Gene Symbol: tim
Description: timeless
Alias: CG3234, Dmel\CG3234, Ritsu, TIM, Tim, dTIM, dTim, dtim, mel_tim, rit, tim1, timeless, CG3234-PB, CG3234-PL, CG3234-PM, CG3234-PN, CG3234-PO, CG3234-PP, CG3234-PR, CG3234-PS, CG3234-PT, TIMELESS, dtimeless, ritsu, tim-PB, tim-PL, tim-PM, tim-PN, tim-PO, tim-PP, tim-PR, tim-PS, tim-PT, timeless1
Species: fruit fly
Products:     tim

Top Publications

  1. Sangoram A, Saez L, Antoch M, Gekakis N, Staknis D, Whiteley A, et al. Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron. 1998;21:1101-13 pubmed
    We report the cloning and mapping of mouse (mTim) and human (hTIM) orthologs of the Drosophila timeless (dtim) gene...
  2. Weber F, Kay S. A PERIOD inhibitor buffer introduces a delay mechanism for CLK/CYC-activated transcription. FEBS Lett. 2003;555:341-5 pubmed
    We investigated the functions of clock genes period (per) and timeless (tim) in establishing negative feedback on circadian transcription factors clock/cycle (Clk/cyc) in Drosophila...
  3. McDonald M, Rosbash M, Emery P. Wild-type circadian rhythmicity is dependent on closely spaced E boxes in the Drosophila timeless promoter. Mol Cell Biol. 2001;21:1207-17 pubmed
    ..The period promoter has been well studied, but the timeless promoter has not been analyzed in detail...
  4. Inoue S, Shimoda M, Nishinokubi I, Siomi M, Okamura M, Nakamura A, et al. A role for the Drosophila fragile X-related gene in circadian output. Curr Biol. 2002;12:1331-5 pubmed
    ..In addition, the clock-controlled eclosion rhythm is normal in DFMR1-deficient flies. These results suggest that DFMR1 plays a critical role in the circadian output pathway regulating locomotor activity in Drosophila. ..
  5. Cyran S, Buchsbaum A, Reddy K, Lin M, Glossop N, Hardin P, et al. vrille, Pdp1, and dClock form a second feedback loop in the Drosophila circadian clock. Cell. 2003;112:329-41 pubmed
    ..Thus, VRI and PDP1, together with dClock itself, comprise a second feedback loop in the Drosophila clock that gives rhythmic expression of dClock, and probably of other genes, to generate accurate circadian rhythms...
  6. Yu W, Hardin P. Circadian oscillators of Drosophila and mammals. J Cell Sci. 2006;119:4793-5 pubmed
  7. Myers M, Wager Smith K, Wesley C, Young M, Sehgal A. Positional cloning and sequence analysis of the Drosophila clock gene, timeless. Science. 1995;270:805-8 pubmed
    The Drosophila genes timeless (tim) and period (per) interact, and both are required for production of circadian rhythms. Here the positional cloning and sequencing of tim are reported...
  8. Suri V, Hall J, Rosbash M. Two novel doubletime mutants alter circadian properties and eliminate the delay between RNA and protein in Drosophila. J Neurosci. 2000;20:7547-55 pubmed
    ..Both cause a lengthening of behavioral period and profoundly alter period (per) and timeless (tim) transcript and protein profiles...
  9. Rieger D, Shafer O, Tomioka K, Helfrich Forster C. Functional analysis of circadian pacemaker neurons in Drosophila melanogaster. J Neurosci. 2006;26:2531-43 pubmed

More Information

Publications110 found, 100 shown here

  1. Taylor P, Hardin P. Rhythmic E-box binding by CLK-CYC controls daily cycles in per and tim transcription and chromatin modifications. Mol Cell Biol. 2008;28:4642-52 pubmed publisher
    The Drosophila melanogaster circadian oscillator comprises interlocked per/tim and Clk transcriptional feedback loops...
