Thyroid Hormone Regulation of Thyrotropin Gene Expression

Thyroid hormones suppress the synthesis and release of thyrotropin from thyrotropes in the anterior pituitary gland, a feature that is critical in the classic negative-feedback loop of the pituitary-thyroid endocrine axis. The major effect of thyroid hormones in this system is exerted at the transcriptional level. The molecular mechanisms by which there is negative regulation of TSH subunit gene expression by thyroid hormone have been elucidated. The TSH subunit genes have isolated and characterized. Structure-function analyses using fusion genes and DNA transfection approaches have defined the putative negative TREs among the promoters of the rat, mouse, and human alpha and TSH beta genes. These sequences are either largely overlapping direct TRE half-sites, TRE half-sites as direct repeats gapped by two nucleotides, or single TRE half-sites. These arrangements are distinct from those seen in positive TREs. Recent knowledge regarding the molecular mechanisms of thyroid action in general forces consideration of multiple TR isoforms, TR heterodimer partners (TRAPs), and thyroid hormones in the ultimate mechanisms of negative action. Several models have been proposed, but none has yet been proved. In addition, the role of thyroid hormone in the regulation of gene expression at the posttranscriptional level is beginning to be addressed. Future work should continue to illuminate these important facets of gene regulation.