title: Role of the CLOCK protein in the mammalian circadian mechanism.
abstract: The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor-binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA. 02115, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gekakis
authors.forename: D
authors.initials: D
authors.lastname: Staknis
authors.forename: H B
authors.initials: HB
authors.lastname: Nguyen
authors.forename: F C
authors.initials: FC
authors.lastname: Davis
authors.forename: L D
authors.initials: LD
authors.lastname: Wilsbacher
authors.forename: D P
authors.initials: DP
authors.lastname: King
authors.forename: J S
authors.initials: JS
authors.lastname: Takahashi
authors.forename: C J
authors.initials: CJ
authors.lastname: Weitz
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005246:Feedback; D015870:Gene Expression; D018257:Helix-Loop-Helix Motifs; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056950:Period Circadian Proteins; D011401:Promoter Regions, Genetic; D012160:Retina / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D004247:DNA; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C538944:Clock protein, mouse