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David M Virshup - One of the best experts on this subject based on the ideXlab platform.
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Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Shusaku Masuda, Hikari Yoshitane, Yoshitaka Fukada, Rajesh Narasimamurthy, Jae Kyoung Kim, David M VirshupAbstract:Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned whether the degradation of the core circadian machinery is a critical step in clock regulation. Prior cell-based studies found that CK1 phosphorylation of PER2 at Ser478 recruits the ubiquitin E3 ligase β-TrCP, leading to PER2 degradation. Creation of this phosphodegron is regulated by a phosphoswitch that is also implicated in temperature compensation. However, in vivo evidence that this phosphodegron influences circadian period is lacking. Here, we generated and analyzed PER2-Ser478Ala knock-in mice. The mice showed longer circadian period in behavioral analysis. Molecularly, mutant PER2 protein accumulated in both the nucleus and cytoplasm of the mouse liver, while PER2 messenger RNA (mRNA) levels were minimally affected. Nuclear PER1, CRY1, and CRY2 proteins also increased, probably due to stabilization of PER2-containing complexes. In mouse embryonic fibroblasts derived from PER2-Ser478Ala::LUC mice, three-phase decay and temperature compensation of the circadian period was perturbed. These data provide direct in vivo evidence for the importance of phosphorylation-regulated PER2 stability in the circadian clock and validate the phosphoswitch in a mouse model.
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Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch
bioRxiv, 2019Co-Authors: Shusaku Masuda, Hikari Yoshitane, Yoshitaka Fukada, Rajesh Narasimamurthy, Jae Kyoung Kim, David M VirshupAbstract:Abstract Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned whether the degradation of the core circadian machinery is a critical step in clock regulation. Prior cell-based studies found that CK1 phosphorylation of PER2 at Ser478 recruits the ubiquitin E3 ligase β-TrCP, leading to PER2 degradation. Creation of this phosphodegron is regulated by a phosphoswitch that is also implicated in temperature compensation. However, in vivo evidence that this phosphodegron influences circadian period is lacking. Here, we generated and analyzed PER2-Ser478Ala knock-in mice. The mice showed longer circadian period in behavioral analysis. Molecularly, mutant PER2 protein accumulated in both the nucleus and cytoplasm of the mouse liver, while PER2 mRNA levels were minimally affected. Nuclear PER1, CRY1 and CRY2 proteins also increased, probably due to stabilization of PER2-containing complexes. In mouse embryonic fibroblasts derived from PER2-Ser478Ala::LUC mice, three-phase decay and temperature compensation of the circadian period was perturbed. These data provide direct in vivo evidence for the importance of phosphorylation-regulated PER2 stability in the circadian clock and validate the phosphoswitch in a mouse model.
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CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch.
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Rajesh Narasimamurthy, Hitoshi Okamura, Jae Kyoung Kim, Sabrina R. Hunt, Jean-michel Fustin, Carrie L. Partch, Daniel B. Forger, David M VirshupAbstract:Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation, and lengthen the period of the circadian clock. Here, we perform a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1δ/e is indeed the priming kinase. We find that both CK1e and a recently characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl-terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.
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Protein phosphatase 1 regulates the stability of the circadian protein PER2.
Biochemical Journal, 2006Co-Authors: Monica Gallego, Heeseog Kang, David M VirshupAbstract:The circadian clock is regulated by a transcription/translation negative feedback loop. A key negative regulator of circadian rhythm in mammals is the PER2 (mammalian PERIOD 2) protein. Its daily degradation at the end of the night accompanies de-repression of transcription. CKIϵ (casein kinase I ϵ) has been identified as the kinase that phosphorylates PER2, targeting it for ubiquitin-mediated proteasomal degradation. We now report that PER2 degradation is also negatively regulated by PP1 (protein phosphatase 1)-mediated dephosphorylation. In Xenopus egg extract, PP1 inhibition by Inhibitor-2 accelerated mPER2 degradation. Co-immunoprecipitation experiments showed that PER2 bound to PP1c in transfected HEK-293 cells. PP1 immunoprecipitated from HEK-293 cells, mouse liver and mouse brain, dephosphorylated CKIϵ-phosphorylated PER2, showing that PER2 is a substrate for mammalian endogenous PP1. Moreover, over-expression of the dominant negative form of PP1c, the D95N mutant, accelerated ubiquitin and proteasome-mediated degradation of PER2, and shortened the PER2 half-life in HEK-293 cells. Over-expression of the PP1 inhibitors, protein phosphatase 1 holoenzyme inhibitor-1 and Inhibitor-2, confirmed these results. Thus PP1 regulates PER2 stability and is therefore a candidate to regulate mammalian circadian rhythms.
