title: Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm.
abstract: Glucocorticoid (GC) signaling synchronizes the circadian rhythm of individual peripheral cells and induces the expression of circadian genes, including Period1 (Per1) and Period2 (Per2). However, no GC response element (GRE) has been reported in the Per2 promoter region. Here we report the molecular mechanisms of Per2 induction by GC signaling and its relevance to the regulation of circadian timing. We found that GC prominently induced Per2 expression and delayed the circadian phase. The overlapping GRE and E-box (GE2) region in the proximal Per2 promoter was responsible for GC-mediated Per2 induction. The GRE in the Per2 promoter was unique in that brain and muscle ARNT-like protein-1 (BMAL1) was essential for GC-induced Per2 expression, whereas other GRE-containing promoters, such as Per1 and mouse mammary tumor virus, responded to dexamethasone in the absence of BMAL1. This specialized regulatory mechanism was mediated by BMAL1-dependent binding of the GC receptor to GRE in Per2 promoter. When Per2 induction was abrogated by the mutation of the GRE or E-box, the circadian oscillation phase failed to be delayed compared with that of the wild-type. Therefore, the current study demonstrates that the rapid Per2 induction mediated by GC is crucial for delaying the circadian rhythm.
authors.affiliation: Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
authors.forename: Solmi
authors.initials: S
authors.lastname: Cheon
authors.forename: Noheon
authors.initials: N
authors.lastname: Park
authors.forename: Sehyung
authors.initials: S
authors.lastname: Cho
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D056930:ARNTL Transcription Factors / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D017124:Conserved Sequence; D003907:Dexamethasone / Q000494:pharmacology; D024721:E-Box Elements; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D055029:Inverted Repeat Sequences; D051379:Mice; D008969:Molecular Sequence Data; D056950:Period Circadian Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020218:Response Elements; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D005938:Glucocorticoids; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone