|ZFIN ID: ZDB-PUB-020820-4|
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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.
|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|
|PubMed:||12167159 Full text @ Genes Cells|
Kobayashi, M., Itoh, K., Suzuki, T., Osanai, H., Nishikawa, K., Katoh, Y., Takagi, Y., and Yamamoto, M. (2002) Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes to cells : devoted to molecular & cellular mechanisms. 7(8):807-820.
ABSTRACTBACKGROUND: 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.