The thyrotrope-restricted isoform of the retinoid-X receptor-gamma 1 mediates 9-cis-retinoic acid suppression of thyrotropin-beta promoter activity

TSH beta is a subunit of TSH that is uniquely expressed and regulated in the thyrotrope cells of the anterior pituitary gland. Thyroid hormone receptors (TR) are known to mediate T-3 suppression of TSH beta gene expression at the level of promoter activity. The role of other nuclear receptors in regulation of this gene is less clearly defined. Retinoid X receptors (RXR) are a family of nuclear transcription factors that function both as 9-cis-retinoic acid (RA) ligand-dependent receptors and heterodimeric partners with TR and other nuclear receptors. Recently, the RXR isoform, RXR gamma, has been identified in the anterior pituitary gland and found to be restricted to thyrotrope cells within the pitutiary. In this report, we have further characterized the distribution of RXR gamma 1, the thyrotrope-restricted isoform of RXR gamma, in murine tissues and different cell types. We have found that RXR gamma 1 mRNA and protein are expressed in the TtT-97 thyrotropic tumor, but not the thyrotrope-variant alpha TSH cells or somatotrope-derived GH3 cells. Furthermore, we have studied the effects of RXR gamma 1 on TSH beta promoter activity and hormone regulation in these pituitary-derived cell types. Both T3 and 9-cis-RA independently suppressed promoter activity in the TtT-97 thyrotropes. Interestingly, the combination of ligands suppressed promoter activity more than either alone, indicating that these hormones may act cooperatively to regulate TSH beta gene expression in thyrotropes. The RXR gamma 1 isoform was necessary for the 9-cis-RA-mediated suppression of TSH beta promoter activity in alpha TSH and GH3 cells, both of which lack this isoform. RXR beta, a more widely distributed isoform, did not mediate these effects. Finally, we showed that the murine TSH beta promoter region between -200 and -149 mediated a majority of the 9-cis-RA suppression of promoter activity in thyrotropes. This region is distinct from the T-3-mediated response region near the transcription start site. These data suggest that retinoids can mediate TSH beta gene regulation in thyrotropes and the thyrotrope-restricted isoform, RXR gamma 1, is required for this effect.