Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1.
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.[1]References
- Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1. Sanada, K., Okano, T., Fukada, Y. J. Biol. Chem. (2002) [Pubmed]
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