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2015 ; 88
(Pt B
): 158-167
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Crosstalk between Nrf2 and Notch signaling
#MMPMID26003520
Wakabayashi N
; Chartoumpekis DV
; Kensler TW
Free Radic Biol Med
2015[Nov]; 88
(Pt B
): 158-167
PMID26003520
show ga
The transcription factor Nrf2 (nuclear factor, erythroid derived 2, like 2)
belongs to the CNC-bZip protein family, forming a transcriptosome with its direct
heterodimer partner, sMaf, and co-factors such as CBP/p300. Nrf2 binds to one or
more AREs (antioxidant response elements) that are located in the gene regulatory
regions of the hundreds of Nrf2 target genes. The AREs are key enhancers that are
activated in response to endogenous or exogenous stresses to maintain cellular
and tissue homeostasis. Data emanating from gene expression microarray analyses
comparing Nrf2-disrupted and wild-type mouse embryonic fibroblasts (MEF) showed
that expression of Notch1 and Notch-signaling-related genes were decreased in
Nrf2-disrupted cells. This observation triggered our research on Nrf2-Notch
crosstalk. A functional ARE has been identified upstream of the Notch1 major
transcription start site. Furthermore, an Rbpj? binding site is conserved on the
promoters of Nrf2 among animal species. Notch1 is one of the transmembrane Notch
family receptors that drive Notch signaling, together with the Rbpj?
transcription factor. After canonically accepting ligands such as Jags and
Deltas, the receptor undergoes cleavage to yield the Notch intracellular domain,
which translocates to the nucleus. Recent studies using conditional knockout mice
indicate that Notch1 as well as Notch2 plays an important role postnatally in
liver development and in maintenance of hepatic function. In this review, we
summarize current understanding of the role of reciprocal transcriptional
regulation between Nrf2 and Notch in adult liver from studies using Nrf2, Keap1,
and Notch1 genetically engineered mice.
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