Molecular Aspects of Thyroid Hormone Actions

Abstract

Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear receptors (TRs) mediate the biological activities of T(3) via transcriptional regulation. Two TR genes, alpha and beta, encode four T(3)-binding receptor isoforms (alpha1, beta1, beta2, and beta3). The transcriptional activity of TRs is regulated at multiple levels. Besides being regulated by T(3), transcriptional activity is regulated by the type of thyroid hormone response elements located on the promoters of T(3) target genes, by the developmental- and tissue-dependent expression of TR isoforms, and by a host of nuclear coregulatory proteins. These nuclear coregulatory proteins modulate the transcription activity of TRs in a T(3)-dependent manner. In the absence of T(3), corepressors act to repress the basal transcriptional activity, whereas in the presence of T(3), coactivators function to activate transcription. The critical role of TRs is evident in that mutations of the TRbeta gene cause resistance to thyroid hormones to exhibit an array of symptoms due to decreasing the sensitivity of target tissues to T(3). Genetically engineered knockin mouse models also reveal that mutations of the TRs could lead to other abnormalities beyond resistance to thyroid hormones, including thyroid cancer, pituitary tumors, dwarfism, and metabolic abnormalities. Thus, the deleterious effects of mutations of TRs are more severe than previously envisioned. These genetic-engineered mouse models provide valuable tools to ascertain further the molecular actions of unliganded TRs in vivo that could underlie the pathogenesis of hypothyroidism. Actions of thyroid hormone that are not initiated by liganding of the hormone to intranuclear TR are termed nongenomic. They may begin at the plasma membrane or in cytoplasm. Plasma membrane-initiated actions begin at a receptor on integrin alphavbeta3 that activates ERK1/2 and culminate in local membrane actions on ion transport systems, such as the Na(+)/H(+) exchanger, or complex cellular events such as cell proliferation. Concentration of the integrin on cells of the vasculature and on tumor cells explains recently described proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on certain cancer cells, including gliomas. Thus, hormonal events that begin nongenomically result in effects in DNA-dependent effects. l-T(4) is an agonist at the plasma membrane without conversion to T(3). Tetraiodothyroacetic acid is a T(4) analog that inhibits the actions of T(4) and T(3) at the integrin, including angiogenesis and tumor cell proliferation. T(3) can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alphavbeta3. Downstream consequences of phosphatidylinositol 3-kinase activation by T(3) include specific gene transcription and insertion of Na, K-ATPase in the plasma membrane and modulation of the activity of the ATPase. Thyroid hormone, chief...

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

“…This receptor is required for local effects of iodothyronines that relate to nearby polypeptide receptors, such as those for growth factors, and to ion transporters (Cheng et al, 2010;Davis et al, 2011), such as the Na + /H + antiporter. The receptor mediates hormone analogue effects on protein trafficking within cells, directing, for example, cytoplasmic TR to the nucleus (Cao et al, 2009).…”

“…These effects are initiated nongenomically, i.e., are independent of the classical nuclear receptor for thyroid hormone (TR) (Cheng et al, 2010), and may have downstream intracellular consequences that involve specific protein trafficking (Cao et al, 2009) and modulation of expression of specific genes involved in cancer cell survival pathways. Covalently bound to a biodegradable nanoparticle that is unable to access the interior of the cell, a thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), acts exclusively at a receptor site on integrin v3 to block actions of L-thyroxine (T 4 ) and 3, 5, 3'-triiodo-L-thyronine (T 3 ) on new blood vessel formation and cancer cell division ; However, nanoparticulate tetrac (nanotetrac) and, to a lesser extent, unmodified tetrac have a panel of cancer-relevant actions in the absence of T 4 and T 3 Davis et al, 2011).…”

Modulation of thyroid hormone receptors, TRα and TRβ, by using different doses of triiodothyronine (T3) at different times

“…TH action is mediated mainly by the modification of gene expression by nuclear receptors, which are transcriptional factors regulated by ligands that adhere to the chromatin (2). TH receptors (TR) are proteins that belong to the nuclear hormone receptor superfamily.…”

Thyroid hormones and the heart

“…Increasing evidence also supports the role of thyroid hormones in preventing deleterious cardiac remodeling. Many interrelated mechanisms could account for these complex actions including antiapoptotic effects, decrease of collagen expression, increase in contractility [10], switch from maladaptive to adaptive hypertrophy [11], improving mitochondrial metabolism and promoting angiogenesis and cell viability. Interesting, the anti-remodeling thyroid hormone activity is not limited to ventricle, but also prevents atrial fibrosis and atrial fibrillation induction [12].…”