  2. Kivimäe S, Saez L, Young M. Activating PER repressor through a DBT-directed phosphorylation switch. PLoS Biol. 2008;6:e183 pubmed publisher
  3. Knowles A, Koh K, Wu J, Chien C, Chamovitz D, Blau J. The COP9 signalosome is required for light-dependent timeless degradation and Drosophila clock resetting. J Neurosci. 2009;29:1152-62 pubmed publisher
    ..the ubiquitin-proteasome system also plays a critical role in light-dependent degradation of the clock protein Timeless (TIM), a key step in the entrainment of the molecular clocks to light-dark cycles...
  4. Rakshit K, Krishnan N, Guzik E, Pyza E, Giebultowicz J. Effects of aging on the molecular circadian oscillations in Drosophila. Chronobiol Int. 2012;29:5-14 pubmed publisher
    ..Transcriptional oscillations of four clock genes, period, timeless, Par domain protein 1?, and vrille, were significantly reduced in heads, but not in bodies, of aging flies...
  5. Rutila J, Maltseva O, Rosbash M. The timSL mutant affects a restricted portion of the Drosophila melanogaster circadian cycle. J Biol Rhythms. 1998;13:380-92 pubmed
    The circadian rhythm genes period (per) and timeless (tim) are central to contemporary studies on Drosophila circadian rhythms...
  6. Smolen P, Baxter D, Byrne J. Modeling circadian oscillations with interlocking positive and negative feedback loops. J Neurosci. 2001;21:6644-56 pubmed
    ..In the model of the Drosophila oscillator, PER and TIM are represented by a "lumped" variable, "PER...
  7. Wijnen H, Naef F, Young M. Molecular and statistical tools for circadian transcript profiling. Methods Enzymol. 2005;393:341-65 pubmed
    ..Both comparative and temporal study designs are discussed, and their use in circadian research is illustrated with examples. Data analysis methods to assess periodic components in time series data are outlined in detail. ..
  8. Houl J, Ng F, Taylor P, Hardin P. CLOCK expression identifies developing circadian oscillator neurons in the brains of Drosophila embryos. BMC Neurosci. 2008;9:119 pubmed publisher
    ..feedback loops in which CLOCK-CYCLE (CLK-CYC) heterodimers activate their feedback regulators period (per) and timeless (tim) via E-box mediated transcription...
  9. Blanchard F, Collins B, Cyran S, Hancock D, Taylor M, Blau J. The transcription factor Mef2 is required for normal circadian behavior in Drosophila. J Neurosci. 2010;30:5855-65 pubmed publisher
    ..Thus, a normal level of Mef2 activity is required in clock neurons to maintain robust and accurate circadian behavioral rhythms. ..
  10. Grima B, Dognon A, Lamouroux A, Chélot E, Rouyer F. CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock. PLoS Biol. 2012;10:e1001367 pubmed publisher
    Eukaryotic circadian clocks rely on transcriptional feedback loops. In Drosophila, the PERIOD (PER) and TIMELESS (TIM) proteins accumulate during the night, inhibit the activity of the CLOCK (CLK)/CYCLE (CYC) transcriptional complex, and ..
  11. Kaneko M, Hall J. Neuroanatomy of cells expressing clock genes in Drosophila: transgenic manipulation of the period and timeless genes to mark the perikarya of circadian pacemaker neurons and their projections. J Comp Neurol. 2000;422:66-94 pubmed
    Subsets of brain neurons expressing the clock genes period (per) and timeless (tim) are involved in the generation of circadian behavioral rhythms...
  12. Rosato E, Codd V, Mazzotta G, Piccin A, Zordan M, Costa R, et al. Light-dependent interaction between Drosophila CRY and the clock protein PER mediated by the carboxy terminus of CRY. Curr Biol. 2001;11:909-17 pubmed
    ..CRY), a putative circadian photoreceptor, has previously been reported to interact with the clock protein TIMELESS (TIM) in a light-dependent manner...
  13. Levine J, Funes P, Dowse H, Hall J. Advanced analysis of a cryptochrome mutation's effects on the robustness and phase of molecular cycles in isolated peripheral tissues of Drosophila. BMC Neurosci. 2002;3:5 pubmed
    Previously, we reported effects of the cry(b) mutation on circadian rhythms in period and timeless gene expression within isolated peripheral Drosophila tissues...
