amentioning

confidence: 56%

“…Indeed, circadian changes of phosphorylation and dephosphorylation of kinases have been reported in cyanobacteria and mammals. 23,25,26) It is therefore conceivable that an orchestrated temporal program of protein phosphorylation contributing to control a proper 24-h clockwork may exist in zebrafish as well. Such a program would require the activity of kinases and, necessarily, phosphatases.…”

Section: Fig 3 Effects Of Zclock3-deltac On Transcription Of Zcry1amentioning

confidence: 99%

CLOCK:BMAL-Independent Circadian Oscillation of Zebrafish Cryptochrome1a Gene

Miyamura

Hirayama

Sawanobori

et al. 2009

Biological & Pharmaceutical Bulletin

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In the vertebrate circadian feedback loop, CLOCK:BMAL heterodimers induce the expression of Cry genes. The CRY proteins in turn inhibit CLOCK:BMAL-mediated transcription closing the negative feedback loop. Four CRYs, which all inhibit CLOCK:BMAL-mediated transcription, exist in zebrafish. Although these zebrafish Crys (zCry1a, 1b, 2a, and 2b) show a circadian pattern of expression, previous studies have indicated that the circadian oscillation of zCry1a could be CLOCK:BMAL-independent. Here we show that abrogation of CLOCK:BMAL-dependent transcription in zebrafish cells by the dominant negative zCLOCK3-DeltaC does not affect the circadian oscillation of zCry1a. Moreover, we provide several lines of evidence indicating that the extracellular signal-regulated kinase (ERK) signaling cascade modulates the circadian expression of zCry1a gene in constant darkness. Taken together, our data strongly support the notion that circadian oscillation of zCry1a is CLOCK:BMAL-independent and further indicate that mechanisms involving non-canonical clock genes could contribute to the circadian expression of zCry1a gene in a cell autonomous manner.

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“…Yamaguchi et al 35 and Welsh et al 4,5 pioneered real-time bioluminescence imaging by integrating a specially designed microscope with a highly sensitive, low-noise CCD camera 15 to achieve single cell resolution. In recent years, more sensitive imaging systems have become commercially available, including LV200 (Olympus) and CellGraph (AB3000-B, Atto) with an ultrasensitive cooled and back-illuminated electron multiplying CCD and multicolor filters 36,37 . Imaging has also been used in more sophisticated HTS experiments, e.g., a ViewLux CCD imager (Perkin-Elmer) combined with the GNF automated robotic system (GNF Systems).…”

Section: Recording Devices and Throughput Considerationsmentioning

confidence: 99%

Monitoring Cell-autonomous Circadian Clock Rhythms of Gene Expression Using Luciferase Bioluminescence Reporters

Ramanathan

Khan

Kathale

et al. 2012

JoVE

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In mammals, many aspects of behavior and physiology such as sleep-wake cycles and liver metabolism are regulated by endogenous circadian clocks (reviewed 1,2 ). The circadian time-keeping system is a hierarchical multi-oscillator network, with the central clock located in the suprachiasmatic nucleus (SCN) synchronizing and coordinating extra-SCN and peripheral clocks elsewhere 1,2 . Individual cells are the functional units for generation and maintenance of circadian rhythms 3,4 , and these oscillators of different tissue types in the organism share a remarkably similar biochemical negative feedback mechanism. However, due to interactions at the neuronal network level in the SCN and through rhythmic, systemic cues at the organismal level, circadian rhythms at the organismal level are not necessarily cell-autonomous [5][6][7] . Compared to traditional studies of locomotor activity in vivo and SCN explants ex vivo, cell-based in vitro assays allow for discovery of cell-autonomous circadian defects 5,8 . Strategically, cell-based models are more experimentally tractable for phenotypic characterization and rapid discovery of basic clock mechanisms 5,[8][9][10][11][12][13] . Because circadian rhythms are dynamic, longitudinal measurements with high temporal resolution are needed to assess clock function. In recent years, real-time bioluminescence recording using firefly luciferase as a reporter has become a common technique for studying circadian rhythms in mammals 14,15 , as it allows for examination of the persistence and dynamics of molecular rhythms. To monitor cell-autonomous circadian rhythms of gene expression, luciferase reporters can be introduced into cells via transient transfection 13,16,17 or stable transduction 5,10,18,19 . Here we describe a stable transduction protocol using lentivirus-mediated gene delivery. The lentiviral vector system is superior to traditional methods such as transient transfection and germline transmission because of its efficiency and versatility: it permits efficient delivery and stable integration into the host genome of both dividing and non-dividing cells 20 . Once a reporter cell line is established, the dynamics of clock function can be examined through bioluminescence recording. We first describe the generation of P(Per2)-dLuc reporter lines, and then present data from this and other circadian reporters. In these assays, 3T3 mouse fibroblasts and U2OS human osteosarcoma cells are used as cellular models. We also discuss various ways of using these clock models in circadian studies. Methods described here can be applied to a great variety of cell types to study the cellular and molecular basis of circadian clocks, and may prove useful in tackling problems in other biological systems. Video LinkThe video component of this article can be found at http://www.jove.com/video/4234/ Protocol Construction of Lentiviral Luciferase ReportersA mammalian circadian reporter construct usually contains an expression cassette in which a circadian promoter is fused with the lucifer...

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Mitogen-Activated Protein Kinase Is a Functional Component of the Autonomous Circadian System in the Suprachiasmatic Nucleus

Cited by 48 publications

References 24 publications

Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock

Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock

CLOCK:BMAL-Independent Circadian Oscillation of Zebrafish Cryptochrome1a Gene

Monitoring Cell-autonomous Circadian Clock Rhythms of Gene Expression Using Luciferase Bioluminescence Reporters

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