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Molecular Aspects of Thyroid Hormone Actions
Open accessAbstract
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.
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In the citing paper
“TH, in the form of T3, has classically been considered to act by binding to cytosolic TH receptors (TR) (TRα1, TRβ1, and TRβ2) that bind to TH response elements on the DNA and regulate expression of TH target genes (canonical TH/TR action) (26,27).”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [27]
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“Both T3 and T4 following its conversion into T3 bind to specific intracellular TR receptors exerting a repressive action on various genes, including TSHβ and, to a lesser degree, α-subunit (47–52).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [48]
In the citing paper
“TH, in the form of T3, has classically been considered to act by binding to cytosolic TH receptors (TR) (TRα1, TRβ1, and TRβ2) that bind to TH response elements on the DNA and regulate expression of TH target genes (canonical TH/TR action) [26, 27].”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [27]
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Metadata
- Authors
- Cheng, S.-Y., Leonard, J. L., & Davis, P. J.
- Affiliations
- National Institutes of Health (US)
- University of Massachusetts Chan Medical School (US)
- Albany Medical College (US)
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2010-04-01
- Volume
- 31
- Issue
- 2
- Pages
- 139-170
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC2852208
- OpenAlex
- W2021932599
- Cited by
- 1,384
- References
- 299
- Citations by year
- 2026: 39 · 2025: 78 · 2024: 68 · 2023: 95 · 2022: 104 · 2021: 90 · 2020: 101 · 2019: 91 · 2018: 70 · 2017: 100 · 2016: 93 · 2015: 82 · 2014: 120 · 2013: 91 · 2012: 62
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- thyroid hormones, thyroid hormone receptor, thyroid hormone receptor beta, TRα, transcriptional regulation, thyroid hormone response element, transcriptional coactivator, corepressors, thyroid hormone resistance, knockin mouse model, hypothyroidism, nongenomic thyroid hormone action, integrin αvβ3, ERK signaling, Na+/H+ exchanger, angiogenesis, glioma proliferation, tetraiodothyroacetic acid, levothyroxine
- MeSH terms
- Animals, Humans, Receptors, Thyroid Hormone, Thyroid Hormones, Thyroxine, Triiodothyronine
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