title: Circadian regulation of a Drosophila homolog of the mammalian Clock gene: PER and TIM function as positive regulators.
abstract: The Clock gene plays an essential role in the manifestation of circadian rhythms (approximately 24 h) in mice and is a member of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) superfamily of transcription factors. Here we report the characterization of a novel Drosophila bHLH-PAS protein that is highly homologous to mammalian CLOCK. (Similar findings were recently described by Allada et al. Cell 93:791-804, 1998, and Darlington et al., Science 280:1599-1603, 1998.) Transcripts from this putative Clock ortholog (designated dClock) undergo daily rhythms in abundance that are antiphase to the cycling observed for the RNA products from the Drosophila melanogaster circadian clock genes period (per) and timeless (tim). Furthermore, dClock RNA cycling is abolished and the levels are at trough values in the absence of either PER or TIM, suggesting that these two proteins can function as transcriptional activators, a possibility which is in stark contrast to their previously characterized role in transcriptional autoinhibition. Finally, the temporal regulation of dClock expression is quickly perturbed by shifts in light-dark cycles, indicating that this molecular rhythm is closely connected to the photic entrainment pathway. The isolation of a Drosophila homolog of Clock together with the recent discovery of mammalian homologs of per indicate that there is high structural conservation in the integral components underlying circadian oscillators in Drosophila and mammals. Nevertheless, because mammalian Clock mRNA is constitutively expressed, our findings are a further example of striking differences in the regulation of putative circadian clock orthologs in different species.
authors.affiliation: Graduate Program in Microbiology and Molecular Genetics, Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bae
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Sidote
authors.forename: K Y
authors.initials: KY
authors.lastname: Chuang
authors.forename: I
authors.initials: I
authors.lastname: Edery
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D018076:DNA, Complementary; D003624:Darkness; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs; D019476:Insect Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008027:Light; D008322:Mammals; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D056950:Period Circadian Proteins; D012313:RNA / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018076:DNA, Complementary; D029721:Drosophila Proteins; D019476:Insect Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012313:RNA; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1; C539040:PER protein, Drosophila; C096445:tim protein, Drosophila; C538944:Clock protein, mouse