DOCSLIB.ORG

The Period of the Circadian Oscillator Is Primarily Determined by the Balance Between Casein Kinase 1 and Protein Phosphatase 1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Period of the Circadian Oscillator Is Primarily Determined by the Balance Between Casein Kinase 1 and Protein Phosphatase 1 The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1 Hyeong-min Leea,1,2, Rongmin Chena,1, Hyukmin Kima, Jean-Pierre Etchegarayb,3, David R. Weaverb, and Choogon Leea,4 aDepartment of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306; and bDepartment of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605-2324 Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 30, 2011 (received for review May 4, 2011) Mounting evidence suggests that PERIOD (PER) proteins play a PAGE—occurs progressively over several hours (12, 19), which is central role in setting the speed (period) and phase of the circadian critical for stretching the feedback loop to ∼24 h. However, PER2 clock. Pharmacological and genetic studies have shown that changes can be maximally phosphorylated by CK1ε in vitro kinase reac- in PER phosphorylation kinetics are associated with changes in tions within 30 min (20, 21), suggesting that PER phosphorylation circadian rhythm period and phase, which can lead to sleep disorders must be counterbalanced by phosphatases in vivo. such as Familial Advanced Sleep Phase Syndrome in humans. We Because the phase and period of the clock are primarily de- and others have shown that casein kinase 1δ and ε (CK1δ/ε) are termined by temporal regulation of PER phosphorylation (12, 15, essential PER kinases, but it is clear that additional, unknown mech- 21–26), the characterization of PER kinases and phosphatases is anisms are also crucial for regulating the kinetics of PER phosphor- vital to understanding the circadian clock mechanism. CK1δ and ε ylation. Here we report that circadian periodicity is determined have been shown to be PER kinases and are important for clock primarily through PER phosphorylation kinetics set by the balance function, but PER phosphorylation is largely intact in several between CK1δ/ε and protein phosphatase 1 (PP1). In CK1δ/ε-defi- CK1δ or CK1ε mutants (12, 21, 23, 27). Furthermore, PER can be cient cells, PER phosphorylation is severely compromised and non- phosphorylated by several other kinases in vitro, including CK1α rhythmic, and the PER proteins are constitutively cytoplasmic. and γ, CK2, and GSK3β (28–32). Thus, it remains unclear which However, when PP1 is disrupted, PER phosphorylation is dramati- kinases are responsible for the majority of mobility-shifting, pro- cally accelerated; the same effect is not seen when PP2A is disrupted. gressive phosphorylation of PER in vivo. In this study, we show Our work demonstrates that the speed and rhythmicity of PER phos- δ ε δ ε that CK1 and are the major PER kinases and that they are phorylation are controlled by the balance between CK1 / and PP1, largely redundant with each other, such that PER phosphorylation which in turn determines the period of the circadian oscillator. Thus, and the circadian clock’s function can endure the loss of just one our findings provide clear insights into the molecular basis of how kinase. Moreover, we identify PP1 as the major PER phosphatase NEUROSCIENCE the period and phase of our daily rhythms are determined. that counterbalances CK1δ/ε and other PER kinases in vivo. dynamic regulation of phosphorylation | stoichiometry | Results period determination PER Phosporylation Is Severely Compromised and the Molecular Clock Is Not Functional in CK1δ/ε-Deficient Fibroblasts. We previously he circadian clock controls so much of mammalian physiology provided evidence for the importance of CK1δ/ε for clock function Tthat dysregulation of the clock contributes to medical con- by combining CK1δ gene deficiency with dominant negative CK1ε ditions such as jet lag, shift work sleep disorder, metabolic dis- expression (21). However, the dominant negative CK1ε may have ’ eases, and mood disorders (1, 2). In most of the body s cells, from interfered not only with wild-type CK1ε (wtCK1ε) activity, but also the neurons of the suprachiasmatic nucleus (SCN) to hepatocytes, with other isoforms of CK1 as suggested by Hirota et al. (29). To fi lung epithelial cells, and even broblasts, the clock is present and definitively test how CK1δ/ε contribute to temporal PER phos- – its molecular mechanism is essentially the same (3 6). The back- phorylation in vivo, we assessed circadian rhythms and the molec- bone of the oscillator mechanism is a transcriptional negative fi fi δ ε – ular clock in mouse broblasts de cient in both CK1 and . feedback loop driven by positive and negative elements (7 10). Because CK1δ deletion results in embryonic lethality, we derived The positive elements are three bHLH/PAS-containing tran- the fibroblasts from mice with floxed CK1δ/ε genes, so that the scription factors, CLOCK, NPAS2, and BMAL1; the CLOCK (or genes could be deleted conditionally using the Cre-loxP recom- NPAS2):BMAL1 heterodimer binds to E-box enhancer motifs bination system (27). Cre recombinase was expressed using an and activates transcription of the negative element genes, Per1 and 2, and Cryptochrome (Cry)1 and 2. The PER:CRY complexes com- plete the feedback loop by inhibiting CLOCK:BMAL1. Author contributions: H.