Research: Project 3

The role of secondary proteins in aryl hydrocarbon receptor biology

The aryl hydrocarbon receptor (AHR) is responsible for sensing environmental contaminants, such as 2,3,7,8-tetrachloro-r-dioxin (TCDD) and instigating the cellular response to their presence. Primarily, this response involves the activation of cytochrome p450 enzymes. The AHR is also responsible for regulating the toxic effects of these ligands upon biological systems. For example, TCDD is recognized as one of the most harmful chemicals known to man but it is mostly non-toxic in mice that have no functional AHR. However, the expression pattern of the AHR does not completely explain the pleiotropic effects seen in different tissues following exposure to AHR agonist, like TCDD. We have hypothesized this pleiotropy is dependent upon varying degrees of secondary proteins that can influence AHR biology through direct interaction with the AHR or through modulation of the activity of proteins already known to bind the receptor, such as Hsp90 and ARA9. To address this hypothesis we have begun a series of screens looking for proteins capable of interacting with the AHR. This project focuses on characterizing the effects of these identified proteins on AHR signaling and AHR-mediated toxicity. This project uses state of the art proteomic technology hear at Michigan State University and several engineered cell lines and animal models. The ultimate goal is to link tissue specific AHR binding partners with tissue specific toxicity with the hopes of understanding the signaling necessary to instigate the pathology of TCDD, as well as other AHR agonist, exposure.