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Reed P Larsen - One of the best experts on this subject based on the ideXlab platform.
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thyroid hormones and skeletal muscle new insights and potential implications
Nature Reviews Endocrinology, 2014Co-Authors: Domenico Salvatore, Ann Marie Zavacki, Warner S Simonides, Monica Dentice, Reed P LarsenAbstract:The authors review the roles of T3 in skeletal muscle development, homeostasis and pathology, with a focus on the emerging local Deiodinase-mediated control of T3signalling. Moreover, this Review addresses how manipulation of Deiodinase activity in skeletal muscle might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury. Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine Deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyses outer-ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone tri-iodothyronine (T3). T3 can remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner-ring iodine. Regulation of the expression and activity of Deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local Deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how skeletal muscle Deiodinase activity might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury.
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the Deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation
Biochimica et Biophysica Acta, 2013Co-Authors: Monica Dentice, Ann Marie Zavacki, Reed P Larsen, Alessandro Marsili, Domenico SalvatoreAbstract:Background Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenoDeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenoDeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of Deiodinases in specific cell types are not known, many important regulatory factors have been deciphered.
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β catenin regulates Deiodinase levels and thyroid hormone signaling in colon cancer cells
Gastroenterology, 2012Co-Authors: Monica Dentice, Reed P Larsen, Cristina Luongo, Annarita Sibilio, Raffaele Ambrosio, Antonella Casillo, Antonino Iaccarino, Giancarlo Troncone, Gianfranco Fenzi, Domenico SalvatoreAbstract:Background & Aims Activation of the β-catenin/T-cell factor (TCF) complex occurs in most colon tumors, and its actions correlate with the neoplastic phenotype of intestinal epithelial cells. Type 3 Deiodinase (D3), the selenoenzyme that inactivates thyroid hormone (3,5,3′ triiodothyronine [T3]), is frequently expressed by tumor cells, but little is known about its role in the regulation of T3 signaling in cancer cells. Methods We measured D3 expression in 6 colon cancer cell lines and human tumors and correlated it with the activity of the β-catenin/TCF complex. We also determined the effects of D3 loss on local thyroid hormone signaling and colon tumorigenesis. Results We show that D3 is a direct transcriptional target of the β-catenin/TCF complex; its expression was higher in human intestinal adenomas and carcinomas than in healthy intestinal tissue. Experimental attenuation of β-catenin reduced D3 levels and induced type 2 Deiodinase (the D3 antagonist that converts 3,5,3′,5′ tetraiodothyronine into active T3) thereby increasing T3-dependent transcription. In the absence of D3, excess T3 reduced cell proliferation and promoted differentiation in cultured cells and in xenograft mouse models. This occurred via induction of E-cadherin, which sequestered β-catenin at the plasma membrane and promoted cell differentiation. Conclusions Deiodinases are at the interface between the β-catenin and the thyroid hormone pathways. Their synchronized regulation of intracellular T3 concentration is a hitherto unrecognized route by which the multiple effects of β-catenin are generated and may be targeted to reduce the oncogenic effects of β-catenin in intestinal cells.
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il 6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells
Journal of Clinical Investigation, 2011Co-Authors: Simone Magagnin Wajner, Reed P Larsen, Iuri Martin Goemann, Ana Laura Bueno, Ana Luiza MaiaAbstract:Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3′ triiodothyronine (T3) that occurs in chronically ill patients; the degree of reduction in T3 is associated with overall prognosis and survival. Iodothyronine Deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II Deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T4 to active T3, whereas the type III enzyme (D3) inactivates T4 and T3. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor–mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate Deiodinase activities in human cell lines. Active T3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate Deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6–induced inhibitory effect on D1- and D2-mediated T3 production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3–mediated inactivation of T3. Taken together, these results identify a single pathway by which IL-6–induced oxidative stress can reduce D1- and D2-mediated T4-to-T3 conversion as well as increasing D3-mediated T3 (and T4) inactivation, thus mimicking events during illness.
