Cross-talk between Transcription Factors AhR and Nrf2: Lessons for Cancer Chemoprevention from Dioxin

Extract

Throughout life, humans are subjected episodically to numerous stressors, including ultraviolet irradiation, products of combustion, pesticides, herbicides, heavy metals, and other environmental pollutants, as well as various toxicants ingested in food, such as phytochemicals in edible plants; pyrolysis products in cooked meat; and mycotoxin contaminants in cereals, nuts, and maize. To ensure survival in the face of such challenges, mammalian cells have evolved a variety of inducible genetic programs that enable them to adapt to the presence of harmful xenobiotics. These programs entail upregulation of discrete batteries of genes for drug-metabolizing enzymes, drug transporters, and various cytoprotective proteins that allow an increased rate of xenobiotic elimination from the body, restoration of normal homeostasis, and removal of damaged macromolecules. Among transcription factors that mediate adaptation to foreign compounds, the aryl hydrocarbon receptor (AhR) and nuclear factor-erythroid 2–related factor 2 (Nrf2) have been widely studied. It is well established that the AhR is responsible for induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs) of genes that contain a xenobiotic response element (XRE, also sometimes called a dioxin response element) in their promoter regions. It is also clear that Nrf2 is responsible for induction by structurally diverse electrophiles and quinones of genes that contain an antioxidant response element (ARE, also sometimes called an electrophile response element) in their promoter regions. For many years, the pathways leading to induction of XRE-driven genes and induction of ARE-driven genes were thought to be entirely separate. In particular, TCDD was assumed to activate transcription essentially only through the XRE. In the highlighted paper, however, Klaassen and colleagues have presented strong in vivo evidence that TCDD can stimulate cross-talk between AhR and Nrf2, insofar that they have demonstrated induction by dioxin of numerous mouse glutathione S-transferase (Gst) genes that are not known to contain functional XREs in their upstream regulatory regions (Yeager et al., 2009).