title: Interacting molecular loops in the mammalian circadian clock.
abstract: We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.
authors.affiliation: Laboratory of Developmental Chronobiology, MassGeneral Hospital for Children, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Shearman
authors.forename: S
authors.initials: S
authors.lastname: Sriram
authors.forename: D R
authors.initials: DR
authors.lastname: Weaver
authors.forename: E S
authors.initials: ES
authors.lastname: Maywood
authors.forename: I
authors.initials: I
authors.lastname: Chaves
authors.forename: B
authors.initials: B
authors.lastname: Zheng
authors.forename: K
authors.initials: K
authors.lastname: Kume
authors.forename: C C
authors.initials: CC
authors.lastname: Lee
authors.forename: G T
authors.initials: GT
authors.lastname: van der Horst
authors.forename: M H
authors.initials: MH
authors.lastname: Hastings
authors.forename: S M
authors.initials: SM
authors.lastname: Reppert
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes; D019281:Dimerization; D029721:Drosophila Proteins; D005136:Eye Proteins; D005246:Feedback; D005260:Female; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012313:RNA; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C119828:cry protein, Drosophila; C538944:Clock protein, mouse