Short Heterodimer Partner (SHP) Orphan Nuclear Receptor Inhibits the Transcriptional Activity of Aryl Hydrocarbon Receptor (AHR)/AHR Nuclear Translocator (ARNT)

SHP (short heterodimer partner) is an orphan nuclear receptor lacking a DNA binding domain that interacts with nuclear receptors (NR) including thyroid receptor (TR), retinoic acid receptors (RAR and RXR), and estrogen receptors α and β (ERα and ERβ). SHP acts as a negative regulator of these receptors by inhibiting DNA binding and transcriptional activation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds to arylhydrocarbon receptor (AHR), activating the AHR/AHR nuclear translocator (ARNT) heterodimer. We investigated the physical and functional interaction of SHP with AHR/ARNT. In RL95-2 human endometrial carcinoma cells, SHP inhibited TCDD-stimulated reporter activity from the AHR-responsive CYP1A1 and UGT1A6 gene promoters in a concentration-dependent manner. In GST pull-down assays, ARNT interacted directly with SHP in vitro, but AHR did not interact with GST-SHP. SHP inhibited AHR/ARNT–DNA binding in vitro. These results identify ARNT as a novel SHP target. We speculate a role for SHP in the suppression of agonist-activated AHR/ARNT activity.