Novel AHR Interactions

The aryl hydrocarbon receptor (AHR) is a member of the PAS (Per-Arnt-Sim) superfamily of receptors, which mediate responses to environmental stresses such as hypoxia and circadian rhythm, and control basic physiologic processes like vascular development, learning, and neurogenesis. The AHR protein is the primary mediator of the toxic effects of the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and of hundreds of other HAH and polycyclic aromatic hydrocarbon (PAH) ligands. The mechanisms by which the AHR acts to mediate toxicity of these compounds include the activity of the AHR as a potent transcriptional activator. The ligand-bound AHR, with its dimerization-binding partner ARNT, upregulates the expression of a battery of genes that function in the metabolism of PAH and HAH compounds. However, the diversity of toxic responses mediated by compounds such as TCDD is not adequately explained by the expression of this battery of genes. Research efforts spanning the last three decades have unraveled a myriad of molecular signaling pathways affected by exposure to AHR ligands. These pathways include those regulating cell division, apoptosis, and differentiation, a number of different hormone signaling pathways, oxidative stress, inflammation, and development. Literally hundreds of genes have been implicated as being regulated either directly or indirectly by the AHR, and many of the underlying regulatory mechanisms involve the interaction of the AHR with proteins involved in basic transcriptional regulation in addition to the specific pathways mentioned above. This chapter will focus on the molecular interaction partners of the AHR and the implications of these interactions for the response of cells or organisms to xenobiotic ligands.