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 hormo ne receptors (TR) are known to mediate T-3 suppression of TSH beta gen e expression at the level of promoter activity. The role of other nucl ear receptors in regulation of this gene is less clearly defined. Reti noid X receptors (RXR) are a family of nuclear transcription factors t hat function both as 9-cis-retinoic acid (RA) ligand-dependent recepto rs and heterodimeric partners with TR and other nuclear receptors. Rec ently, 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 dist ribution of RXR gamma 1, the thyrotrope-restricted isoform of RXR gamm a, 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-derive d GH3 cells. Furthermore, we have studied the effects of RXR gamma 1 o n TSH beta promoter activity and hormone regulation in these pituitary -derived cell types. Both T3 and 9-cis-RA independently suppressed pro moter activity in the TtT-97 thyrotropes. Interestingly, the combinati on of ligands suppressed promoter activity more than either alone, ind icating 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 i n alpha TSH and GH3 cells, both of which lack this isoform. RXR beta, a more widely distributed isoform, did not mediate these effects. Fina lly, we showed that the murine TSH beta promoter region between -200 a nd -149 mediated a majority of the 9-cis-RA suppression of promoter ac tivity in thyrotropes. This region is distinct from the T-3-mediated r esponse region near the transcription start site. These data suggest t hat retinoids can mediate TSH beta gene regulation in thyrotropes and the thyrotrope-restricted isoform, RXR gamma 1, is required for this e ffect.