ZFIN ID: ZDB-PUB-020820-4
Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system
Kobayashi, M., Itoh, K., Suzuki, T., Osanai, H., Nishikawa, K., Katoh, Y., Takagi, Y., and Yamamoto, M.
Date: 2002
Source: Genes to cells : devoted to molecular & cellular mechanisms   7(8): 807-820 (Journal)
Registered Authors: Kobayashi, Makoto, Nakajima-Takagi, Yaeko, Nishikawa, Keizo, Osanai, Hitoshi, Suzuki, Takafumi, Yamamoto, Masayuki
Keywords: none
MeSH Terms:
  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Carrier Proteins/chemistry
  • Carrier Proteins/genetics*
  • Carrier Proteins/physiology
  • Cytoskeletal Proteins*
  • DNA Primers
  • DNA, Complementary
  • DNA-Binding Proteins/chemistry
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/physiology
  • Hydroquinones/pharmacology
  • Mice
  • Molecular Sequence Data
  • NF-E2-Related Factor 2
  • Phylogeny*
  • Sequence Homology, Amino Acid
  • Trans-Activators/chemistry
  • Trans-Activators/genetics*
  • Trans-Activators/physiology
  • Zebrafish
  • Zebrafish Proteins
PubMed: 12167159 Full text @ Genes Cells
ABSTRACT
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.
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