Loss of cellular homeostasis through exposures to endogenous (e.g., inflammation) and exogenous (e.g., carcinogens) stresses contributes to many diseases including carcinogenesis. The Keap1-Nrf2-ARE signaling pathway evokes an adaptive response to these stresses that serves to enhance cell survival. Through gene expression analyses of the signaling cascade linked to Nrf2, using both Keap1- and Nrf2-disrupted mice, it appears that multiple signaling pathways intersect with Nrf2 signaling. Our research goals are to elucidate novel signaling crosstalk based on genes bearing functional ARE (Nrf2-sMaf recognition enhancer element) in the promoter of target genes and the underlying mechanistic roles of the Keap1-Nrf2 system in protecting against chronic degenerative diseases in vivo. Currently, we are focusing on the role of Nrf2 signaling in tissue repair and regeneration.

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Important Publications

Wakabayashi N, S Shin, S Slocum, ES Agoston, J Wakabayashi, MK Kwak, V Misra, S Biswal, M Yamamoto and TW Kensler.  Regulation of Notch1 signaling by Nrf2:  Implications for tissue regeneration.  Science Signaling3:ra52, 2010.

Wakabayashi N, SL Slocum, JJ Skoko, S Shin and TW Kensler.  When Nrf2 talks, who's listening?  Antioxid Redox Signal 13:1649-1663, 2010.

Shin S, N Wakabayashi, V Misra, S Biswal, GH Lee, ES Agoston, M Yamamoto and TW Kensler.  NRF2 modulates aryl hydrocarbon receptor signaling:  Influence on adipogenesis.  Mol Cell Biol 27:7188-7197, 2007.

Wakabayashi N, AT Dinkova-Kostova, WD Holtzclaw, ML Kang, A Kobayashi, M Yamamoto, TW Kensler and P Talalay.  Protection against electrophile and oxidant stress by induction of the phase 2 response:  Fate of cysteines of the Keap1 sensor modified by inducers.  Proc Natl Acad Sci USA 101:2040-2045, 2004.

Wakabayashi N, K Itoh, J Wakabayashi, H Motohashi, S Noda, S Takahashi, S Imakado, T Kotsuji, F Otsuka, DR Roop, T Harada, JD Engel and M Yamamoto.  Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation.  Nat Genet 35:238-245, 2003.

Itoh K, N Wakabayashi, Y Katoh, T Ishii, K Igarashi, JD Engel and M Yamamoto.  Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.  Genes & Dev 13:76-86, 1999.