Date Published: March 16, 2004
Publisher: Public Library of Science
Author(s): Guang Yao, Mark Craven, Norman Drinkwater, Christopher A Bradfield
Abstract: The aryl hydrocarbon receptor (AHR) is a vertebrate protein that mediates the toxic and adaptive responses to dioxins and related environmental pollutants. In an effort to better understand the details of this signal transduction pathway, we employed the yeast S. cerevisiae as a model system. Through the use of arrayed yeast strains harboring ordered deletions of open reading frames, we determined that 54 out of the 4,507 yeast genes examined significantly influence AHR signal transduction. In an effort to describe the relationship between these modifying genes, we constructed a network map based upon their known protein and genetic interactions. Monte Carlo simulations demonstrated that this network represented a description of AHR signaling that was distinct from those generated by random chance. The network map was then explored with a number of computational and experimental annotations. These analyses revealed that the AHR signaling pathway is defined by at least five distinct signaling steps that are regulated by functional modules of interacting modifiers. These modules can be described as mediating receptor folding, nuclear translocation, transcriptional activation, receptor level, and a previously undescribed nuclear step related to the receptor’s Per–Arnt–Sim domain.
Partial Text: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor found in a variety of vertebrate species. The AHR is a prototype member of the Per–Arnt–Sim (PAS) superfamily of signaling molecules. Members of this superfamily regulate cellular responses to a variety of environmental stimuli, including pollutants, hypoxia, and external light cues (Gu et al. 2000). Our initial interest in AHR biology arose from its pivotal role in mediating the adaptive metabolic response to both polycyclic aromatic hydrocarbons (PAHs) and the toxic effects of more potent agonists like the halogenated dioxins (Schmidt and Bradfield 1996; Whitlock 1999). More recently, it has been observed that the AHR plays an important role in normal vascular development, suggesting the existence of an endogenous ligand (Lahvis et al. 2000). From the broader perspective, the AHR can be viewed as a prototype of all PAS protein signaling. That is, what we learn about AHR biology will have a direct influence on how we think about PAS-mediated hypoxia, circadian, and developmental pathways.