  14. Yu W, Zheng H, Houl J, Dauwalder B, Hardin P. PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription. Genes Dev. 2006;20:723-33 pubmed
    Transcriptional activation by CLOCK-CYCLE (CLK-CYC) heterodimers and repression by PERIOD-TIMELESS (PER-TIM) heterodimers are essential for circadian oscillator function in Drosophila...
  15. Tang C, Hinteregger E, Shang Y, Rosbash M. Light-mediated TIM degradation within Drosophila pacemaker neurons (s-LNvs) is neither necessary nor sufficient for delay zone phase shifts. Neuron. 2010;66:378-85 pubmed publisher
    ..the model of light-mediated phase shifting begins with photon capture by CRYPTOCHROME (CRY) followed by rapid TIMELESS (TIM) degradation...
  16. Akten B, Jauch E, Genova G, Kim E, Edery I, Raabe T, et al. A role for CK2 in the Drosophila circadian oscillator. Nat Neurosci. 2003;6:251-7 pubmed
    ..mechanism, we show that CK2beta is localized within clock neurons and that the clock proteins Period (Per) and Timeless (Tim) accumulate to abnormally high levels in the Andante mutant...
  17. Stoleru D, Nawathean P, Fernández M, Menet J, Ceriani M, Rosbash M. The Drosophila circadian network is a seasonal timer. Cell. 2007;129:207-19 pubmed
    ..Together with the different entraining properties of the two clock centers, the results suggest that the functional organization of the network underlies the behavioral adjustment to variations in daylength and season. ..
  18. Fang Y, Sathyanarayanan S, Sehgal A. Post-translational regulation of the Drosophila circadian clock requires protein phosphatase 1 (PP1). Genes Dev. 2007;21:1506-18 pubmed
    ..for protein phosphatase 1 (PP1) in the regulation of the major timekeeping molecules in the Drosophila clock, TIMELESS (TIM) and PERIOD (PER)...
  19. Rieger D, Wülbeck C, Rouyer F, Helfrich Forster C. Period gene expression in four neurons is sufficient for rhythmic activity of Drosophila melanogaster under dim light conditions. J Biol Rhythms. 2009;24:271-82 pubmed publisher
    ..Indeed, they found by PER and TIM immunohistochemistry that 2 LN(d) advanced their phase upon moonlight as predicted for M oscillators, whereas the ..
  20. Lim C, Lee J, Choi C, Kilman V, Kim J, Park S, et al. The novel gene twenty-four defines a critical translational step in the Drosophila clock. Nature. 2011;470:399-403 pubmed publisher
    ..by marked reductions in the levels of the clock protein Period (PER) as well as more modest effects on Timeless (TIM). Nonetheless, PER induction in pacemaker neurons can rescue tyf mutant rhythms...
  21. Kaneko M. Neural substrates of Drosophila rhythms revealed by mutants and molecular manipulations. Curr Opin Neurobiol. 1998;8:652-8 pubmed
    ..Similar studies in other insect species have suggested considerable diversity in the anatomical and neurochemical properties of pacemaker cells, as well as in the mechanisms of clock-gene regulation. ..
  22. Lin F, Song W, Meyer Bernstein E, Naidoo N, Sehgal A. Photic signaling by cryptochrome in the Drosophila circadian system. Mol Cell Biol. 2001;21:7287-94 pubmed
    Oscillations of the period (per) and timeless (tim) gene products are an integral part of the feedback loop that underlies circadian behavioral rhythms in Drosophila melanogaster...
  23. Dockendorff T, Su H, McBride S, Yang Z, Choi C, Siwicki K, et al. Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest. Neuron. 2002;34:973-84 pubmed
    ..Morphological analysis of neurons required for normal circadian behavior reveals subtle abnormalities, suggesting that defects in axonal pathfinding or synapse formation may cause the observed behavioral defects. ..
  24. Peschel N, Veleri S, Stanewsky R. Veela defines a molecular link between Cryptochrome and Timeless in the light-input pathway to Drosophila's circadian clock. Proc Natl Acad Sci U S A. 2006;103:17313-8 pubmed
    ..circadian clock is synchronized with the natural environment by light-dependent degradation of the clock protein Timeless, mediated by the blue-light photoreceptor Cryptochrome (Cry)...