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control of mammalian circadian rhythm by ckie regulated proteasome mediated PER2 degradation
Molecular and Cellular Biology, 2005Co-Authors: Erik J Eide, David M Virshup, Heeseog Kang, Margaret Woolf, Peter J Woolf, William J Hurst, Fernando Camacho, Erica Vielhaber, Andrew GiovanniAbstract:The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKI (casein kinase I) has been postulated to prime PER2 for degradation. Supporting this idea, CKI inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKI inhibition also slows the degradation of PER2 in cells. CKI-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein -TrCP to a specific site, and dominant negative -TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock. Diverse organisms from prokaryotes to mammals coordinate behavioral and physiological rhythms with the daily dark-light cycle by means of a circadian clock. In mammals, the master circadian clock is located in the suprachiasmatic nucleus of the brain, and it entrains peripheral cell-autonomous clocks throughout the body. In mice, a positively acting heterodimeric transcription factor composed of the PAS-bHLH proteins CLOCK (CLK) and BMAL1 drives transcription of tissuespecific circadian output genes, as well as its own negative regulators, the Period (denoted mPer1, mPER2, and mPer3), and Cryptochrome (mCry1 and mCry2) genes. The mammalian PER and CRY proteins form multimeric complexes that enter the nucleus and repress the transcriptional activity of CLK/ BMAL1, modulating circadian output (reviewed in references 29 and 41). Additional stabilizing feedback loops, including inhibition of Bmal1 transcription by REV-ERB (37), further contribute to the timing and robustness of the cycle. The daily rhythmic degradation of PERIOD proteins leading to derepression of CLK/BMAL1 is postulated to be critical to the proper functioning of the clock. Therefore, the mechanism and control of this process are of great interest. Genetic studies have identified CKIe (casein kinase Ie )a s a key regulator of metazoan circadian rhythm and both genetic and biochemical studies suggest that the PER proteins are
Hitoshi Ozawa - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic suppression of mouse PER2 expression in the suprachiasmatic nucleus by the inhalational anesthetic, sevoflurane.
PloS one, 2014Co-Authors: Keisuke Mori, Norio Iijima, Atsuhiro Sakamoto, Ken Takumi, Shimpei Higo, Satoko Aikawa, Izumi Matsuo, Hitoshi OzawaAbstract:Background We previously reported that sevoflurane anesthesia reversibly suppresses the expression of the clock gene, Period2 (PER2), in the mouse suprachiasmatic nucleus (SCN). However, the molecular mechanisms underlying this suppression remain unclear. In this study, we examined the possibility that sevoflurane suppresses PER2 expression via epigenetic modification of the PER2 promoter. Methods Mice were anesthetized with a gas mixture of 2.5% sevoflurane/40% oxygen at a 6 L/min flow for 1 or 4 h. After termination, brains were removed and samples of SCN tissue were derived from frozen brain sections. Chromatin immunoprecipitation (ChIP) assays using anti-acetylated-histone antibodies were performed to investigate the effects of sevoflurane on histone acetylation of the PER2 promoter. Interaction between the E’-box (a cis-element in the PER2 promoter) and CLOCK (the Clock gene product) was also assessed by a ChIP assay using an anti-CLOCK antibody. The SCN concentration of nicotinamide adenine dinucleotide (NAD+), a CLOCK regulator, was assessed by liquid chromatography-mass spectrometry. Results Acetylation of histone H4 in the proximal region of the PER2 promoter was significantly reduced by sevoflurane. This change in the epigenetic profile of the PER2 gene was observed prior to suppression of PER2 expression. Simultaneously, a reduction in the CLOCK-E’-box interaction in the PER2 promoter was observed. Sevoflurane treatment did not affect the concentration of NAD+ in the SCN. Conclusions Independent of NAD+ concentration in the SCN, sevoflurane decreases CLOCK binding to the PER2 promoter E’-box motif, reducing histone acetylation and leading to suppression of PER2 expression.
