A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer

Kazuhiro Sogawa, Keiko Numayama-Tsuruta, Tomohiro Takahashi, Natsuki Matsushita, Chisa Miura, Jun Ichi Nikawa, Osamu Gotoh, Yasuo Kikuchi, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

Abstract

We have identified an enhancer responsible for induction by 3-methylcholanthrene in the upstream region of the CYP1A2 gene. The enhancer does not contain the invariant core sequence of XREs that are binding sites for the Ah receptor (AhR) and Arnt heterodimer. The enhancer did not show any inducible expression in Hepa-1-derived cell lines, C4 and C12, deficient of Arnt and AhR, respectively. On the other hand, bacterially expressed AhR-Arnt heterodimer could not bind to the enhancer. Mutational analysis of the enhancer revealed that a repeated sequence separated by six nucleotides is important for expression. A factor binding specifically to the enhancer was found by using gel shift assays. Bacterially expressed AhR-Arnt heterodimer interacted with the factor. A dominant negative mutant of the AhR to XRE activated the enhancer. Collectively, these results demonstrate that a novel induction mechanism is present in which the AhR-Arnt heterodimer functions as a coactivator.

Original languageEnglish
Pages (from-to)746-755
Number of pages10
JournalBiochemical and biophysical research communications
Volume318
Issue number3
DOIs
Publication statusPublished - 2004 Jun 4

Keywords

  • Ah receptor
  • Arnt
  • CYP1A2
  • Coactivator
  • Enhancer
  • Inducible expression
  • Xenobiotic response

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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