p53 regulates Period2 expression and the circadian clock.
The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2), a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter, leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviourally, p53⁻/⁻ mice have a shorter period length that lacks stability, and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behaviour.
1] Department of Biochemistry and Molecular Biology, Medical School, University of Texas Health Science Center-Houston, Houston, Texas 77030, USA [2].
Takao
T
Miki
Tomoko
T
Matsumoto
Zhaoyang
Z
Zhao
Cheng Chi
CC
Lee
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001665:Binding Sites; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008027:Light; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D014796:Visual Perception
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D007093:Imidazoles; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D056926:CLOCK Proteins; C538944:Clock protein, mouse