-m.L., R.C., and C.L. designed research; H.-m.L., R.C., and H.K. Although all of these clock proteins are essential, PERIOD performed research; J.-P.E. and D.R.W. contributed new reagents/analytic tools; H.-m.L., (PER) is of special importance for clock regulation. PER is the R.C., and C.L. analyzed data; and H.-m.L., R.C., D.R.W., and C.L. wrote the paper. rate-limiting component for PER:CRY complex formation, and The authors declare no conflict of interest. thus the timing and duration of PER nuclear entry and accumu- This article is a PNAS Direct Submission. lation dictate the phase and period of the molecular clock (11–13). 1 ’ H.-m.L. and R.C. contributed equally to this work. Of all of the core clock proteins, only PER s expression is abso- 2Present address: Department of Pharmacology, University of North Carolina, Chapel Hill, lutely required to oscillate for the clock to function; constitutive NC 27514. high expression of PER completely disrupts circadian rhythms in 3Present address: Massachusetts General Hospital Cancer Center, Harvard Medical School, cells and mice (11). Phosphorylation of PER is a vital part of clock Boston, MA 02114. regulation, as it affects PER’s nuclear translocation, interaction 4To whom correspondence should be addressed. E-mail: [email protected]. – with other clock proteins, and timely degradation (14 18). In vivo, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. PER phosphorylation—detectable as a mobility shift in SDS/ 1073/pnas.1107178108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1107178108 PNAS | September 27, 2011 | vol. 108 | no. 39 | 16451–16456 Downloaded by guest on September 26, 2021 CK1δfl/fl; CK1εfl/fl CK1δfl/fl; CK1εfl/fl (Fig. S3), these protein levels suggest that PER1 and PER2 are A B GFP Cre 0 3 4 days more stable in the mutant cells. Time (hr) 12 18 24 30 12 18 24 30 fi GFP Cre GFP Cre Our ndings are further supported when degradation rates were PER1 CK1δ measured after the cells were treated with cycloheximide. Both PER1 and PER2 were significantly more stable in the mutant PER2 cells compared with control cells (Fig. 1D). Nonphosphorylated CK1ε CLOCK was also more pronounced in the mutant cells (Fig. 1B), NS long which suggests that CLOCK is also a substrate of CK1δ/ε, likely CLOCK δ ε fi ACTIN via CK1 / :PER complexes. This nding is reminiscent of what short * – * has been found in Neurospora and Drosophila (33 36). Deletion of CK1δ/ε also caused PER1 and PER2 to accumu- CK1δ CK1δfl/fl; CK1εfl/fl + Cre late predominantly in the cytoplasm, whereas they were mostly C ε λ Pase - + + CK1 nuclear in control cells (Fig. 2A and Fig. S4 A and B). These vanadate -- + ACTIN results suggest that PER phosphorylation is required for nuclear PER1 translocation or accumulation, as has been reported in Dro- sophila (37). Our findings are consistent with data obtained from PER2 PER1 Cre 100 liver tissue, where hypophosphorylated PER species are cyto- ** GFP ** plasmic and not complexed with CK1δ/ε (12). 50 * fl/fl fl/fl Because previous research suggested that hyperphosphorylation D CK1δ ; CK1ε Cre+CHX GFP+CHX 0 targets PER for proteasomal degradation (22, 28, 38), we con- 0 3 6 9 12 hrs Time (hr) 0 3 6 9 12 0 3 6 9 12 sidered the possibility that the lack of hyperphosphorylated, nu- PER2 clear PER1/2 may have been due to rapid degradation as opposed PER1 Cre 100 GFP Relative abundance to reduced phosphorylation and lack of nuclear transport. To test * * * this possibility, we treated the cells with a mixture of proteasome PER2 50 * inhibitors (MG132 + PSI + lactacystin). In control cells, in- 0 hibition of proteasomal degradation increased levels of hyper- ACTIN 0 3 6 9 12 hrs phosphorylated PER1 and both hypo- and hyperphosphorylated CHX treatment PER2 levels, consistent with previous work (Fig. 2B) (21). The Fig. 1. PER1/2 do not oscillate, and their phosphorylation is severely com- same treatment in the CK1δ/ε-deficient cells did not result in the Δ Δ − − promised in CK1 double-mutant (CK1δ 2/ 2:CK1ε / ) fibroblasts. (A) CK1δ and ε detection of hyperphosphorylated forms, demonstrating that were successfully deleted by introducing adenoviral cre into the double- elimination of CK1δ/ε does prevent a substantial amount of PER fl oxed mutant cells. Cells were harvested 3 and 4 d after adenoviral cre or gfp phosphorylation. However, the treatment induced accumulation infection, and then subjected to immunoblotting for CK1δ/ε and ACTIN.
