title: Inducible cAMP early repressor regulates the Period 1 gene of the hepatic and adrenal clocks.
abstract: Light, restricted feeding, and hormonal inputs may operate as time givers (zeitgebers) for the circadian clock within peripheral organs through the activation of tissue-specific signaling cascades. cAMP signaling through CREM (cAMP-responsive element modulator) and its variant ICER (inducible cAMP early repressor) is linked to the circadian regulation of pineal melatonin synthesis, although little is known about its influence in other organs. We performed experiments in the absence of light and feeding-time cues to test which core clock genes are controlled by CREM/ICER in the liver and adrenal gland. In vivo, Crem loss-of-function mutation resulted in fine-tuning of all measured adrenal clock genes (Per1/2/3, Cry1/2, Bmal1, and Rev-erbα), whereas only Per1 and Cry1 were affected in the liver. Icer expression was circadian in the adrenal gland, with peak gene expression at zeitgeber 12 and the highest protein levels at zeitgeber ∼20. The expression of both Icer and Per1 genes responded to cAMP stimuli in an immediate-early fashion. In immortal cells, forskolin induced expression of Per1 after 2 h, and de novo protein synthesis led to Per1 attenuation. We show that the de novo synthesized protein responsible for Per1 attenuation is ICER. Indeed, Per1 expression is up-regulated in cells ectopically expressing antisense Icer, and mobility shift experiments identified ICER binding to cAMP-responsive elements of the Per1 promoter. We propose that ICER acts as a noise filter for different signals that could affect transcription in the adrenal gland. Because ICER is an immediate-early repressor, the circadian nature of adrenal Icer expression could serve a role in a time-dependent gating mechanism.
authors: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
authors: Uršula Prosenc
authors: UP
authors: Zmrzljak
authors: Anja
authors: A
authors: Korenčič
authors: Rok
authors: R
authors: Košir
authors: Marko
authors: M
authors: Goličnik
authors: Paolo
authors: P
authors: Sassone-Corsi
authors: Damjana
authors: D
authors: Rozman
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000502:physiology; D056950:Period Circadian Proteins / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis / Q000502:physiology
chemical_list: C497411:Crem protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP