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Sci. Signal., 13 July 2010
Vol. 3, Issue 130, p. ra52
[DOI: 10.1126/scisignal.2000762]


Regulation of Notch1 Signaling by Nrf2: Implications for Tissue Regeneration

Nobunao Wakabayashi1*{dagger}, Soona Shin2, Stephen L. Slocum3, Elin S. Agoston2{ddagger}, Junko Wakabayashi1§, Mi-Kyoung Kwak4, Vikas Misra1||, Shyam Biswal1, Masayuki Yamamoto5, and Thomas W. Kensler1,2*

1 Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
2 Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
3 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
4 College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Gyeongsan-si, Gyeongsangbuk-do 712-749, South Korea.
5 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.

* Present address: Department of Pharmacology and Chemical Biology, BSTWR E1316, University of Pittsburgh, Pittsburgh, PA 15261, USA.

{ddagger} Present address: Brigham and Women’s Hospital, Department of Pathology, Division of Women’s and Perinatal Pathology, Boston, MA 02115, USA.

§ Present address: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

|| Present address: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Abstract: The Keap1-Nrf2-ARE signaling pathway elicits an adaptive response for cell survival after endogenous and exogenous stresses, such as inflammation and carcinogens, respectively. Keap1 inhibits the transcriptional activation activity of Nrf2 (p45 nuclear factor erythroid-derived 2–related factor 2) in unstressed cells by facilitating its degradation. Through transcriptional analyses in Keap1- or Nrf2-disrupted mice, we identified interactions between the Keap1-Nrf2-ARE and the Notch1 signaling pathways. We found that Nrf2 recognized a functional antioxidant response element (ARE) in the promoter of Notch1. Notch1 regulates processes such as proliferation and cell fate decisions. We report a functional role for this cross talk between the two pathways and show that disruption of Nrf2 impeded liver regeneration after partial hepatectomy and was rescued by reestablishment of Notch1 signaling.

{dagger} To whom correspondence should be addressed. E-mail: nw99{at}

Citation: N. Wakabayashi, S. Shin, S. L. Slocum, E. S. Agoston, J. Wakabayashi, M.-K. Kwak, V. Misra, S. Biswal, M. Yamamoto, T. W. Kensler, Regulation of Notch1 Signaling by Nrf2: Implications for Tissue Regeneration. Sci. Signal. 3, ra52 (2010).

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