Mitogen-activated Protein Kinase Phosphorylates and Negatively Regulates Basic Helix-Loop-Helix-PAS Transcription Factor BMAL1

• Published in: The Journal of biological chemistry Vol. 277; no. 1; pp. 267 - 271
• Main Authors: Sanada, Kamon, Okano, Toshiyuki, Fukada, Yoshitaka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2002; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; ARNTL Transcription Factors; Basic Helix-Loop-Helix Transcription Factors; BMAL1 protein; circadian clocks; CLOCK protein; CLOCK Proteins; Helix-Loop-Helix Motifs; Mitogen-Activated Protein Kinases - physiology; Molecular Sequence Data; Phosphorylation; Trans-Activators - physiology; Transcription Factors - chemistry; Transcription Factors - metabolism; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M107850200

In vertebrates, mitogen-activated protein kinase (MAPK) exhibits circadian activation in several clock structures and likely participates in the timekeeping mechanism of the circadian clock. Here we show that MAPK associates with a basic helix-loop-helix-PAS transcription factor BMAL1, a positive regulator for the autoregulatory feedback loop of the circadian oscillator. MAPK phosphorylates BMAL1 at multiple sites, including Ser-527, Thr-534, and Ser-599, in vitro, and BMAL1:CLOCK-induced transactivation from the E-box element is inhibited by expression of a constitutive active form of MAPK kinase in 293 cells. The inhibitory effect is reversed by coexpression of the kinase-dead mutant of MAPK or by mutation of BMAL1 at Thr-534. These results indicate that BMAL1:CLOCK-induced transcription is negatively regulated by MAPK-mediated phosphorylation of BMAL1 at Thr-534 and suggest a molecular link between circadian-activated MAPK and the clock oscillator.