CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

Abstract

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 Rbpjκ 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 Rbpjκ 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.

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

“…Recent literature suggests a cross talk between the NRF2 and Notch signaling pathways . We also showed that expression of both NICD1 and HES1 in oral squamous epithelial cells were regulated by NRF2, consistent with previous findings in hematopoietic stem cells, airway basal stem cells, and mouse embryonic fibroblasts .…”

Context‐dependent function of ROS in the vascular endothelium: The role of the Notch pathway and shear stress

“…Nuclear factor (erythroid‐derived2)‐like 2 (Nrf2) is a transcription factor activated by ROS that regulates the expression of antioxidant proteins protecting against oxidative damage triggered by injury and inflammation. The interaction between Notch and Nfr2 is well known and appears to be crucial in many biological contexts as recently reviewed by Wakabayashi et al . In the endothelium it has been shown that Nfr2 can positively regulate the endothelial cells sprouting and vascularization by suppressing DII4/Notch4 pathway , thus suggesting that ROS can modulate Notch via Nfr2.…”

Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals

“…In the downstream, ATF4 is found to be an interacting protein of Nrf2 , and Nrf2 is a positive regulator of ATF4 . Both Notch1 and HIF‐1α pathways can be regulated by Nrf2 .…”