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PNAS 109 (37): 2457-2465

Copyright © 2012 by the National Academy of Sciences.

PNAS Plus


PNAS PLUS / BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Core circadian protein CLOCK is a positive regulator of NF-{kappa}B–mediated transcription

Mary L. Spenglera, Karen K. Kuropatwinskia, Maria Comasa, Alexander V. Gasparianb,1, Natalia Fedtsovac, Anatoli S. Gleibermanb, Ilya I. Gitlinc, Natalia M. Artemichevac,2, Krysta A. Delucaa,3, Andrei V. Gudkovc, and Marina P. Antocha,4

Departments of aMolecular and Cellular Biology and cCell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263; and b Cleveland BioLabs, Inc., Buffalo, NY 14263

4To whom correspondence should be addressed. E-mail: marina.antoch{at}roswellpark.org.

Abstract: The circadian clock controls many physiological parameters including immune response to infectious agents, which is mediated by activation of the transcription factor NF-{kappa}B. 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-{kappa}B response to a variety of immunomodulators are mediated by core circadian protein CLOCK, which can up-regulate NF-{kappa}B–mediated transcription in the absence of BMAL1; moreover, BMAL1 counteracts the CLOCK-dependent increase in the activation of NF-{kappa}B–responsive genes. Consistent with its regulatory function, CLOCK is found in protein complexes with the p65 subunit of NF-{kappa}B, and its overexpression correlates with an increase in specific phosphorylated and acetylated transcriptionally active forms of p65. In addition, activation of NF-{kappa}B 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-{Delta}19 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-{kappa}B–responsive promoters. These findings establish a molecular link between two essential determinants of the circadian and immune mechanisms, the transcription factors CLOCK and NF-{kappa}B, respectively.


 

Conflict of interest statement: A. V. Gudkov is a co-founder and a shareholder of Cleveland Biolabs, Inc., the company that is developing CBLB502 for medical and biodefense applications.

This article is a PNAS Direct Submission.

See full research article on page E2457 of www.pnas.org.

Cite this Author Summary as: PNAS 10.1073/pnas.1206274109.


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