Advances in Our Understanding of Thyroid Hormone Action at the Cellular Level*

DESPITE the fact that the clinical and biological importance of the thyroid hormones have been recognized for approximately 100 yr (1–3), until recently our understanding of the biological effects of these hormones has been largely descriptive and based on a catalog of effects observed to accompany an excess or deficiency of these hormones. In the past 15 yr, however, there has been substantial progress in defining the molecular basis of thyroid hormone action at the nuclear level. In the mid-60s Tata and colleagues (4, 5) first proposed that the nucleus might be the target for thyroid hormone action. This inference was based on sequential measurements of thyroid hormone effects in thyroidectomized animals treated with T4. Nevertheless, the importance and uniqueness of this pathway were not fully appreciated (6). Full understanding of the nuclear site of initiation of thyroid hormone action was dependent on the recognition that T3 was the active hormone, that T4 largely served as a precursor (7, 8), and the recognition of specific nuclear binding sites which could serve as the site of initiation of the sequence of biochemical events resulting in thyroid hormone action (9).