Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system

Makoto Kobayashi, Ken Itoh, Takafumi Suzuki, Hitoshi Osanai, Keizo Nishikawa, Yasutake Katoh, Yaeko Takagi, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

289 Citations (Scopus)


Background: The transcription factor Nrf2 and its negative regulator Keap1 play important roles in transcriptional induction of a set of detoxifying and anti-oxidant enzymes. To gain an insight into our present enigma as to how cells receive oxidative and electrophilic signals and transduce them to Nrf2, we have developed a zebrafish model system for molecular toxicological studies. Results: We systematically cloned zebrafish cytoprotective enzyme cDNAs and found their expression to be efficiently induced by electrophilic agents. We consequently identified the presence of Nrf2 and Keap1 in zebrafish. Both loss- and gain-of-function. analyses demonstrated that Nrf2 is the primary regulator of a subset of cytoprotective enzyme genes, while Keap1 suppresses Nrf2 activity in zebrafish. An ETGE motif, critical for the Nrf2-Keap1 interaction, was identified in the Neh2 domain of Nrf2 by reverse two-hybrid screening and found to be indispensable for the regulation of Nrf2 activity in zebrafish. Conclusion: Taken together, these results indicate that the Nrf2-Keap1 system is highly conserved among vertebrates and that the interface between Nrf2 and Keap1 forms an important molecular basis of this regulatory system.

Original languageEnglish
Pages (from-to)807-820
Number of pages14
JournalGenes to Cells
Issue number8
Publication statusPublished - 2002 Aug
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Cell Biology


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