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lack of association between the type 2 Deiodinase a g polymorphism and hypertensive traits the framingham heart study
Hypertension, 2008Co-Authors: Ana Luiza Maia, Reed P Larsen, Shihjen Hwang, Daniel Levy, Martin G Larson, Caroline S FoxAbstract:To the Editor: Thyroxine (T4) activation to T3 via the iodothyronine Deiodinase type 2 allows for changes in intracellular thyroid status in a tissue-specific manner independent of serum T3. A single nucleotide polymorphism in type 2 deodinase (DIO2) gene (A/G) in humans, in which a threonine changes to alanine at codon 92, has been associated with decreased enzyme activity and higher insulin resistance in type 2 diabetes patients.1 Nevertheless, these findings were not replicated in larger studies.2 Recently, Gumieniak et al3 reported that the alanine allele doubles the risk for development of hypertension in euthyroid subjects. Pituitary and hypothalamic type 2 Deiodinase play a critical role in feedback regulation of thyroid-stimulating hormone (TSH) secretion, and higher serum TSH concentrations have been demonstrated in euthyroid hypertensive compared with normotensive control subjects.4 In this context, we thought it would be of interest to evaluate whether the previous reported association of Thr92Ala polymorphism and hypertension is also present in a large unselected, community-based population. The present sample size consists of 1557 individuals who had complete phenotype and genotype information available drawn from a subset of unrelated individuals from the Framingham Heart Study offspring cohort, …
Domenico Salvatore - One of the best experts on this subject based on the ideXlab platform.
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Deiodinases and their intricate role in thyroid hormone homeostasis.
Nature Reviews Endocrinology, 2019Co-Authors: Cristina Luongo, Monica Dentice, Domenico SalvatoreAbstract:The Deiodinase family of enzymes mediates the activation and inactivation of thyroid hormone. The role of these enzymes in the regulation of the systemic concentrations of thyroid hormone is well established and underpins the treatment of common thyroid diseases. Interest in this field has increased in the past 10 years as the Deiodinases became implicated in tissue development and homeostasis, as well as in the pathogenesis of a wide range of human diseases. Three Deiodinases have been identified, namely, types 1, 2 and 3 iodothyronine Deiodinases, which differ in their catalytic properties and tissue distribution. Notably, the expression of these enzymes changes during the lifetime of an individual in relation to the different needs of each organ and to ageing. The systemic homeostatic role of Deiodinases clearly emerges during changes in serum concentrations of thyroid hormone, as seen in patients with thyroid dysfunction. By contrast, the role of Deiodinases at the tissue level allows thyroid hormone signalling to be finely tuned within a given cell in a precise time–space window without perturbing serum concentrations of thyroid hormone. This Review maps the overall functional role of the Deiodinases and explores challenges and novel opportunities arising from the expanding knowledge of these ‘master’ components of the thyroid homeostatic system. This Review discusses the two main functions of the human Deiodinases: the homeostatic control of plasma concentrations of thyroid hormone and the control of intracellular T3 concentrations.
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Deiodinases and stem cells: an intimate relationship
Journal of Endocrinological Investigation, 2017Co-Authors: Domenico SalvatoreAbstract:Thyroid hormone is a major determinant of tissue functions in vivo. The Deiodinase family controls the tissue-specific activation or inactivation of intracellular thyroid hormones. Precise control of the T3-dependent transcriptional program is required by multiple cell systems, including the stem cell. In this context, the identification of a close connection between thyroid hormones and different signal pathways involved in the control of stem cell functions suggested that the Deiodinases may play a role in the definition of stem cell biology and physiology. Stem cells have an unlimited self-renewal capacity and the potential to differentiate into different types of mature cells. Deciphering how all these events are achieved, how the T3 signal is controlled and integrated in stem cells and their niches, and how it can impact on them is essentially unknown and represents a challenge for coming years. In this review, I will explore the role played by the Deiodinases in the modulation of the TH signal in stem cells of adult tissues, namely muscle and intestine, and how their actions control the delicate balance among self-renewal, proliferation and differentiation. Elucidation of the molecular mechanisms presiding thyroid hormone action in stem cells may reveal therapeutic potential, for example in the fields of regenerative diseases and cancer.
