Selective antagonism of thyroid hormone action by retinoic acid

Thyroid hormone (T3) and retinoic acid (RA) regulate gene transcription by binding to similar nuclear receptors. We have investigated the effects of RA, alone and in combination with T3, on a number of T3-responsive genes expressed in rat pituitary adenoma cells. Like T3, RA increased growth hormone gene expression in GH3 as well as in GH1 cells, and the effects of the hormones were additive. In contrast, RA alone had little effect on the expression of the beta 2 form of T3 receptor (TR beta 2), which is markedly decreased by T3. Remarkably, however, RA completely inhibited the down-regulation of TR beta 2 mRNA by T3. RA alone also had little effect on TR beta 1 mRNA, but its presence did not prevent the up-regulation of TR beta 1 mRNA by T3. The target-gene-specific antagonism of T3 action by RA was observed in both GH cell lines. Nuclear run-on assays demonstrated that the effect occurred at the level of TR beta 2 gene transcription, and the half-life of the TR beta 2 mRNA was unchanged by RA in the presence or absence of T3. The half-maximal RA dose required for these effects suggested that they were mediated by one or more of the nuclear receptors for RA. Indeed, GH3 cells contain mRNAs encoding the three distinct RA receptor subtypes, alpha, beta, and gamma, as well as retinoid X receptors. These results demonstrate that the effects of RA and T3 on gene expression are dependent on the nature of the target gene as well as on hormonal interactions, probably at the level of the receptors.