Regulation of notch1 signaling by nrf2: implications for tissue regeneration.
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.
Wakabayashi
Nobunao
N
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. nw99@pitt.edu
Shin
Soona
S
Slocum
Stephen L
SL
Agoston
Elin S
ES
Wakabayashi
Junko
J
Kwak
Mi-Kyoung
MK
Misra
Vikas
V
Biswal
Shyam
S
Yamamoto
Masayuki
M
Kensler
Thomas W
TW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000975:Antioxidants; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006498:Hepatectomy; D000072019:Kelch-Like ECH-Associated Protein 1; D008115:Liver Regeneration; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020239:Receptor Cross-Talk; D051881:Receptor, Notch1 / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1