Pituitary NR4A1 is negatively regulated by thyroid hormone without direct binding of thyroid hormone receptors on the gene.

We previously reported that TRH stimulated pituitary TSHβ gene expression via an immediate increase in NR4A1 in thyrotrophs. We demonstrated that NR4A1 mRNA levels are regulated by thyroid hormone. Pituitary NR4A1 mRNA levels were decreased in mice injected with L-T4. NR4A1 promoter activity was increased by the overexpression of TRβs, and these increases were decreased by T3, and the −27∼+152 bp region was responsible for these changes in vitro. An EMSA showed the lack of TRβs-isoforms binding, and a ChIP assay demonstrated the recruitment of TRβs and NCoR in the −147∼+148 bp region in the absence of T3, whereas T3 induced their release. Experiments on the overexpression and knockdown of NCoR, and using the mutant TRs supported the involvement of NCoR in the TR-induced stimulation. These results demonstrate that thyroid hormone down-regulated basal NR4A1 mRNA levels in the pituitary, and the direct binding of TR was not required.