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thyroid hormones and skeletal muscle new insights and potential implications
Nature Reviews Endocrinology, 2014Co-Authors: Domenico Salvatore, Ann Marie Zavacki, Warner S Simonides, Monica Dentice, Reed P LarsenAbstract:The authors review the roles of T3 in skeletal muscle development, homeostasis and pathology, with a focus on the emerging local Deiodinase-mediated control of T3signalling. Moreover, this Review addresses how manipulation of Deiodinase activity in skeletal muscle might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury. Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine Deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyses outer-ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone tri-iodothyronine (T3). T3 can remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner-ring iodine. Regulation of the expression and activity of Deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local Deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how skeletal muscle Deiodinase activity might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury.
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type 3 Deiodinase and consumptive hypothyroidism a common mechanism for a rare disease
Frontiers in Endocrinology, 2013Co-Authors: Cristina Luongo, Luigi Trivisano, Fausta Alfano, Domenico SalvatoreAbstract:The major product secreted by the thyroid is thyroxine (T4), whereas most of the biologically active triiodothyronine (T3) derives from the peripheral conversion of T4 into T3. The Deiodinase enzymes are involved in activation and inactivation of thyroid hormones. Type 1 and type 2 Deiodinase (D1 and D2) convert T4 into T3 whereas D3 degrades T4 and T3 into inactive metabolites and is thus the major physiological thyroid hormone inactivator. The hypothalamic-pituitary-thyroid axis maintains circulating thyroid hormone levels constant, while the Deiodinases tissue-specifically regulate intracellular thyroid status by controlling thyroid hormone action in a precise spatio-temporal fashion. Here we review the data related to the recent identification of a paraneoplastic syndrome called “consumptive hypothyroidism”, which exemplifies how Deiodinases alter substantially the concentration of thyroid hormone in blood. This syndrome results from the aberrant uncontrolled expression of D3 that can induce a severe form of hypothyroidism by inactivating T4 and T3 in defined tumor tissue. This rare thyroid hormone insufficiency generally affects patients in the first years of life, and has distinct features in terms of diagnosis, treatment and prognosis with respect to other forms of hypothyroidism.
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Type 3 Deiodinase and solid tumors: an intriguing pair.
Expert Opinion on Therapeutic Targets, 2013Co-Authors: Monica Dentice, Dario Antonini, Domenico SalvatoreAbstract:Introduction: Thyroid hormone (TH) metabolism is mediated by Deiodinases, a family of thioredoxin fold-containing enzymes that remove iodide from thyroxine and its derivatives. The coordinated action of Deiodinases allows target cells to modulate rapidly their own TH availability in response to different cues. Type 3 Deiodinase (D3), the physiological inactivator of TH, is an oncofetal protein whose re-activation in adult tissues has been correlated with hyperproliferative states and with human solid tumors. This suggests a link between Deiodinase-mediated TH metabolism and carcinogenesis. Areas covered: D3 is overexpressed in basal cell carcinomas (BCCs) and sustains the proliferation of BCC cells. It exerts a similar function in colon cancer, which suggests that attenuating the TH signal is part of a widespread neoplastic program. Here, recent advances in D3 research, particularly as regards the role of D3 regulation and function in solid tumors are reviewed. Expert opinion: Given the vast array of TH's...
Ann Marie Zavacki - One of the best experts on this subject based on the ideXlab platform.
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thyroid hormones and skeletal muscle new insights and potential implications
Nature Reviews Endocrinology, 2014Co-Authors: Domenico Salvatore, Ann Marie Zavacki, Warner S Simonides, Monica Dentice, Reed P LarsenAbstract:The authors review the roles of T3 in skeletal muscle development, homeostasis and pathology, with a focus on the emerging local Deiodinase-mediated control of T3signalling. Moreover, this Review addresses how manipulation of Deiodinase activity in skeletal muscle might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury. Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine Deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyses outer-ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone tri-iodothyronine (T3). T3 can remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner-ring iodine. Regulation of the expression and activity of Deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local Deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how skeletal muscle Deiodinase activity might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury.