  25. Yoshii T, Wülbeck C, Sehadova H, Veleri S, Bichler D, Stanewsky R, et al. The neuropeptide pigment-dispersing factor adjusts period and phase of Drosophila's clock. J Neurosci. 2009;29:2597-610 pubmed publisher
    ..Under natural conditions PDF may be required for adapting Drosophila's clock to varying photoperiods. Indeed, we show here that Pdf(01) mutants are not able to adapt their activity to long photoperiods in a wild-type manner. ..
  26. Sun W, Jeong E, Jeong H, Ko H, Edery I, Kim E. Two distinct modes of PERIOD recruitment onto dCLOCK reveal a novel role for TIMELESS in circadian transcription. J Neurosci. 2010;30:14458-69 pubmed publisher
    ..Intriguingly, the interaction between dPER(?CBD) and dCLK is TIM-dependent and modulated by light, revealing a novel and unanticipated in vivo role for TIM in circadian ..
  27. Yu W, Houl J, Hardin P. NEMO kinase contributes to core period determination by slowing the pace of the Drosophila circadian oscillator. Curr Biol. 2011;21:756-61 pubmed publisher
    ..feedback loops that are activated by CLOCK (CLK) and CYCLE (CYC) and repressed by PERIOD (PER) and TIMELESS (TIM) [1]...
  28. Yang Z, Sehgal A. Role of molecular oscillations in generating behavioral rhythms in Drosophila. Neuron. 2001;29:453-67 pubmed
    ..In Drosophila, RNA and protein levels of the period and timeless genes oscillate and the proteins autoregulate their transcription...
  29. Zhou X, Yuan C, Guo A. Drosophila olfactory response rhythms require clock genes but not pigment dispersing factor or lateral neurons. J Biol Rhythms. 2005;20:237-44 pubmed
    ..They were also independent of locomotor activity. The olfactory response rhythms were lost in period or timeless mutant flies (per0, tim0), indicating that clock genes control circadian rhythms of olfactory behavior...
  30. Boothroyd C, Wijnen H, Naef F, Saez L, Young M. Integration of light and temperature in the regulation of circadian gene expression in Drosophila. PLoS Genet. 2007;3:e54 pubmed
    ..Transcripts encoding the clock components Period, Timeless, Clock, Vrille, PAR-domain protein 1, and Cryptochrome were all confirmed to be rhythmic after entrainment to a ..
  31. Tauber E, Zordan M, Sandrelli F, Pegoraro M, Osterwalder N, Breda C, et al. Natural selection favors a newly derived timeless allele in Drosophila melanogaster. Science. 2007;316:1895-8 pubmed
    ..We report that a mutation in the circadian clock gene timeless in Drosophila melanogaster has arisen and spread by natural selection relatively recently in Europe...
  32. Ueda H, Hagiwara M, Kitano H. Robust oscillations within the interlocked feedback model of Drosophila circadian rhythm. J Theor Biol. 2001;210:401-6 pubmed
    ..After the discovery of per and tim, a model with a simple feedback loop involving per and tim has been proposed...
  33. Shafer O, Rosbash M, Truman J. Sequential nuclear accumulation of the clock proteins period and timeless in the pacemaker neurons of Drosophila melanogaster. J Neurosci. 2002;22:5946-54 pubmed
    Antisera against the circadian clock proteins Period (PER) and Timeless (TIM) were used to construct a detailed time course of PER and TIM expression and subcellular localization in a subset of the ventrolateral neurons (vLNs) in the ..
  34. Zhao J, Kilman V, Keegan K, Peng Y, Emery P, Rosbash M, et al. Drosophila clock can generate ectopic circadian clocks. Cell. 2003;113:755-66 pubmed
    ..We propose that Clock is uniquely able to induce and organize the core elements of interdependent feedback loops necessary for circadian rhythms. ..
  35. Chen W, Majercak J, Edery I. Clock-gated photic stimulation of timeless expression at cold temperatures and seasonal adaptation in Drosophila. J Biol Rhythms. 2006;21:256-71 pubmed
    ..the initial photoresponse of the circadian clock in Drosophila melanogaster is the light-induced degradation of TIMELESS (TIM)...
