title: cAMP-response element (CRE)-mediated transcription by activating transcription factor-4 (ATF4) is essential for circadian expression of the Period2 gene.
abstract: Activating transcription factor (ATF)/cAMP-response element (CRE)-binding (CREB) proteins induce the CRE-mediated gene transcription depending on the cAMP stimulation. cAMP-dependent signaling oscillates in a circadian manner, which in turn also sustains core oscillation machinery of the circadian clock. Here, we show that among the ATF/CREB family proteins, ATF4 is essential for the circadian expression of the Period2 (Per2) gene, a key component of the circadian clock. Transcription of the Atf4 gene was regulated by core components of the circadian clock, and its expression exhibited circadian oscillation in mouse tissues as well as embryonic fibroblasts. ATF4 bound to the CRE of the Per2 promoter in a circadian time-dependent manner and periodically activated the transcription of the Per2 gene. Consequently, the oscillation of the Per2 expression was attenuated in embryonic cells prepared from Atf4-null mice. Furthermore, the loss of ATF4 also disrupted the rhythms in the expression of other clock genes. These results suggest that ATF4 is a component responsible for sustaining circadian oscillation of CRE-mediated gene expression and also constitute a molecular link connecting cAMP-dependent signaling to the circadian clock.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Hamdan
authors.forename: Michiko
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Kusunose
authors.forename: Akinori
authors.initials: A
authors.lastname: Okamoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000502:physiology*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C081452:Atf4 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D051701:Activating Transcription Factor 4; D000242:Cyclic AMP