Notch-Nrf2 axis: Regulation of Nrf2 gene expression and cytoprotection by notch signaling

Nobunao Wakabayashi, John J. Skoko, Dionysios V. Chartoumpekis, Shoko Kimura, Stephen L. Slocum, Kentaro Noda, Dushani L. Palliyaguru, Masahiro Fujimuro, Patricia A. Boley, Yugo Tanaka, Norihisa Shigemura, Shyam Biswal, Masayuki Yamamoto, Thomas W. Kensler

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65 Citations (Scopus)

Abstract

The Notch signaling pathway enables regulation and control of development, differentiation, and homeostasis through cell-cell communication. Our investigation shows that Notch signaling directly activates the Nrf2 stress adaptive response pathway through recruitment of the Notch intracellular domain (NICD) transcriptosome to a conserved Rbpj site in the promoter of Nrf2. Stimulation of Notch signaling through Notch ligand expression in cells and by overexpression of the NICD in RosaNICD/-::AlbCre mice in vivo induces expression of Nrf2 and its target genes. Continuous and transient NICD expression in the liver produces a Notch-dependent cytoprotective response through direct transcriptional activation of Nrf2 signaling to rescue mice from acute acetaminophen toxicity. This response can be reversed upon genetic disruption of Nrf2. Morphological studies showed that the characteristic phenotype of high-density intrahepatic bile ducts and enlarged liver in RosaNICD/-::AlbCre mice could be at least partially reversed after Nrf2 disruption. Furthermore, the liver and bile duct phenotypes could be recapitulated with constitutive activation of Nrf2 signaling in Keap1F/F::AlbCre mice. It appears that Notch-to-Nrf2 signaling is another important determinant in liver development and function and promotes cell-cell cytoprotective signaling responses.

Original languageEnglish
Pages (from-to)653-663
Number of pages11
JournalMolecular and cellular biology
Volume34
Issue number4
DOIs
Publication statusPublished - 2014 Feb 1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Wakabayashi, N., Skoko, J. J., Chartoumpekis, D. V., Kimura, S., Slocum, S. L., Noda, K., Palliyaguru, D. L., Fujimuro, M., Boley, P. A., Tanaka, Y., Shigemura, N., Biswal, S., Yamamoto, M., & Kensler, T. W. (2014). Notch-Nrf2 axis: Regulation of Nrf2 gene expression and cytoprotection by notch signaling. Molecular and cellular biology, 34(4), 653-663. https://doi.org/10.1128/MCB.01408-13