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the Deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation
Biochimica et Biophysica Acta, 2013Co-Authors: Monica Dentice, Ann Marie Zavacki, Reed P Larsen, Alessandro Marsili, Domenico SalvatoreAbstract:Background Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenoDeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenoDeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of Deiodinases in specific cell types are not known, many important regulatory factors have been deciphered.
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paracrine signaling by glial cell derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells
Journal of Clinical Investigation, 2010Co-Authors: Beatriz C G Freitas, Balazs Gereben, Ann Marie Zavacki, Aniko Zeold, Melany Castillo, Imre Kallo, Peter Egri, Zsolt Liposits, Rui M B Maciel, Sungro JoAbstract:Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) in the brain. Despite this, not much is known about the signaling pathways that control TH action in the brain. What is known is that the prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by type 2 Deiodinase (D2) and that this occurs in astrocytes, while TH receptors and type 3 Deiodinase (D3), which inactivates T3, are found in adjacent neurons. Here, we modeled TH action in the brain using an in vitro coculture system of D2-expressing H4 human glioma cells and D3-expressing SK-N-AS human neuroblastoma cells. We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying Deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease.
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cellular and molecular basis of Deiodinase regulated thyroid hormone signaling
Endocrine Reviews, 2008Co-Authors: Balazs Gereben, Antonio C. Bianco, Ann Marie Zavacki, Scott Ribich, Stephen A Huang, Warner S Simonides, Aniko ZeoldAbstract:The iodothyronine Deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T3 during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating Deiodinase (D2) and the inactivating Deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because Deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-κB, growth factors, bile acids, hypoxia-inducible factor-1α, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that Deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.
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type 1 iodothyronine Deiodinase is a sensitive marker of peripheral thyroid status in the mouse
Endocrinology, 2005Co-Authors: Ann Marie Zavacki, Reed P Larsen, John W. Harney, Hao Ying, Marcelo A Christoffolete, Goele Aerts, Sheueyann Cheng, Antonio C. BiancoAbstract:Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 iodothyronine Deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine Deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 iodothyronine Deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the Deiodinases in the cerebral cortex.
Antonio C. Bianco - One of the best experts on this subject based on the ideXlab platform.
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Pathophysiological relevance of Deiodinase polymorphism.
Current Opinion in Endocrinology & Diabetes and Obesity, 2018Co-Authors: Antonio C. Bianco, Brian S. KimAbstract:PURPOSE OF REVIEW To assess new findings and clinical implications of Deiodinase gene polymorphism. Deiodinases are enzymes that can activate or inactivate thyroid hormone molecules. Whereas the types 1 and 2 Deiodinase (D1 and D2) activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3) via deiodination of T4's outer ring, D1 and D3 inactivate both T4 and T3 and terminate thyroid hormone action via deiodination of T4's inner molecular ring. A number of polymorphisms have been identified in the three Deiodinase genes; the most investigated and likely to have clinical relevance is the Thr92 substitution for Ala substitution in DIO2 (Thr92Ala-DIO2). There are a number of reports describing the association between the Thr92Ala-DIO2 polymorphism and clinical syndromes that include hypertension, type 2 diabetes, mental disorders, lung injury, bone turnover, and autoimmune thyroid disease; but these associations have not been reproduced in all population studies. RECENT FINDINGS A new report indicates that carriers of the Thr92Ala-DIO2 polymorphism exhibit lower D2 catalytic activity and localized/systemic hypothyroidism. This could explain why certain groups of levothyroxine-treated hypothyroid patients have improved quality of life when also treated with liothyronine (LT3). Furthermore, Ala92-D2 was abnormally found in the Golgi apparatus, what could constitute a disease mechanism independent of T3 signaling. Indeed, brain samples of Thr92Ala-DIO2 carriers exhibit gene profiles suggestive of brain degenerative disease. In addition, African American carriers of Thr92Ala-DIO2 exhibit an about 30% higher risk of developing Alzheimer's disease. SUMMARY The finding of Deiodinase polymorphisms that can diminish thyroid hormone signaling and/or disrupt normal cellular function opens the door to customized treatment of hypothyroidism. Future studies should explore how the racial background modulates the clinical relevance of the Thr92Ala-DIO2 gene polymorphism.
