Core circadian protein CLOCK is a positive regulator of NF-κB-mediated transcription.
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.
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Mary L
ML
Spengler
Karen K
KK
Kuropatwinski
Maria
M
Comas
Alexander V
AV
Gasparian
Natalia
N
Fedtsova
Anatoli S
AS
Gleiberman
Ilya I
II
Gitlin
Natalia M
NM
Artemicheva
Krysta A
KA
Deluca
Andrei V
AV
Gudkov
Marina P
MP
Antoch
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000378:metabolism*; D002940:Circadian Rhythm / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D010455:Peptides; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*
C528306:CBLB502; D010455:Peptides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D008156:Luciferases; D056926:CLOCK Proteins; C538944:Clock protein, mouse