  36. Lee G, Bahn J, Park J. Sex- and clock-controlled expression of the neuropeptide F gene in Drosophila. Proc Natl Acad Sci U S A. 2006;103:12580-5 pubmed
    ..Based on these data, we propose that NPF also plays a role in clock-controlled sexual dimorphism in adult Drosophila. ..
  37. Johard H, Yoishii T, Dircksen H, Cusumano P, Rouyer F, Helfrich Forster C, et al. Peptidergic clock neurons in Drosophila: ion transport peptide and short neuropeptide F in subsets of dorsal and ventral lateral neurons. J Comp Neurol. 2009;516:59-73 pubmed publisher
    ..Our findings emphasize that the LN(d)s are heterogeneous both anatomically and with respect to content of neuropeptides, cryptochrome, and other markers and suggest diverse functions of these neurons. ..
  38. Hughes M, Grant G, Paquin C, Qian J, Nitabach M. Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res. 2012;22:1266-81 pubmed publisher
    ..These studies demonstrate extensive circadian control of ncRNA expression, reveal the extent of clock control of alternative splicing and RNA editing, and provide a novel, genome-wide map of splicing in Drosophila brain. ..
  39. Matsumoto A, Ukai Tadenuma M, Yamada R, Houl J, Uno K, Kasukawa T, et al. A functional genomics strategy reveals clockwork orange as a transcriptional regulator in the Drosophila circadian clock. Genes Dev. 2007;21:1687-700 pubmed
  40. Górska Andrzejak J, Makuch R, Stefan J, Görlich A, Semik D, Pyza E. Circadian expression of the presynaptic active zone protein Bruchpilot in the lamina of Drosophila melanogaster. Dev Neurobiol. 2013;73:14-26 pubmed publisher
    ..This peak is present in Canton-S flies in DD, as well as in the norpA(7) mutant in LD, but is absent in per(01), tim,(01) and cry(01) mutants in LD...
  41. Ko H, Jiang J, Edery I. Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature. 2002;420:673-8 pubmed
    ..Our findings suggest that hyperphosphorylated Per is targeted to the proteasome by interactions with Slimb. ..
  42. Krupp J, Kent C, Billeter J, Azanchi R, So A, Schonfeld J, et al. Social experience modifies pheromone expression and mating behavior in male Drosophila melanogaster. Curr Biol. 2008;18:1373-83 pubmed publisher
    ..These results demonstrate that social context exerts a regulatory influence on the expression of chemical signals, while modulating sexual behavior in the fruit fly. ..
  43. Ceriani M, Darlington T, Staknis D, Mas P, Petti A, Weitz C, et al. Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science. 1999;285:553-6 pubmed
    ..CRY), a protein involved in circadian photoperception in Drosophila, is shown to block the function of PERIOD/TIMELESS (PER/TIM) heterodimeric complexes in a light-dependent fashion...
  44. Suh J, Jackson F. Drosophila ebony activity is required in glia for the circadian regulation of locomotor activity. Neuron. 2007;55:435-47 pubmed
    ..We thus suggest a model for ebony function wherein Ebony glia participate in the clock control of dopaminergic function and the orchestration of circadian activity rhythms. ..
  45. Picot M, Klarsfeld A, Chélot E, Malpel S, Rouyer F. A role for blind DN2 clock neurons in temperature entrainment of the Drosophila larval brain. J Neurosci. 2009;29:8312-20 pubmed publisher
    ..Our results show that the larval clock neurons respond very differently to light and temperature, and strongly suggest that the CRY-negative DN2s play a prominent role in the temperature entrainment of the network. ..
  46. Fogle K, Parson K, Dahm N, Holmes T. CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate. Science. 2011;331:1409-13 pubmed publisher
    ..The CRY-mediated light response requires a flavin redox-based mechanism and depends on potassium channel conductance, but is independent of the classical circadian CRY-TIMELESS interaction.
  47. Saez L, Young M. Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron. 1996;17:911-20 pubmed
    Two genes, period (per) and timeless (tim), are essential for circadian rhythmicity in Drosophila. The encoded proteins (PER and TIM) physically interact...
  48. So W, Rosbash M. Post-transcriptional regulation contributes to Drosophila clock gene mRNA cycling. EMBO J. 1997;16:7146-55 pubmed
    The period (per) and timeless (tim) genes are intimately involved in the generation and maintenance of Drosophila circadian rhythms...
