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 thyroi d receptor (TR), retinoic acid receptors (RAR and RXR), and estrogen recept ors alpha and beta (ER alpha and ER beta). SHP acts as a negative regulator of these receptors by inhibiting DNA binding and transcriptional activatio n, 2,3,7,8-Tetra-chlorodibenzo-p-dioxin (TCDD) binds to arylhydrocarbon rec eptor (AI-IR), activating the AHR/AHR nuclear translocator (ARNT) heterodim er. We investigated the physical and functional interaction of SHP with AHR /ARNT. In RL95-2 human endometrial carcinoma cells, SHP inhibited TCDD-stim ulated reporter activity from the AHR-responsive CYP1A1 and UGT1A6 gene pro moters in a concentration-dependent manner. In GST pull-down assays, ARNT i nteracted 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 ag onist-activated AHR/ARNT activity. (C) 2001 Academic Press.