TY - JOUR
T1 - Notch-Nrf2 axis
T2 - Regulation of Nrf2 gene expression and cytoprotection by notch signaling
AU - Wakabayashi, Nobunao
AU - Skoko, John J.
AU - Chartoumpekis, Dionysios V.
AU - Kimura, Shoko
AU - Slocum, Stephen L.
AU - Noda, Kentaro
AU - Palliyaguru, Dushani L.
AU - Fujimuro, Masahiro
AU - Boley, Patricia A.
AU - Tanaka, Yugo
AU - Shigemura, Norihisa
AU - Biswal, Shyam
AU - Yamamoto, Masayuki
AU - Kensler, Thomas W.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.01408-13
DO - 10.1128/MCB.01408-13
M3 - Article
C2 - 24298019
AN - SCOPUS:84892956594
SN - 0270-7306
VL - 34
SP - 653
EP - 663
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 4
ER -