  49. Cheng Y, Hardin P. Drosophila photoreceptors contain an autonomous circadian oscillator that can function without period mRNA cycling. J Neurosci. 1998;18:741-50 pubmed
    ..These results show that per mRNA cycling is not required for PER cycling and indicate that Drosophila photoreceptors R1-R6 contain a tissue autonomous circadian oscillator. ..
  50. Sidote D, Majercak J, Parikh V, Edery I. Differential effects of light and heat on the Drosophila circadian clock proteins PER and TIM. Mol Cell Biol. 1998;18:2004-13 pubmed
    ..heat pulses on the protein and mRNA products from the Drosophila circadian clock genes period (per) and timeless (tim)...
  51. Suri V, Qian Z, Hall J, Rosbash M. Evidence that the TIM light response is relevant to light-induced phase shifts in Drosophila melanogaster. Neuron. 1998;21:225-34 pubmed
    ..melanogaster, recent experiments suggest that photic information is transduced to the clock through the timeless gene product, TIM...
  52. Park J, Helfrich Forster C, Lee G, Liu L, Rosbash M, Hall J. Differential regulation of circadian pacemaker output by separate clock genes in Drosophila. Proc Natl Acad Sci U S A. 2000;97:3608-13 pubmed
    ..This posttranslational rhythm is eliminated by period or timeless null mutations, which do not affect PDF staining in cell bodies or pdf mRNA levels...
  53. Kaneko M, Park J, Cheng Y, Hardin P, Hall J. Disruption of synaptic transmission or clock-gene-product oscillations in circadian pacemaker cells of Drosophila cause abnormal behavioral rhythms. J Neurobiol. 2000;43:207-33 pubmed
    ..chemical synaptic transmission, was expressed under the control of promoters of the clock genes period (per) and timeless (tim), each fused to GAL4-encoding sequences...
  54. Martinek S, Young M. Specific genetic interference with behavioral rhythms in Drosophila by expression of inverted repeats. Genetics. 2000;156:1717-25 pubmed
    ..As an example, we show that inverted-repeat-mediated interference with the period gene produces a hypomorphic period phenotype. A selective decrease of period RNA appears to be a component of the cellular response. ..
  55. Lin Y, Han M, Shimada B, Wang L, Gibler T, Amarakone A, et al. Influence of the period-dependent circadian clock on diurnal, circadian, and aperiodic gene expression in Drosophila melanogaster. Proc Natl Acad Sci U S A. 2002;99:9562-7 pubmed
    ..Thus, the period-dependent circadian clock regulates only a limited set of rhythmically expressed transcripts. Unexpectedly, period regulates basal and light-regulated gene expression to a very broad extent. ..
  56. Dunlap J. Molecular bases for circadian clocks. Cell. 1999;96:271-90 pubmed
  57. Giebultowicz J. Peripheral clocks and their role in circadian timing: insights from insects. Philos Trans R Soc Lond B Biol Sci. 2001;356:1791-9 pubmed
    ..Circadian systems in complex animals may include many peripheral clocks with tissue-specific functions and a varying degree of autonomy, which seems to be correlated with their sensitivity to external entraining signals. ..
  58. Froy O, Chang D, Reppert S. Redox potential: differential roles in dCRY and mCRY1 functions. Curr Biol. 2002;12:147-52 pubmed
    ..The data provide a multistep redox model for the light-dependent activities of dCRY and suggest that such a model does not apply to mCRY1 transcriptional responses. ..
  59. Sandrelli F, Tauber E, Pegoraro M, Mazzotta G, Cisotto P, Landskron J, et al. A molecular basis for natural selection at the timeless locus in Drosophila melanogaster. Science. 2007;316:1898-900 pubmed
    ..The ls-tim mutation in the Drosophila melanogaster clock gene timeless has spread in Europe over the past 10,000 years, possibly because it enhances diapause...
