Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism

  1. Shigeru Mitsui1,3,
  2. Shun Yamaguchi1,3,
  3. Takuya Matsuo1,2,
  4. Yoshiki Ishida1, and
  5. Hitoshi Okamura1,4
  1. 1Department of Anatomy and Brain Science, Kobe University School of Medicine, Chuo-ku, Kobe 650-0017, Japan; 2Department of Physics, Informatics and Biology, Yamaguchi University, Yamaguchi 753-8512, Japan

Abstract

E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tefrhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. Moreover, all PAR proteins activate, whereas E4BP4 suppresses, the transcriptional activity of the reporter gene containing a common binding sequence in transcriptional assays in vitro. An electrophoretic mobility shift assay demonstrated that E4BP4 is not able to dimerize with the PAR proteins, but is able to compete for the same binding sites with them. Furthermore, we showed sustained low e4bp4 and high dbp mRNA levels inmCry-deficient mice. These results indicate that the E4BP4 and PAR proteins are paired components of a reciprocating mechanism wherein E4BP4 suppresses the transcription of target genes during the time of day when E4BP4 is abundant, and the PAR proteins activate them at another time of day. E4BP4 and the PAR proteins may switch back and forth between the on-off conditions of the target genes.

Keywords

Footnotes

  • 3 These authors contributed equally to this work.

  • 4 Corresponding author.

  • E-MAIL okamurah{at}kobe-u.ac.jp; FAX 81-78-382-5341.

  • Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.873501.

    • Received December 13, 2000.
    • Accepted February 14, 2001.
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