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Scope and limitations of iodothyronine Deiodinases in hypothyroidism
Nature Reviews Endocrinology, 2015Co-Authors: Balazs Gereben, Elizabeth A. Mcaninch, Miriam O. Ribeiro, Antonio C. BiancoAbstract:The coordinated expression and activity of the iodothyronine Deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine Deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine Deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition.
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Thyroid Hormone Deiodinases and Cancer
Frontiers in Endocrinology, 2012Co-Authors: Sabina Casula, Antonio C. BiancoAbstract:Deiodinases constitute a group of thioredoxin-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known Deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4) to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that Deiodinase expression is altered in several types of cancers, suggesting that (i) they may represent a useful cancer marker and/or (ii) could play a role in modulating cell proliferation - in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS)-13 cells is 3-4 fold higher. In basal cell carcinoma (BCC) cells, sonic hedgehog (Shh)-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a 5-fold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma and in anaplastic thyroid cancer. It is conceivable that understanding how Deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches.
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Type 2 Deiodinase at the crossroads of thyroid hormone action.
The International Journal of Biochemistry & Cell Biology, 2011Co-Authors: Rafael Arrojo E Drigo, Antonio C. BiancoAbstract:Thyroid hormone action can be customized on a cell-specific fashion through the controlled action of the Deiodinase group of enzymes, which are homodimeric thioredoxin fold containing selenoproteins. Whereas the type II Deiodinase (D2) initiates thyroid hormone signaling by activating the pro-hormone thyroxine (T4) to the biologically active T3 molecule, the type III Deiodinase (D3) terminates thyroid hormone action by catalyzing the inactivation of both T4 and T3 molecules. Deiodinases play a role in thyroid hormone homeostasis, development, growth and metabolic control by affecting the intracellular levels of T3 and thus gene expression on a cell-specific basis. Whereas both Dio2 and Dio3 are transcriptionally regulated, ubiquitination of D2 is a switch mechanism that controls D2 activity and intracellular T3 production. The hedgehog-inducible WSB-1 and the yeast Doa10 mammalian ortholog TEB4 are two E3 ligases that inactivate D2 via ubiquitination. Inactivation involves disruption of the D2:D2 dimer and can be reversed via two ubiquitin-specific proteases, USP20 and USP33, rescuing catalytic activity and T3 production. The ubiquitin-based switch mechanism that controls D2 activity illustrates how different cell types fine-tune thyroid hormone signaling, making D2 a suitable target for pharmacological intervention. This article reviews the cellular and molecular aspects of D2 regulation and the current models of D2-mediated thyroid hormone signaling.
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cellular and molecular basis of Deiodinase regulated thyroid hormone signaling
Endocrine Reviews, 2008Co-Authors: Balazs Gereben, Antonio C. Bianco, Ann Marie Zavacki, Scott Ribich, Stephen A Huang, Warner S Simonides, Aniko ZeoldAbstract:The iodothyronine Deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T3 during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating Deiodinase (D2) and the inactivating Deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because Deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-κB, growth factors, bile acids, hypoxia-inducible factor-1α, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that Deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.
Monica Dentice - One of the best experts on this subject based on the ideXlab platform.
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Deiodinases and their intricate role in thyroid hormone homeostasis.
Nature Reviews Endocrinology, 2019Co-Authors: Cristina Luongo, Monica Dentice, Domenico SalvatoreAbstract:The Deiodinase family of enzymes mediates the activation and inactivation of thyroid hormone. The role of these enzymes in the regulation of the systemic concentrations of thyroid hormone is well established and underpins the treatment of common thyroid diseases. Interest in this field has increased in the past 10 years as the Deiodinases became implicated in tissue development and homeostasis, as well as in the pathogenesis of a wide range of human diseases. Three Deiodinases have been identified, namely, types 1, 2 and 3 iodothyronine Deiodinases, which differ in their catalytic properties and tissue distribution. Notably, the expression of these enzymes changes during the lifetime of an individual in relation to the different needs of each organ and to ageing. The systemic homeostatic role of Deiodinases clearly emerges during changes in serum concentrations of thyroid hormone, as seen in patients with thyroid dysfunction. By contrast, the role of Deiodinases at the tissue level allows thyroid hormone signalling to be finely tuned within a given cell in a precise time–space window without perturbing serum concentrations of thyroid hormone. This Review maps the overall functional role of the Deiodinases and explores challenges and novel opportunities arising from the expanding knowledge of these ‘master’ components of the thyroid homeostatic system. This Review discusses the two main functions of the human Deiodinases: the homeostatic control of plasma concentrations of thyroid hormone and the control of intracellular T3 concentrations.