Load more

Recommended publications
  • Distinct Patterns of Period Gene Expression in the Suprachiasmatic Nucleus Underlie Circadian Clock Photoentrainment by Advances Or Delays
    University of Massachusetts Medical School eScholarship@UMMS Neurobiology Publications and Presentations Neurobiology 2011-10-11 Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays William J. Schwartz University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/neurobiology_pp Part of the Neuroscience and Neurobiology Commons Repository Citation Schwartz WJ, Tavakoli-Nezhad M, Lambert CM, Weaver DR, de la Iglesia HO. (2011). Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays. Neurobiology Publications and Presentations. https://doi.org/10.1073/ pnas.1107848108. Retrieved from https://escholarship.umassmed.edu/neurobiology_pp/114 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Neurobiology Publications and Presentations by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays William J. Schwartza,1, Mahboubeh Tavakoli-Nezhada, Christopher M. Lambertb, David R. Weaverb, and Horacio O. de la Iglesiac,1 Departments of aNeurology and bNeurobiology, University of Massachusetts Medical School, Worcester, MA 01655; and cDepartment of Biology, University of Washington, Seattle, WA 98195 Edited by Michael Rosbash, Howard Hughes Medical Institute, Waltham, MA, and approved September 9, 2011 (received for review May 19, 2011) The circadian clock in the mammalian hypothalamic suprachias- and Per3) genes is activated. PER proteins accumulate in the matic nucleus (SCN) is entrained by the ambient light/dark cycle, cytoplasm, are regulated through their phosphorylation and their which differentially acts to cause the clock to advance or delay.
    [Show full text]
  • Regulation of Drosophila Circadian Rhythms by Mirna Let-7 Is Mediated by a Regulatory Cycle
    ARTICLE Received 10 Jul 2014 | Accepted 10 Oct 2014 | Published 24 Nov 2014 DOI: 10.1038/ncomms6549 Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle Wenfeng Chen1,*, Zhenxing Liu1,*, Tianjiao Li1, Ruifeng Zhang1, Yongbo Xue1, Yang Zhong1, Weiwei Bai1, Dasen Zhou1 & Zhangwu Zhao1 MicroRNA-mediated post-transcriptional regulations are increasingly recognized as important components of the circadian rhythm. Here we identify microRNA let-7, part of the Drosophila let-7-Complex, as a regulator of circadian rhythms mediated by a circadian regulatory cycle. Overexpression of let-7 in clock neurons lengthens circadian period and its deletion attenuates the morning activity peak as well as molecular oscillation. Let-7 regulates the circadian rhythm via repression of CLOCKWORK ORANGE (CWO). Conversely, upregulated cwo in cwo-expressing cells can rescue the phenotype of let-7-Complex overexpression. Moreover, circadian prothoracicotropic hormone (PTTH) and CLOCK- regulated 20-OH ecdysteroid signalling contribute to the circadian expression of let-7 through the 20-OH ecdysteroid receptor. Thus, we find a regulatory cycle involving PTTH, a direct target of CLOCK, and PTTH-driven miRNA let-7. 1 Department of Entomology, College of Agronomy and Biotechnology, China Agricultural University, Beijing 100193, China. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to Z.Z. (email: [email protected]). NATURE COMMUNICATIONS | 5:5549 | DOI: 10.1038/ncomms6549 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6549 lmost all animals display a wide range of circadian bantam-dependent regulation of Clk expression is required for rhythms in behaviour and physiology, such as locomotor circadian rhythm.