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time dependent repression of mPER2 expression in the suprachiasmatic nucleus by inhalation anesthesia with sevoflurane
Neuroscience Letters, 2012Co-Authors: Kana Kadota, Norio Iijima, Atsuhiro Sakamoto, Yumiko Ohehayashi, Ken Takumi, Shimpei Higo, Hitoshi OzawaAbstract:Abstract Some anesthetics can affect gene expression. Previously, we reported that sevoflurane anesthesia drastically and reversibly repressed the expression of mouse PER2 ( mPer 2), a core clock gene in the suprachiasmatic nucleus (SCN). In the current study, we examined the time-dependent effect of sevoflurane on mPER2 expression and its interactions with the circadian rest/activity rhythm of mice. During certain hours of the day, mice were anesthetized with 2.5% sevoflurane in 40% oxygen for 4 h. The expression level of mPER2 in the SCN was measured by in situ hybridization using a radiolabeled cRNA probe. Anesthesia during the morning hours showed the greatest repressive effect on mPER2 expression. Sevoflurane anesthesia repressed mPER2 expression during the conditions of light/dark and constant dark, and the light conditions modified the repression rate under anesthesia. Moreover, anesthesia in the morning also repressed mPER2 expression the following day. This dominant effect of anesthesia in the morning indicates that sevoflurane anesthesia affects the onset of mPER2 transcription. Behavior analysis revealed that the anesthetic treatment also induced a phase-delay in the rest/activity rhythm. However, no time-dependent effects of anesthesia on the circadian rest/activity rhythm were observed. Further investigation into the molecular events caused by anesthesia are required to explain atypical clinical signs observed in patients after surgical procedures, such as fatigue, sleep disorder, mood alteration and delirium.
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the general anesthetic sevoflurane affects the expression of clock gene mPER2 accompanying the change of nad level in the suprachiasmatic nucleus of mice
Neuroscience Letters, 2011Co-Authors: Norio Iijima, Kana Kadota, Atsuhiro Sakamoto, Hitoshi OzawaAbstract:Abstract Sevoflurane is an anesthetic for the general anesthesia. In this study, we showed that sevoflurane anesthesia affects the expression of mouse PER2 ( mPER2 ), which is a clock gene in the brain which is considered the organ where the anesthetics act in. 64.5% of mPER2 circadian expression was repressed under anesthesia in the suprachiasmatic nucleus (SCN) of the brain. After recovering from the anesthesia, the repressed mPER2 expression was restored to the same level as in non anesthesia-treated mice. This repression pattern was also observed in the subsequent phases of diurnal mPER2 expression. However, obvious phase-shift in the mPER2 expression was not showed in this study. On the other hand, the behavior analysis in this experiment exhibited that the phases in the circadian behavioral rhythm were shifted backwards. We also measured the NAD + level in the SCN, which was a mediator regulating the mPER2 expression. Then, significant increase of NAD + was detected under the anesthesia. These results indicate that the anesthesia induces the increase of NAD + , and consequently leads to the repression of mPER2 expression and modifies the circadian expression pattern and diurnal behavioral rhythm of mice. Furthermore, the modification of mPER2 expression by the anesthesia is considered to affect various gene expressions.
Xiaoming Yang - One of the best experts on this subject based on the ideXlab platform.
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Mammalian PER2 regulates AKT activation and DNA damage response.
