Core circadian protein CLOCK is a positive regulator of NF-κB-mediated transcription

Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2457-65. doi: 10.1073/pnas.1206274109. Epub 2012 Aug 15.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • CLOCK Proteins / metabolism*
  • Circadian Rhythm / physiology*
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology*
  • Gene Expression Regulation / physiology*
  • Humans
  • Immunoprecipitation
  • Luciferases
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Fluorescence
  • Peptides
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic / genetics
  • Transcription, Genetic / physiology*


  • CBLB502
  • Peptides
  • Rela protein, mouse
  • Transcription Factor RelA
  • Luciferases
  • CLOCK Proteins
  • Clock protein, mouse