    [Show full text]
  • A Circadian Biomarker Associated with Breast Cancer in Young Women
    268 Cancer Epidemiology, Biomarkers & Prevention Period3 Structural Variation: A Circadian Biomarker Associated with Breast Cancer in Young Women Yong Zhu,1 Heather N. Brown,1 Yawei Zhang,1 Richard G. Stevens,2 and Tongzhang Zheng1 1Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut and 2University of Connecticut Health Center, Farmington, Connecticut Abstract Circadian disruption has been indicated as a risk factor for blood samples collected from a recently completed breast breast cancer in recent epidemiologic studies. A novel cancer case-control study in Connecticut. There were 389 finding in circadian biology is that genes responsible for Caucasian cases and 432 Caucasian controls included in our circadian rhythm also regulate many other biological path- analysis. We found that the variant Per3 genotype (heterozy- ways, including cell proliferation, cell cycle regulation, and gous + homozygous 5-repeat alleles) was associated with an apoptosis. Therefore, mutations in circadian genes could increased risk of breast cancer among premenopausal women conceivably result in deregulation of these processes and (odds ratio, 1.7; 95% confidence interval, 1.0-3.0). Our find- contribute to tumor development, and be markers for ing suggests that the circadian genes might be a novel panel susceptibility to human cancer. In this study, we investi- of potential biomarkers for breast cancer and worth further gated the association between an exonic length variation in a investigation. (Cancer Epidemiol Biomarkers Prev circadian gene, Period3 (Per3), and breast cancer risk using 2005;14(1):268–70) Introduction Genetic determinants have been found to be responsible for a Per2 gene can activate c-Myc signaling pathways leading to fundamental biological phenomenon: a universal 24-hour genomic instability and cell proliferation.
    [Show full text]
  • Spatial and Temporal Expression of the Period and Timeless Genes in the Developing Nervous System of Drosophila
    The Journal of Neuroscience, September 1, 1997, 17(17):6745–6760 Spatial and Temporal Expression of the period and timeless Genes in the Developing Nervous System of Drosophila: Newly Identified Pacemaker Candidates and Novel Features of Clock Gene Product Cycling Maki Kaneko,1 Charlotte Helfrich-Fo¨ rster,2 and Jeffrey C. Hall1 1Department of Biology, Brandeis University, Waltham, Massachusetts 02254, and 2Botanisches Institut, 72076 Tu¨ bingen, Germany The circadian timekeeping system of Drosophila functions from onward, throughout metamorphosis and into adulthood. There- the first larval instar (L1) onward but is not known to require the fore, they are the best candidates for being pacemaker neurons expression of clock genes in larvae. We show that period ( per) responsible for the larval “time memory” (inferred from previous and timeless (tim) are rhythmically expressed in several groups experiments). In addition to the LNs, a subset of the larval of neurons in the larval CNS both in light/dark cycles and in dorsal neurons (DNLs) expresses per and tim. Intriguingly, two constant dark conditions. Among the clock gene-expressing neurons of this DNL group cycle in PER and TIM immunoreac- cells there is a subset of the putative pacemaker neurons, the tivity almost in antiphase to the other DNLs and to the LNs. “lateral neurons” (LNs), that have been analyzed mainly in adult Thus, the temporal expression of per and tim are regulated flies. Like the adult LNs, the larval ones are also immunoreac- differentially in different cells. Furthermore, the light sensitivity tive to a peptide called pigment-dispersing hormone. Their associated with levels of the TIM protein is different from that in putative dendritic trees were found to be in close proximity to the heads of adult Drosophila.