Biochemistry and cell biology = Biochimie et biologie cellulaire, 2012Co-Authors: Xiaoming Yang, Zhengguan Yang, Esmaiel JabbariAbstract:PER2 is a key mammalian circadian clock protein. It also has a tumor suppressive function. Down regulation of PER2 in the cultured cancer cells accelerates cell proliferation, while overexpression of PER2 inhibits cell growth and induces apoptosis. The PER2 mutant mice have a cancer prone phenotype and an altered DNA damage response. Here we report that PER2 regulates AKT activity. Cells with down-regulated PER2 expression have prolonged high levels of AKT T308 phosphorylation after growth factor stimulation or DNA damage. PER2 down-regulation delays DNA damage induced Chk2 activation and overrides DNA damage induced apoptosis and cell cycle arrest.
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Circadian Time-Dependent Tumor Suppressor Function of Period Genes
Integrative cancer therapies, 2009Co-Authors: Xiaoming Yang, Patricia A. Wood, Christine M Ansell, William J. M. HrusheskyAbstract:The mammalian core clock genes, Periods (Per1 and PER2), have tumor suppressor properties. Decreased expression of Per1 and PER2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or PER2 inhibits cancer cell growth in culture. The authors have shown that downregulation of Per1 or PER2 enhances cancer growth in vitro. These genes also regulate the amount of cell proliferation-related molecules, many of which are therapeutic targets. In animals, tumors grow with clear circadian organization, and Per1 and PER2 exert their tumor suppressor functions in a circadian time-dependent manner. Downregulation of Per1 or PER2 increases tumor growth only at certain specific times of the day. Per1 and PER2 differentially regulate tumor growth rhythm in vivo. These data suggest that the therapeutic efficacy of antiproliferation agents depends on the time of day of drug delivery. The optimal times of day may be shifted in tumors that have mutant Period genes.
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down regulation of circadian clock gene period 2 accelerates breast cancer growth by altering its daily growth rhythm
Breast Cancer Research and Treatment, 2009Co-Authors: Xiaoming Yang, Patricia A. Wood, Christine M Ansell, Jovelyn Duquiton, William J. M. HrusheskyAbstract:Purpose PER2, a core circadian clock gene, has tumor suppressor properties and is mutated or down regulated in human breast cancers. We have manipulated the expression of this gene in vitro and in vivo to more fully understand how the PER2 clock gene product affects cancer growth. Methods We used siRNA and shRNA to down regulate PER2 expression in vitro and in vivo and measured cancer cell proliferation, tumor growth rate and several molecular pathways relevant to cancer growth and their circadian organizations. All statistical tests were two-sided. Results Down regulation of functional PER2 gene expression increases Cyclin D and Cyclin E levels and doubles in vitro breast cancer cell proliferation (P < 0.05). Down regulation of PER2 also accelerates in vivo tumor growth and doubles the daily amplitude of the tumor growth rhythm (P < 0.05). Conclusions The clock gene PER2 exerts its tumor suppressor function in a circadian time dependent manner. Therefore, PER2 and perhaps other clock genes represent a new class of potential therapeutic targets whose manipulation will modulate cancer growth and cancer cell proliferation.
Urs Albrecht - One of the best experts on this subject based on the ideXlab platform.
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Mutation of the Circadian Clock Gene PER2 Alters Vascular Endothelial Function
Circulation, 2007Co-Authors: Hema Viswambharan, Urs Albrecht, João Miguel Carvas, Vladan Antic, Ana Marecic, Corinne Jud, Christian E. Zaugg, Xiu-fen Ming, Jean-pierre Montani, Zhihong YangAbstract:Background—The circadian clock regulates biological processes including cardiovascular function and metabolism. In the present study, we investigated the role of the circadian clock gene Period2 (PER2) in endothelial function in a mouse model. Methods and Results—Compared with the wild-type littermates, mice with PER2 mutation exhibited impaired endotheliumdependent relaxations to acetylcholine in aortic rings suspended in organ chambers. During transition from the inactive to active phase, this response was further increased in the wild-type mice but further decreased in the PER2 mutants. The endothelial dysfunction in the PER2 mutants was also observed with ionomycin, which was improved by the cyclooxygenase inhibitor indomethacin. No changes in the expression of endothelial acetylcholine-M3 receptor or endothelial nitric oxide synthase protein but increased cyclooxygenase-1 (not cyclooxygenase-2) protein levels were observed in the aortas of the PER2 mutants. Compared with PER2 mutants, a greater endothelium-dependent relaxation to ATP was observed in the wild-type mice, which was reduced by indomethacin. In quiescent aortic rings, ATP caused greater endothelium-dependent contractions in the PER2 mutants than in the wild-type mice, contractions that were abolished by indomethacin. The endothelial dysfunction in the PER2 mutant mice is not associated with hypertension or dyslipidemia. Conclusions—Mutation in the PER2 gene in mice is associated with aortic endothelial dysfunction involving decreased production of NO and vasodilatory prostaglandin(s) and increased release of cyclooxygenase-1–derived vasoconstrictor(s). The results suggest an important role of the PER2 gene in maintenance of normal cardiovascular functions. (Circulation. 2007;115:2188-2195.)
