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Title: The Regulation of Nuclear Factor Erythroid-Derived 2- Related Factor 2 (NRF2) in the Phase 2 Response
Keywords: Nrf2, Keap1, Cullin3, antioxidant response, oxidative stress, cancer chemoprevention
Issue Date: 22-Aug-2014
Citation: WONG PEI WEN, DAPHNE (2014-08-22). The Regulation of Nuclear Factor Erythroid-Derived 2- Related Factor 2 (NRF2) in the Phase 2 Response. ScholarBank@NUS Repository.
Abstract: The detrimental effects of oxidative stress has been linked to major diseases such as cancer and neurodegenerative diseases. Oxidative stress can be sensed by the Keap1-Nrf2 system in the cell, which triggers cytoprotection via the phase 2 response. Nrf2, a transcription factor, binds to the antioxidant response element (ARE) to induce the expression of phase 2 detoxifying and antioxidant enzymes. Nrf2 is regulated at the protein level by Keap1, a substrate receptor for the Cullin3 E3 ubiquitin ligase. Binding of Keap1 to Nrf2 facilitates the Cullin3-mediated ubiquitination and subsequent degradation of Nrf2. Nrf2 inducers form adducts at critical cysteine residues on Keap1 to inhibit Keap1-dependent ubiquitination of Nrf2. In this study, we investigate a novel Nrf2 inducer, andrographolide which targets cysteine151 of Keap1. We have also identified a class of quinol compounds as Nrf2 inducers that function independently of cysteine151. We propose that cysteine151-independent Nrf2 inducers function via a novel mechanism involving an increase in Keap1-Cullin3 interaction. In addition, we also demonstrated the presence of a potential novel Nrf2 inducer in the organic extract of a fungal endophyte, Phomopsis sp.. The characterization of the regulation of Nrf2 would provide useful approaches in the treatment of oxidative stress-related diseases.
Appears in Collections:Ph.D Theses (Open)

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