The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: Two mechanisms for repression

The orphan nuclear hormone receptor SHP interacts with a number of other nu clear hormone receptors and inhibits their transcriptional activity. Severa l mechanisms have been suggested to account for this inhibition. Here we sh ow that SHP inhibits transactivation by the orphan receptor hepatocyte nucl ear factor 4 (HNF-4) and the retinoid X receptor (RXR) by at least two mech anisms. SHP interacts with the same HNF-4 surface recognized by transcripti onal coactivators and competes with them for binding in vivo. The minimal S HP sequences previously found to be required for interaction with other rec eptors are sufficient for interaction with HNF-4, although deletion results indicate that additional C-terminal sequences are necessary for full bindi ng and coactivator competition. These additional sequences include those as sociated with direct transcriptional repressor activity of SHP. SHP also co mpetes with coactivators for binding to ligand-activated RXR, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of SHP-mediated repressi on. The minimal receptor interaction domain of SHP is sufficient for full i nteraction with RXR, as previously described. This domain is also sufficien t for full coactivator competition. Functionally, however, full inhibition of RXR transactivation requires the presence of the C-terminal repressor do main, with only weak inhibition associated with this receptor interaction d omain. Overall, these results suggest that SHP represses nuclear hormone re ceptor-mediated transactivation via two separate steps: first by competitio n with coactivators and then by direct effects of its transcriptional repre ssor function.