Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

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, chiefly T(3) and diiodothyronine, has important effects on mitochondrial energetics and on the cytoskeleton. Modulation by the hormone of the basal proton leak in mitochondria accounts for heat production caused by iodothyronines and a substantial component of cellular oxygen consumption. Thyroid hormone also acts on the mitochondrial genome via imported isoforms of nuclear TRs to affect several mitochondrial transcription factors. Regulation of actin polymerization by T(4) and rT(3), but not T(3), is critical to cell migration. This effect has been prominently demonstrated in neurons and glial cells and is important to brain development. The actin-related effects in neurons include fostering neurite outgrowth. A truncated TRalpha1 isoform that resides in the extranuclear compartment mediates the action of thyroid hormone on the cytoskeleton.

Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.

The nongenomic actions of thyroid hormone begin at receptors in the plasma membrane, mitochondria or cytoplasm. These receptors can share structural homologies with nuclear thyroid hormone receptors (TRs) that mediate transcriptional actions of T3, or have no homologies with TR, such as the plasma membrane receptor on integrin αvβ3. Nongenomic actions initiated at the plasma membrane by T4 via integrin αvβ3 can induce gene expression that affects angiogenesis and cell proliferation, therefore, both nongenomic and genomic effects can overlap in the nucleus. In the cytoplasm, a truncated TRα isoform mediates T4-dependent regulation of intracellular microfilament organization, contributing to cell and tissue structure. p30 TRα1 is another shortened TR isoform found at the plasma membrane that binds T3 and mediates nongenomic hormonal effects in bone cells. T3 and 3,5-diiodo-L-thyronine are important to the complex nongenomic regulation of cellular respiration in mitochondria. Thus, nongenomic actions expand the repertoire of cellular events controlled by thyroid hormone and can modulate TR-dependent nuclear events. Here, we review the experimental approaches required to define nongenomic actions of the hormone, enumerate the known nongenomic effects of the hormone and their molecular basis, and discuss the possible physiological or pathophysiological consequences of these actions.