Jump to Main Content
Core circadian protein CLOCK is a positive regulator of NF-κB–mediated transcription
- Spengler, Mary L., Kuropatwinski, Karen K., Comas, Maria, Gasparian, Alexander V., Fedtsova, Natalia, Gleiberman, Anatoli S., Gitlin, Ilya I., Artemicheva, Natalia M., Deluca, Krysta A., Gudkov, Andrei V., Antoch, Marina P.
- Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.37 pp. E2457
- animal models, circadian rhythm, fibroblasts, genes, hepatocytes, immune response, immunomodulators, linkage (genetics), mice, mutation, pathogens, transcription (genetics), transcription factor NF-kappa B, transcriptional activation
- The circadian clock controls many physiological parameters including immune response to infectious agents, which is mediated by activation of the transcription factor NF-κB. It is widely accepted that circadian regulation is based on periodic changes in gene expression that are triggered by transcriptional activity of the CLOCK/BMAL1 complex. Through the use of a mouse model system we show that daily variations in the intensity of the NF-κB response to a variety of immunomodulators are mediated by core circadian protein CLOCK, which can up-regulate NF-κB–mediated transcription in the absence of BMAL1; moreover, BMAL1 counteracts the CLOCK-dependent increase in the activation of NF-κB–responsive genes. Consistent with its regulatory function, CLOCK is found in protein complexes with the p65 subunit of NF-κB, and its overexpression correlates with an increase in specific phosphorylated and acetylated transcriptionally active forms of p65. In addition, activation of NF-κB in response to immunostimuli in mouse embryonic fibroblasts and primary hepatocytes isolated from Clock -deficient mice is significantly reduced compared with WT cells, whereas Clock -Δ19 mutation, which reduces the transactivation capacity of CLOCK on E-box–containing circadian promoters, has no effect on the ability of CLOCK to up-regulate NF-κB–responsive promoters. These findings establish a molecular link between two essential determinants of the circadian and immune mechanisms, the transcription factors CLOCK and NF-κB, respectively.