Overlapping nongenomic and genomic actions of thyroid hormone and steroids

Nuclear receptors for thyroid hormone and steroids are members of a receptor superfamily with similar molecular organization, but discrete transcriptional functions that define genomic actions of these nonpeptide hormones. Nongenomic actions of thyroid hormone and estrogens and androgens are initiated outside the nucleus, at receptors in the plasma membrane or in cytoplasm; these actions are largely regarded to be unique to the respective hormones. However, there is an increasing number of descriptions of overlapping nongenomic and genomic effects of thyroid hormone and estrogens and testosterone. These effects are concentrated in tumor cells, where, for example, estrogens and thyroid hormone have similar mitogen-activate protein kinase (MAPK)-dependent proliferative actions on ERα-positive human breast cancer cells, and where dihydrotestosterone also can stimulate proliferation. Steroids and thyroid hormone have similar anti-apoptotic effects in certain tumors. But thyroid hormone and steroids also have overlapping or interacting nongenomic and genomic actions in heart and brain cells. These various effects of thyroid hormone and estrogens and androgens are reviewed here and their possible clinical consequences are enumerated.

► Nuclear receptors for thyroid hormone and steroids are discrete members of a receptor superfamily that, when complexed with their respective ligands, initiate distinctive transcriptional (‘genomic’) actions. Nongenomic actions of steroids and thyroid hormone are initiated at receptors in the plasma membrane or in cytoplasm. Receptors associated with nongenomic actions may be very different structurally and functionally from nuclear receptors, for example, the plasma membrane thyroid hormone receptor is located on integrin αvβ3; in the case of estrogen, however, nongenomic actions may be initiated at nuclear receptor proteins that are resident in the plasma membrane.
► Nongenomic actions of steroids and thyroid hormone may overlap. Estrogen and thyroid hormone stimulate proliferation of nuclear estrogen receptor (ER)-positive human breast cancer cells. The actions of each hormone begin at different receptors but are mediated downstream by mitogen-activated protein kinase-dependent Ser-118 phosphorylation of ERα. Estrogen and thyroid hormone stimulate proliferation of human thyroid cancer cells by similar, if not identical, p53-dependent mechanisms.
► Thyroid hormone and steroids have anti-apoptotic actions in certain tumor cells that are similar and that are nongenomic in mechanism.
► Thyroid hormone and testosterone may induce experimental myocardial hypertrophy by similar mechanisms involving mammalian target of rapamycin (mTOR), a serine-threonine kinase.
► Nuclear receptors for thyroid hormone and estrogen that are resident in the nucleus may also interact to modify estrogen-ER action.