Figure 8.

Schematic summary of APE1-redox-mediated NF-κB-DLL1-NOTCH activation in response to ABS in EAC. Exposure to ABS, the in vitro mimic of GERD, increases APE1 protein level and activates APE1-redox-dependent transcription factor, NF-κB, which consequently upregulates DLL1 transcription by directly binding to DLL1 promoter region in the signal sending cells. Accumulated DLL1 protein on cell surface facilitates NOTCH1 cleavage in the signal receiving cells, releasing the active form of NOTCH1 receptor, NICD, which is translocated into cell nucleus, forms transcriptional complex with RBPJ and MAML, and activates transcription of downstream targets like HES1 and HEY1. APE1 redox-specific inhibitor, E3330, effectively blocks this ABS-activated NF-κB/DLL1/NICD signaling axis.