title: Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2.
abstract: Transcriptional regulation appears to be fundamental to circadian oscillations of clock gene expression. These oscillations are believed to control output rhythms. The transcriptional feedback loop and a model of interlocked loops have been proposed as the basis for these oscillations. We characterized the genomic structure of the mouse Bmal1 gene (mBmal1) and defined the mBmal1 promoter region. Transcription of mBmal1 was activated by CRY1, CRY2, and PER2, and was repressed by BMAL1-CLOCK dimers. Therefore, CRY, PER2, and BMAL1-CLOCK play bidirectional roles in transcription when they are at high levels by late day and midnight, respectively. This underlies the opposite phase of BMAL1 compared to CRY and PER. We propose that a BMAL1 negative feedback loop interlocks with the CRY and PER2 negative feedback loop by inter-activation, forming a third positive forward loop. This transcriptional model suggests a molecular basis for the maintenance of stability, persistence, and period of circadian rhythms. The transcriptional potency of CRY is predominant within the mammalian clock, suggesting a clearance mechanism for CRY in period maintenance. (c)2002 Elsevier Science (USA).
authors.affiliation: Department of Physiology, Saitama Medical School, 38 Morohongo, Moroyama, Saitama, 350-0495, Japan.
authors.forename: Wangjie
authors.initials: W
authors.lastname: Yu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nomura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D016475:3T3 Cells; D056930:ARNTL Transcription Factors; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm; D056931:Cryptochromes; D015536:Down-Regulation; D029721:Drosophila Proteins; D005136:Eye Proteins; D025461:Feedback, Physiological; D005420:Flavoproteins / Q000502:physiology*; D017930:Genes, Reporter; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
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; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; C513312:Per2 protein, mouse; C119828:cry protein, Drosophila; C538944:Clock protein, mouse