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ethanol self administration and reinstatement of ethanol seeking behavior in per1 brdm1 mutant mice
Psychopharmacology, 2007Co-Authors: Tarek Zghoul, Urs Albrecht, Carolina Abarca, Carles Sanchissegura, Gunter Schumann, Rainer SpanagelAbstract:Rationale Alcohol consumption shows circadian rhythmicity, i.e., alcohol preference and intake change with circadian time. Circadian rhythmicity is controlled by a biological clock, which has been shown to govern behavioral, physiological, and hormonal processes in synchronization with internal as well as external cues. Molecular components of the clock include circadian clock genes such as period (Per) 1, 2, and 3. Previously, our lab demonstrated the involvement of mouse Per1 (mPer1) and PER2 (mPER2) in modulating cocaine sensitization and reward. What is more, we investigated voluntary alcohol consumption in PER2Brdm1 mice with the results suggesting a relationship between this circadian clock gene and ethanol consumption. Objective To further complement the mPER2 study, our lab proceeded to assess mPer1’s possible role on alcohol intake using operant and free choice two bottle paradigms.
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Ethanol self-administration and reinstatement of ethanol-seeking behavior in Per1 ^ Brdm1 mutant mice
Psychopharmacology, 2007Co-Authors: Tarek Zghoul, Urs Albrecht, Carolina Abarca, Gunter Schumann, Carles Sanchis-segura, Rainer SpanagelAbstract:Rationale Alcohol consumption shows circadian rhythmicity, i.e., alcohol preference and intake change with circadian time. Circadian rhythmicity is controlled by a biological clock, which has been shown to govern behavioral, physiological, and hormonal processes in synchronization with internal as well as external cues. Molecular components of the clock include circadian clock genes such as period ( Per ) 1 , 2 , and 3 . Previously, our lab demonstrated the involvement of mouse Per1 ( mPer1 ) and PER2 ( mPER2 ) in modulating cocaine sensitization and reward. What is more, we investigated voluntary alcohol consumption in PER2 ^ Brdm1 mice with the results suggesting a relationship between this circadian clock gene and ethanol consumption. Objective To further complement the mPER2 study, our lab proceeded to assess mPer1 ’s possible role on alcohol intake using operant and free choice two bottle paradigms. Methods Using operant conditions, Per1 ^ Brdm1 and wild type mice were trained to self-administer ethanol (10%) under a fixed ratio 1 (FR1) paradigm. This was ensued by a progressive ratio (PR) schedule. Furthermore, extinction sessions were introduced, followed by reinstatement measures of ethanol-seeking behavior. In another set of animals, the mice were exposed to voluntary long-term alcohol consumption, ensued by a 2-month deprivation phase, after which the alcohol deprivation effect (ADE) was measured. Results Mutant mice did not display a significantly divergent number of reinforced lever presses (FR1 and PR) than wild type animals. Furthermore, no significant differences between groups were obtained regarding reinstatement of ethanol-seeking behavior. Similar results were obtained in the two bottle free choice paradigm. Specifically, no genotype differences concerning consumption and preference were observed over a broad range of different ethanol concentrations. Moreover, after the deprivation phase, both groups exhibited significant ADEs, yet no genotype differences. Conclusions Contrary to the mPER2 data, the present findings do not suggest a relationship between the circadian clock gene mPer1 and ethanol reinforcement, seeking, and relapse behavior.