    [Show full text]
  • Overexpression of C-Myc in ␤-Cells of Transgenic Mice Causes Proliferation and Apoptosis, Downregulation of Insulin Gene Expression, and Diabetes D
    Overexpression of c-Myc in ␤-Cells of Transgenic Mice Causes Proliferation and Apoptosis, Downregulation of Insulin Gene Expression, and Diabetes D. Ross Laybutt,1 Gordon C. Weir,1 Hideaki Kaneto,1 Judith Lebet,1 Richard D. Palmiter,2 Arun Sharma,1 and Susan Bonner-Weir1 To test the hypothesis that c-Myc plays an important role in ␤-cell growth and differentiation, we generated transgenic mice overexpressing c-Myc in ␤-cells under ancreatic ␤-cell failure is fundamental to the control of the rat insulin II promoter. F1 transgenic pathogenesis of all forms of diabetes (1,2). Stud- mice from two founders developed neonatal diabetes ies from animal models suggest that, for the most (associated with reduced plasma insulin levels) and part, ␤-cells have a remarkable capacity to in- died of hyperglycemia 3 days after birth. In pancreata of P crease their mass and secretion to maintain plasma glu- transgenic mice, marked hyperplasia of cells with an altered phenotype and amorphous islet organization cose levels within a narrow range, even in the presence of was displayed: islet volume was increased threefold obesity and insulin resistance (1–4). Diabetes develops versus wild-type littermates. Apoptotic nuclei were in- only when this compensation is inadequate. creased fourfold in transgenic versus wild-type mice, In animal models of diabetes, ␤-cells have been found to suggesting an increased turnover of ␤-cells. Very few lose the unique differentiation that optimizes glucose- cells immunostained for insulin; pancreatic insulin induced insulin secretion and synthesis (5,6). Thus, mRNA and content were markedly reduced. GLUT2 genes that are highly expressed (insulin, GLUT2, and ␤ mRNA was decreased, but other -cell–associated genes PDX-1 [pancreatic and duodenal homeobox-1]) are de- (IAPP [islet amyloid pancreatic polypeptide], PDX-1 [pancreatic and duodenal homeobox-1], and BETA2/ creased with diabetes, whereas several genes that are NeuroD) were expressed at near-normal levels.
    [Show full text]
  • Play Clock Operator Guide
    NFHS GENERAL INSTRUCTIONS FOR FOOTBALL GAME AND PLAY CLOCK OPERATORS A. The game and play clock operators should report to the game officials at the stadium at least 30 minutes before game time for the following purposes: 1. To synchronize timer’s watch with official game time as established by the game official responsible for timing. 2. To advise game officials whether the game clock operator and/or play clock operator will be in the press box or on the field/side- line. Determine procedure for communications with both operators and test procedures prior to the games. 3. To discuss coordination of starting, stopping and adjusting the game clock or play clock in accordance with the playing rules. 4. To discuss if the game clock horn (mechanical signal) can be turned off. Preference is for the game clock horn (mechanical signal) to be turned off for the duration of the game. B. The game clock is normally started 30 minutes before game time. The halftime intermission will start on the referee’s signal when the players and game officials leave the field. All pregame and halftime activities shall be synchronized with the game clock. The mandatory three-minute warm-up period will be put on the game clock after the intermission time has elapsed and shall be started immediately. C. The game clock operator shall have an extra stopwatch available. In case of failure of the game clock, the game clock operator shall immediately contact the game officials, giving them the correct data regarding the official time. The game official responsible for timing will then pick up the correct game time on the stopwatch.
    [Show full text]
  • Agonists and Knockdown of Estrogen Receptor Β Differentially Affect
    Schüler-Toprak et al. BMC Cancer (2016) 16:951 DOI 10.1186/s12885-016-2973-y RESEARCH ARTICLE Open Access Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro Susanne Schüler-Toprak1*, Julia Häring1, Elisabeth C. Inwald1, Christoph Moehle2, Olaf Ortmann1 and Oliver Treeck1 Abstract Background: Estrogen receptor β (ERβ) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple-negative breast cancer (TNBC). Thus, ERβ might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ERβ in invasion of two triple-negative breast cancer cell lines. Methods: MDA-MB-231 and HS578T breast cancer cells were treated with the specific ERβ agonists ERB-041, WAY200070, Liquiritigenin and 3β-Adiol. Knockdown of ERβ expression was performed by means of siRNA transfection. Effects on cellular invasion were assessed in vitro by means of a modified Boyden chamber assay. Transcriptome analyses were performed using Affymetrix Human Gene 1.0 ST microarrays. Pathway and gene network analyses were performed by means of Genomatix and Ingenuity Pathway Analysis software. Results: Invasiveness of MBA-MB-231 and HS578T breast cancer cells decreased after treatment with ERβ agonists ERB-041 and WAY200070. Agonists Liquiritigenin and 3β-Adiol only reduced invasion of MDA-MB-231 cells. Knockdown of ERβ expression increased invasiveness of MDA-MB-231 cells about 3-fold. Transcriptome and pathway analyses revealed that ERβ knockdown led to activation of TGFβ signalling and induced expression of a network of genes with functions in extracellular matrix, tumor cell invasion and vitamin D3 metabolism.
