Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

• Published in: The Journal of biological chemistry 2013-04, Vol.288 (15), p.10318-10327
• Main Authors: Zmrzljak, Uršula Prosenc, Korenčič, Anja, Košir, Rok, Goličnik, Marko, Sassone-Corsi, Paolo, Rozman, Damjana
• Format: Article
• Language: English
• Subjects: Adrenal; Adrenal Glands - cytology; Adrenal Glands - metabolism; Animals; Cell Line, Tumor; Circadian Clocks - physiology; Circadian Rhythms; Clock Genes; Crem Knock-out Mice; Cryptochromes - genetics; Cryptochromes - metabolism; Cyclic AMP (cAMP); Cyclic AMP - genetics; Cyclic AMP - metabolism; Cyclic AMP Response Element Modulator - genetics; Cyclic AMP Response Element Modulator - metabolism; Gene Expression Regulation - physiology; Gene Regulation; ICER; Liver; Liver - cytology; Liver - metabolism; Mice; Mice, Knockout; Organ Specificity - physiology; Per1; Period Circadian Proteins - biosynthesis; Period Circadian Proteins - genetics; Protein Biosynthesis - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.445692

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. Background: We investigated the role of cAMP signaling (Crem and its splice variant Icer) in liver and adrenal clocks. Results: cAMP signaling fine-tunes adrenal clock genes, whereas the hepatic effect is minimal. ICER regulates Per1 by binding to its promoter. Conclusion:Icer fine-tunes clock gene expression in the absence of light and feeding cues. Significance: ICER is a circadian signal mediator.