The subdomains of the transactivation domain of the aryl hydrocarbon receptor (AhR) inhibit AhR and estrogen receptor transcriptional activity

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) activates the aryl hydrocarbon receptor (AhR) to mediate transcriptional activity of dioxin-responsive genes. The transactivation domain (TAD) of human AhR (hAhR) has potentially distinct acidic, glutamine-rich, and proline/serine/threonine-rich subdomains. Cotransfection of exogenous hAhR into BP8 cells with isolated subdomains of hAhR TAD fused to glutathione S-transferase exhibited squelching of TCDD-dependent dioxin-response element (DRE)-driven luciferase reporter-gene activity with each subdomain. To study the potential cross talk between AhR- and estrogen receptor (ER)-mediated activities, BP8 cells were cotransfected with hAhR TAD subdomain constructs and ERα. The three hAhR TAD subdomains inhibited the 17β-estradiol-induced estrogen-response element-mediated reporter-gene transactivation. Cotransfection of hAhR with the ligand-binding domain (LBD) of ERα also squelched TCDD-dependent DRE-driven reporter-gene activity in the presence of 17β-estradiol. Similar results were observed in T47D cells that express functional AhR and ERα. These results indicate that the isolated subdomains of hAhR’s TAD and LBD of ERα are capable of squelching ligand-dependent transactivation of either the AhR or the ER, by titrating crucial proteins from an existing common pool of cofactors.