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the sonic hedgehog induced type 3 Deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing gli2 inactivation
Endocrinology, 2014Co-Authors: Cristina Luongo, Raffaele Ambrosio, Salvatore Salzano, Andrzej A Dlugosz, Caterina Missero, Monica DenticeAbstract:Thyroid hormone (TH) is an important regulator of growth, development, and metabolism. Most of the active TH T3 is generated by peripheral TH metabolism mediated by the iodothyronine Deiodinases. Type 3 Deiodinase (D3) inactivates T3 via specific deiodination reactions. It is an oncofetal protein frequently expressed in neoplastic tissues and is a direct target of the sonic hedgehog (Shh) pathway in basal cell carcinomas (BCCs). However, the molecular mechanisms triggered by T3 in BCC are still mostly unrevealed. Here, we demonstrate that D3 action is critical in the proliferation and survival of BCC cells. D3 depletion or T3 treatment induce apoptosis of BCC cells and attenuate Shh signaling. This is achieved through a direct impairment of Gli2 protein stability by T3. T3 induces protein kinase A, which in turn destabilizes Gli2 protein via its C-terminal degron. Finally, in a mouse model of BCC, T3-topical treatment significantly reduces tumor growth. These results demonstrate the existence of a previou...
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thyroid hormones and skeletal muscle new insights and potential implications
Nature Reviews Endocrinology, 2014Co-Authors: Domenico Salvatore, Ann Marie Zavacki, Warner S Simonides, Monica Dentice, Reed P LarsenAbstract:The authors review the roles of T3 in skeletal muscle development, homeostasis and pathology, with a focus on the emerging local Deiodinase-mediated control of T3signalling. Moreover, this Review addresses how manipulation of Deiodinase activity in skeletal muscle might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury. Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine Deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyses outer-ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone tri-iodothyronine (T3). T3 can remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner-ring iodine. Regulation of the expression and activity of Deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local Deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how skeletal muscle Deiodinase activity might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury.
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Type 3 Deiodinase and solid tumors: an intriguing pair.
Expert Opinion on Therapeutic Targets, 2013Co-Authors: Monica Dentice, Dario Antonini, Domenico SalvatoreAbstract:Introduction: Thyroid hormone (TH) metabolism is mediated by Deiodinases, a family of thioredoxin fold-containing enzymes that remove iodide from thyroxine and its derivatives. The coordinated action of Deiodinases allows target cells to modulate rapidly their own TH availability in response to different cues. Type 3 Deiodinase (D3), the physiological inactivator of TH, is an oncofetal protein whose re-activation in adult tissues has been correlated with hyperproliferative states and with human solid tumors. This suggests a link between Deiodinase-mediated TH metabolism and carcinogenesis. Areas covered: D3 is overexpressed in basal cell carcinomas (BCCs) and sustains the proliferation of BCC cells. It exerts a similar function in colon cancer, which suggests that attenuating the TH signal is part of a widespread neoplastic program. Here, recent advances in D3 research, particularly as regards the role of D3 regulation and function in solid tumors are reviewed. Expert opinion: Given the vast array of TH's...
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the Deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation
Biochimica et Biophysica Acta, 2013Co-Authors: Monica Dentice, Ann Marie Zavacki, Reed P Larsen, Alessandro Marsili, Domenico SalvatoreAbstract:Background Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenoDeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenoDeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of Deiodinases in specific cell types are not known, many important regulatory factors have been deciphered.