Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors

Nuclear receptors (NRs) and POU domain factors form two important transcription factor families for which several levels of functional interference have been described. In this study, the adopted orphan receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were found to perform direct protein-protein interactions with Pit-1, a representative POU domain factor. The ligand-dependent interaction profile of Pit-1 with CAR, PXR, and the vitamin D receptor in solution was shown to be that of a corepressor. In the absence of receptor agonist Pit-1 inhibited the complex formation of NRs with the retinoid X receptor on DNA. Also in living cells, Pit-1 and Oct-1, another POU domain factor, behaved like corepressors of NR signaling, and Pit-1-mediated repression was found to involve histone deacetylases. Conversely vitamin D receptor, CAR, and PXR were shown to act as repressors of Pit-1 signaling in different cell lines (MCF-7, HaCaT, and GH4C1). This repression was found to be independent of histone deacetylases and seems to be based on a competition of NRs with coactivator and corepressor proteins for overlaying interaction interfaces on the surface of Pit-1. Taken together this study suggests that cross-repression should occur in all tissues in which POU domain factors and non-liganded NRs meet each other.