    [Show full text]
  • Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2
    Review Biomol Ther 26(4), 358-367 (2018) Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2 Mikyung Kim, June Bryan de la Peña, Jae Hoon Cheong and Hee Jin Kim* Department of Pharmacy, Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul 01795, Republic of Korea Abstract Most organisms have adapted to a circadian rhythm that follows a roughly 24-hour cycle, which is modulated by both internal (clock-related genes) and external (environment) factors. In such organisms, the central nervous system (CNS) is influenced by the circadian rhythm of individual cells. Furthermore, the period circadian clock 2 (Per2) gene is an important component of the circadian clock, which modulates the circadian rhythm. Per2 is mainly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as other brain areas, including the midbrain and forebrain. This indicates that Per2 may affect various neurobiological activities such as sleeping, depression, and addiction. In this review, we focus on the neurobiological functions of Per2, which could help to better understand its roles in the CNS. Key Words: Circadian rhythm, Per2 gene, Sleep, Depression, Addiction, Neurotransmitter INTRODUCTION and lives in organisms because it can impart effects from the level of cells to organs including the brain. Thus, it is neces- A circadian rhythm is any physiological process that displays sary to understand clock-related genes that are controlling the a roughly 24 hour cycle in living beings, such as mammals, circadian rhythm endogenously. plants, fungi and cyanobacteria (Albrecht, 2012). In organ- The Period2 (Per2) gene is a member of the Period family isms, most biological functions such as sleeping and feeding of genes consisting of Per1, Per2, and Per3, and is mainly patterns are adapted to the circadian rhythm.
    [Show full text]
  • Role of the Nuclear Receptor Rev-Erb Alpha in Circadian Food Anticipation and Metabolism Julien Delezie
    Role of the nuclear receptor Rev-erb alpha in circadian food anticipation and metabolism Julien Delezie To cite this version: Julien Delezie. Role of the nuclear receptor Rev-erb alpha in circadian food anticipation and metabolism. Neurobiology. Université de Strasbourg, 2012. English. NNT : 2012STRAJ018. tel- 00801656 HAL Id: tel-00801656 https://tel.archives-ouvertes.fr/tel-00801656 Submitted on 10 Apr 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE CNRS UPR 3212 · Institut des Neurosciences Cellulaires et Intégratives THÈSE présentée par : Julien DELEZIE soutenue le : 29 juin 2012 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/ Spécialité : Neurosciences Rôle du récepteur nucléaire Rev-erbα dans les mécanismes d’anticipation des repas et le métabolisme THÈSE dirigée par : M CHALLET Etienne Directeur de recherche, université de Strasbourg RAPPORTEURS : M PFRIEGER Frank Directeur de recherche, université de Strasbourg M KALSBEEK Andries
    [Show full text]
  • A Mutant Drosophila Homolog of Mammalian Clock Disrupts
    Cell, Vol. 93, 791±804, May 29, 1998, Copyright 1998 by Cell Press AMutantDrosophila Homolog of Mammalian Clock Disrupts Circadian Rhythms and Transcription of period and timeless Ravi Allada,*²³§ Neal E. White,³ Aronson et al., 1994; Shearman et al., 1997; Sun et al., W. Venus So,²³ Jeffrey C. Hall,²³ 1997; Tei et al., 1997). ²³ and Michael Rosbash* k In Drosophila, there are two well-characterized clock *Howard Hughes Medical Institute genes: period (per) and timeless (tim). Protein levels, ² NSF, Center for Biological Timing RNA levels, and transcription rates of these two genes ³ Department of Biology undergo robust circadian oscillations (Zerr et al., 1990; Brandeis University Hardin et al., 1990, 1992; Hardin, 1994; Sehgal et al., Waltham, Massachusetts 02254 1995; So and Rosbash, 1997). In addition, mutations § Department of Pathology in the two proteins (PER and TIM) alter or abolish the Brigham and Women's Hospital periodicity and phase of these rhythms, demonstrating Boston, Massachusetts 02115 that both proteins regulate their own transcription (Har- din et al., 1990; Sehgal et al., 1995; Marrus et al., 1996). Although there is no evidence indicating that the effects Summary on transcription are direct, PER contains a PAS domain, which has been shown to mediate interactions between We report the identification, characterization, and transcription factors (Huang et al., 1993; Lindebro et cloning of a novel Drosophila circadian rhythm gene, al., 1995). Most of these PAS-containing transcription dClock. The mutant, initially called Jrk, manifests dom- factors also contain the well-characterized basic helix- inant effects: heterozygous flies have a period alter- loop-helix (bHLH) DNA-binding domains (Crews, 1998).