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circadian expression of the clock gene PER2 is altered in the ruin lizard podarcis sicula when temperature changes
Molecular Brain Research, 2005Co-Authors: Maria Chiara Magnone, Urs Albrecht, Birgit Jacobmeier, Cristiano Bertolucci, Augusto FoaAbstract:When exposed to the cold, the body temperature of the ruin lizard (Podarcis sicula), an ectothermic vertebrate, comes into equilibrium with that low environmental temperature. During this time, the behavioral output of the circadian clock, locomotor activity, disappears. We tested the activity of the circadian clockwork at low temperature (6 °C) by following the expression of one of its essential components, the Period2 (PER2) gene. Here we show that lizard PER2 (lPER2) expression, which is rhythmic and paralleling the behavioral rhythm of locomotor activity at higher temperature (29 °C), becomes constantly high at low temperature. When lizards are re-exposed to high temperature, rhythmic lPER2 expression is re-established after 2 days of adaptation and coincides with onset of locomotor activity. The alteration of the lPER2 expression pattern at low temperature indicates that the activity of the molecular feedback loop is modified under these conditions.
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Disruption of mCry2 restores circadian rhythmicity in mPER2 mutant mice
Genes & development, 2002Co-Authors: Henrik Oster, Akira Yasui, Gijsbertus T. J. Van Der Horst, Urs AlbrechtAbstract:Many biochemical, physiological, and behavioral processes display daily rhythms generated by an internal timekeeping mechanism referred to as the circadian clock. The core oscillator driving this clock is located in the ventral part of the hypothalamus, the so called suprachiasmatic nuclei (SCN). At the molecular level, this oscillator is thought to be composed of interlocking autoregulatory feedback loops involving a set of clock genes. Among the components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPER2) and Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in the mPER2 gene leads to a gradual loss of circadian rhythmicity in mice kept in constant darkness (DD). Here we show that inactivation of the mCry2 gene in mPER2 mutant mice restores circadian rhythmicity and normal clock gene expression patterns. Thus, mCry2 can act as a nonallelic suppressor of mPER2, which points to direct or indirect interactions of PER2 and CRY2 proteins. In marked contrast, inactivation of mCry1 in mPER2 mutant mice does not restore circadian rhythmicity but instead results in complete behavioral arrhythmicity in DD, indicating different effects of mCry1 and mCry2 in the clock mechanism
Louis J. Ptáček - One of the best experts on this subject based on the ideXlab platform.
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modeling of a human circadian mutation yields insights into clock regulation by PER2
Cell, 2007Co-Authors: K L Toh, Christopher R Jones, Jiyeon Shin, Louis J. PtáčekAbstract:Summary Circadian rhythms are endogenous oscillations of physiological and behavioral phenomena with period length of ∼24 hr. A mutation in human Period 2 ( hPER2 ), a gene crucial for resetting the central clock in response to light, is associated with familial advanced sleep phase syndrome (FASPS), an autosomal dominant condition with early morning awakening and early sleep times. The FASPS hPER2 S662G mutation resulted in PER2 being hypophosphorylated by casein kinase I (CKI) in vitro. We generated transgenic mice carrying the FASPS hPER2 S662G mutation and faithfully recapitulate the human phenotype. We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation. Altering CKIδ dosage modulates the S662 phenotype demonstrating that CKIδ can regulate period through PER2 in vivo. Modeling a naturally occurring human variant in mice has yielded novel insights into PER2 regulation.
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an hPER2 phosphorylation site mutation in familial advanced sleep phase syndrome
Science, 2001Co-Authors: Christopher R Jones, Erik J Eide, David M Virshup, Louis J. Ptáček, Yan He, William A Hinz, Yinghui FuAbstract:Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are “morning larks” with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (h PER2 ), a human homolog of the period gene in Drosophila , maps to the same locus. Affected individuals have a serine to glycine mutation within the casein kinase I ɛ (CKI ɛ ) binding region of hPER2, which causes hypophosphorylation by CKI ɛ in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.