  60. Keegan K, Pradhan S, Wang J, Allada R. Meta-analysis of Drosophila circadian microarray studies identifies a novel set of rhythmically expressed genes. PLoS Comput Biol. 2007;3:e208 pubmed
  61. Sehadova H, Glaser F, Gentile C, Simoni A, Giesecke A, Albert J, et al. Temperature entrainment of Drosophila's circadian clock involves the gene nocte and signaling from peripheral sensory tissues to the brain. Neuron. 2009;64:251-66 pubmed publisher
    ..Our work reveals surprising and important mechanistic differences between light- and temperature-synchronization and advances our understanding of how clock resetting is accomplished in nature. ..
  62. Garbe D, Fang Y, Zheng X, Sowcik M, Anjum R, Gygi S, et al. Cooperative interaction between phosphorylation sites on PERIOD maintains circadian period in Drosophila. PLoS Genet. 2013;9:e1003749 pubmed publisher
    Circadian rhythms in Drosophila rely on cyclic regulation of the period (per) and timeless (tim) clock genes...
  63. Lee C, Parikh V, Itsukaichi T, Bae K, Edery I. Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex. Science. 1996;271:1740-4 pubmed
    ..In addition, the recently identified clock protein TIM (for timeless) interacted with PER in vivo, and this association was rapidly decreased by light...
  64. Bae K, Lee C, Sidote D, Chuang K, Edery I. Circadian regulation of a Drosophila homolog of the mammalian Clock gene: PER and TIM function as positive regulators. Mol Cell Biol. 1998;18:6142-51 pubmed
    ..the cycling observed for the RNA products from the Drosophila melanogaster circadian clock genes period (per) and timeless (tim)...
  65. Naidoo N, Song W, Hunter Ensor M, Sehgal A. A role for the proteasome in the light response of the timeless clock protein. Science. 1999;285:1737-41 pubmed
    The cyclic expression of the period (PER) and timeless (TIM) proteins is critical for the molecular circadian feedback loop in Drosophila. The entrainment by light of the circadian clock is mediated by a reduction in TIM levels...
  66. Allada R. Circadian clocks: a tale of two feedback loops. Cell. 2003;112:284-6 pubmed
    ..In Drosophila, the first loop has been well characterized and controls rhythmic period expression. In this issue of Cell, define a role for a transcriptional activator and a repressor in the second feedback loop. ..
  67. Peng Y, Stoleru D, Levine J, Hall J, Rosbash M. Drosophila free-running rhythms require intercellular communication. PLoS Biol. 2003;1:E13 pubmed
    ..Also contrary to expectation, we found that all brain clock neurons manifest robust circadian oscillations of timeless and cryptochrome RNA for many days in DD...
  68. Busza A, Emery Le M, Rosbash M, Emery P. Roles of the two Drosophila CRYPTOCHROME structural domains in circadian photoreception. Science. 2004;304:1503-6 pubmed
    CRYPTOCHROME (CRY) is the primary circadian photoreceptor in Drosophila. We show that CRY binding to TIMELESS (TIM) is light-dependent in flies and irreversibly commits TIM to proteasomal degradation...
  69. Yoshii T, Heshiki Y, Ibuki Ishibashi T, Matsumoto A, Tanimura T, Tomioka K. Temperature cycles drive Drosophila circadian oscillation in constant light that otherwise induces behavioural arrhythmicity. Eur J Neurosci. 2005;22:1176-84 pubmed
    ..cycles drive the circadian rhythm both in locomotor activity and molecular abundance of PERIOD (PER) and TIMELESS (TIM)...
  70. Lim C, Chung B, Pitman J, McGill J, Pradhan S, Lee J, et al. Clockwork orange encodes a transcriptional repressor important for circadian-clock amplitude in Drosophila. Curr Biol. 2007;17:1082-9 pubmed
    ..heterodimer, CLOCK/CYCLE (CLK/CYC), transcriptionally activates the clock components period (per), timeless (tim), Par domain protein 1 (Pdp1), and vrille (vri), which feed back and regulate distinct features of CLK/CYC ..
  71. Fernández M, Berni J, Ceriani M. Circadian remodeling of neuronal circuits involved in rhythmic behavior. PLoS Biol. 2008;6:e69 pubmed publisher
    ..We propose this clock-controlled structural plasticity as a candidate mechanism contributing to the transmission of the information downstream of pacemaker cells. ..
