Crosstalk between Nrf2 and Notch signaling #MMPMID26003520
Wakabayashi N; Chartoumpekis DV; Kensler TW
Free Radic Biol Med 2015[Nov]; 88 (0 0): 158-67 PMID26003520show 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 ARE (Antioxidant Response Element) that are located in the gene regulatory regions of the hundreds of Nrf2 target genes. The ARE is a key enhancer that is activated in response to endogenous or exogenous stresses in order 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, which drives 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 play important roles 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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Free+Radic+Biol+Med 2015 ; 88 (0 0): 158-67