    [Show full text]
  • Circadian Rhythmicity and the Influence of 'Clock
    2311 Z Kiss and P M Ghosh Prostate cancer and the 23:11 T123–T134 Thematic Review ‘clock’ genes WOMEN IN CANCER THEMATIC REVIEW Circadian rhythmicity and the influence of ‘clock’ genes on prostate cancer Zsofia Kiss1,2 and Paramita M Ghosh1,2,3 1VA Northern California Health Care System, Mather, California, USA Correspondence 2Department of Urology, University of California at Davis, Sacramento, California, USA should be addressed 3Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, to P M Ghosh California, USA Email [email protected] Abstract Key Words The androgen receptor (AR) plays a key role in the development and progression f circadian clock of prostate cancer (CaP). Since the mid-1990s, reports in the literature pointed out f androgen receptor higher incidences of CaP in some select groups, such as airline pilots and night shift f melatonin workers in comparison with those working regular hours. The common finding in these f per1 ‘high-risk’ groups was that they all experienced a deregulation of the body’s internal f bmal1 circadian rhythm. Here, we discuss how the circadian rhythm affects androgen levels and modulates CaP development and progression. Circadian rhythmicity of androgen Endocrine-Related Cancer Endocrine-Related production is lost in CaP patients, with the clock genes Per1 and Per2 decreasing, and Bmal1 increasing, in these individuals. Periodic expression of the clock genes was restored upon administration of the neurohormone melatonin, thereby suppressing CaP progression. Activation of the melatonin receptors and the AR antagonized each other, and therefore the tumour-suppressive effects of melatonin and the clock genes were most clearly observed in the absence of androgens, that is, in conjunction with androgen deprivation therapy (ADT).
    [Show full text]
  • BMAL1 and Modulates Tissue-Specific Circadian Networks
    Nuclear receptor HNF4A transrepresses CLOCK: BMAL1 and modulates tissue-specific circadian networks Meng Qua, Tomas Duffyb, Tsuyoshi Hirotac, and Steve A. Kaya,1 aKeck School of Medicine, University of Southern California, Los Angeles, CA 90089; bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; and cInstitute of Transformative Bio-Molecules, Nagoya University, 464-8602 Nagoya, Japan Contributed by Steve A. Kay, November 6, 2018 (sent for review September 24, 2018; reviewed by Carla B. Green and John B. Hogenesch) Either expression level or transcriptional activity of various nuclear NRs canonically function as ligand-activated transcription receptors (NRs) have been demonstrated to be under circadian factors that regulate the expression of their target genes to control. With a few exceptions, little is known about the roles of affect physiological pathways (19). The importance of NRs in NRs as direct regulators of the circadian circuitry. Here we show maintaining optimal physiological homeostasis is illustrated in that the nuclear receptor HNF4A strongly transrepresses the their identification as potential targets for therapeutic drug transcriptional activity of the CLOCK:BMAL1 heterodimer. We development to combat a diverse array of diseases, including define a central role for HNF4A in maintaining cell-autonomous reproductive disorders, inflammation, cancer, diabetes, car- circadian oscillations in a tissue-specific manner in liver and colon diovascular disease, and obesity (20). Various NRs have been cells. Not only transcript level but also genome-wide chromosome implicated as targets of the circadian clock, which may con- binding of HNF4A is rhythmically regulated in the mouse liver. tribute to the circadian regulation of nutrient and energy me- ChIP-seq analyses revealed cooccupancy of HNF4A and CLOCK: tabolism.
    [Show full text]