  72. Rouyer F, Rachidi M, Pikielny C, Rosbash M. A new gene encoding a putative transcription factor regulated by the Drosophila circadian clock. EMBO J. 1997;16:3944-54 pubmed
    ..locomotor activity and eclosion in Drosophila depend upon the reciprocal autoregulation of the period (per) and timeless (tim) genes. As part of this regulatory loop, per and tim mRNA levels oscillate in a circadian fashion...
  73. Stanewsky R, Kaneko M, Emery P, Beretta B, Wager Smith K, Kay S, et al. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell. 1998;95:681-92 pubmed
    ..Levels of period or timeless clock gene products in the mutant are flat in daily light-dark cycles or constant darkness (although PER and TIM ..
  74. Leloup J, Goldbeter A. Modeling the molecular regulatory mechanism of circadian rhythms in Drosophila. Bioessays. 2000;22:84-93 pubmed
    ..Modeling is based on the autoregulatory negative feedback exerted by a complex between PER and TIM proteins on the expression of per and tim genes...
  75. Emery P, Stanewsky R, Helfrich Forster C, Emery Le M, Hall J, Rosbash M. Drosophila CRY is a deep brain circadian photoreceptor. Neuron. 2000;26:493-504 pubmed
    ..These brain neurons therefore contain an identified deep brain photoreceptor, as well as the other circadian elements: a central pace-maker and a behavioral output system. ..
  76. Ivanchenko M, Stanewsky R, Giebultowicz J. Circadian photoreception in Drosophila: functions of cryptochrome in peripheral and central clocks. J Biol Rhythms. 2001;16:205-15 pubmed
    ..melanogaster, disruption of night by even short light exposures results in degradation of the clock protein TIMELESS (TIM), leading to shifts in the fly molecular and behavioral rhythms...
  77. Nitabach M, Blau J, Holmes T. Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock. Cell. 2002;109:485-95 pubmed
    ..Pacemaker electrical silencing also stops the free-running oscillation of PERIOD (PER) and TIMELESS (TIM) proteins that constitutes the core of the cell-autonomous molecular clock...
  78. Stanewsky R, Lynch K, Brandes C, Hall J. Mapping of elements involved in regulating normal temporal period and timeless RNA expression patterns in Drosophila melanogaster. J Biol Rhythms. 2002;17:293-306 pubmed
    ..This process is inferred to depend on a function of the PERIOD and TIMELESS proteins, and could further contribute to the observed delay between RNA and protein accumulation...
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    ..CLK has specific targets in different tissues, implying that important CLK partner proteins and/or mechanisms contribute to gene-specific and tissue-specific regulation. ..
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    ..Whereas the period (per), timeless (tim), and dClock (dClk) genes of Drosophila each contribute cycling mRNA and protein to a circadian clock, dbt ..
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    ..Mutations in clock genes in Drosophila melanogaster, period (per), timeless (tim), Clock (Clk), and cycle (cyc), produce multiple phenotypes associated with physiology, behavior, ..
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    ..They also suggest that these mechanisms occur upstream of post-translational events, and that elements of this two-step mechanism likely apply to mammals. ..
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    ..bimodal activity rhythm was absent in the circadian clock mutants Clk(Jrk) and cyc(01) and reduced in per(01) and tim(01) mutants...
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    ..of transcription factors and are required for high-level expression of the circadian clock genes period (per) and timeless (tim)...
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    ..The results taken together indicate that circadian transcription contributes to core circadian function in Drosophila. ..
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    ..the blue-light photoreceptor Cryptochrome (Cry) mediates a rapid light-dependent degradation of the clock protein Timeless (Tim) via the F box protein Jetlag (Jet) and the proteasome, which initiates the resetting of the molecular clock ..
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    ..PP2A also affects PER phosphorylation in vitro and in vivo. We propose that the posttranslational mechanisms that drive cycling of PER require the rhythmic expression of PP2A. ..
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    ..In Drosophila melanogaster, the idea that nuclear entry of PERIOD (PER) is controlled by its partner protein TIMELESS (TIM) has been challenged by several studies...
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    ..The extensive evolutionary conservation of insomniac and Cul3 suggests that protein degradation pathways may have a general role in governing the sleep and wakefulness of animals. ..
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    The timeless protein (TIM) is a central component of the circadian pacemaker machinery of the fruitfly Drosophila melanogaster...