Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy.

Nrf2 is the key transcription factor for cytoprotective gene programs. Nrf2 is normally maintained at very low concentrations by proteasomal degradation, through its interaction with the adapter protein Keap1 and the Cul3 E3 ligase. Increased Nrf2 concentration resulting from loss of function Keap1 mutations has been described in chemoresistant non-small cell lung cancer.

Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.

The aryl hydrocarbon receptor (AHR) and NF-E2 p45-related factor (NRF2) are two distinct transcription factors involved in the regulation of drug-metabolizing enzymes. Increasing evidence from several studies implies that AHR and NRF2 have direct links, but the molecular mechanism remains unknown. In this work we demonstrate for the first time that Nrf2 gene transcription is directly modulated by AHR activation.

A cell-based system to identify and characterize the molecular mechanism of drug-metabolizing enzyme (DME) modulators.

Many naturally occurred or synthetic compounds can modulate the body's drug-metabolizing enzymes to enhance carcinogen detoxification, and some have demonstrated remarkable cancer prevention effects. Understanding the molecular mechanism behind each candidate agent is critically important in designing rational cancer chemoprevention strategies. In this work, we have employed a set of molecular mechanism-based assays and characterized eight classes of known drug-metabolizing enzyme (DME) modulators in a cellular system.

Oltipraz is a bifunctional inducer activating both phase I and phase II drug-metabolizing enzymes via the xenobiotic responsive element.

Oltipraz, a promising cancer chemopreventive agent, has been recognized as a monofunctional inducer selectively activating phase II carcinogen-detoxifying enzymes via the antioxidant responsive element (ARE). However, we report here that oltipraz also induces rat glutathione S-transferase A5 (GSTA5), a potent phase II detoxifying enzyme, by means of the xenobiotic responsive element (XRE). Although an ARE sequence exists in the 5' upstream of the rGSTA5 gene, this cis-acting regulatory element loses its responsiveness to oltipraz treatment because of extensive mutations in its distal-half site.