Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases

Bianco, Antonio C.; Salvatore, Domenico; Gereben, Balázs; Berry, Marla J.; Larsen, P. Reed

doi:10.1210/edrv.23.1.0455

Cited by 1,417 publications

(727 citation statements)

References 443 publications

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“…Accordingly, the increased D2 mRNA levels recently observed in the stem cell-enriched human hair follicle bulge cells (33) suggest that intracellular T3 concentrations even greater than those in plasma are appropriate for the low proliferation state of these cells. It is of interest that D3 is expressed in many different neoplastic cells as well as in placenta and human fetal epithelium, with an as yet unknown function (2). We speculate that the resulting reduced intracellular T3 provides a metabolic advantage for these rapidly proliferating cells.…”

Section: Resultsmentioning

confidence: 91%

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Dentice

Luongo

Huang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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150

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The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. Here we show that Shh, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human BCCs. We demonstrate that Gli-induced D3 reduces intracellular active thyroid hormone, thus resulting in increased cyclin D1 and keratinocyte proliferation. D3 knockdown caused a 5-fold reduction in the growth of BCC xenografts in nude mice. Shh-induced thyroid hormone degradation via D3 synergizes with the Shh-mediated reduction of the type 2 deiodinase, the thyroxine-activating enzyme, and both effects are reversed by cAMP. This previously unrecognized functional cross-talk between Shh/Gli2 and thyroid hormone in keratinocytes is a pathway by which Shh produces its proliferative effects and offers a potential therapeutic approach to BCC.basal cell carcinoma ͉ thyroxine ͉ differentiation ͉ cancer T hyroid hormone action is regulated by the activity of the deiodinases. Type 2 deiodinase (D2) activates the prohormone thyroxine (T4) by converting it to thyroid hormone (T3), whereas D3, by inactivating T3, terminates thyroid hormone action (1). All vertebrates express D2 and D3 that, in adults, contribute to plasma T3 and T4 homeostasis by their concerted actions with the hypothalamic-pituitary feedback axis. This homeostatic mechanism is possible because the Dio3 gene is transcriptionally stimulated by T3, whereas D2 is inhibited by two thyroid hormone-mediated effects, a transcriptional downregulation of Dio2 as well as protein inactivation by ubiquitination (for review, see ref.2). During development, preprogrammed changes in D2 and D3 expression are thought to regulate intracellular T3 concentrations essential to the normal development of the central nervous system, including the retina and the inner ear (3-6). However, the signals governing the changes in D2 and D3 expression during these complex processes are largely unknown.New insight into the developmental regulation of deiodinase expression has recently been obtained in the chicken growth plate, where Indian hedgehog induces WSB-1, an E3 ubiquitin ligase adaptor that inactivates D2 (7). The hedgehog pathway, acting through the Gli family of transcription factors, determines patterns of cell growth and differentiation in a wide variety of developmental settings (8-13). Given that, in general, signals regulating D2 expression affect D3 in a reciprocal fashion (2), we hypothesized that hedgehog proteins could up-regulate D3 while suppressing D2 expression. To explore this possibility, we turned to skin, a system in which Sonic hedgehog (Shh) is known to play dominant physiological as well as pathological roles (14). Both D2 and D3 are present in skin, a well recognized target of thyroid hormone...

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Section: Resultsmentioning

confidence: 91%

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Dentice

Luongo

Huang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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150

139

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“…6. 79 These thyroid hormones regulate various metabolic processes, such as lipid metabolism, thermogenesis, growth and hearing, that are essential for homeostasis but also for the normal development of the fetal brain. 80 Like other Se-proteins families, the functional differences amongst individual isoforms are not yet well elucidated.…”

Section: Iodothyronine Deiodinasesmentioning

confidence: 99%

Selenium biochemistry and its role for human health

Roman¹,

Jitaru²,

Barbante³

2014

Metallomics

629

451

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Despite its very low level in humans, selenium plays an important and unique role among the (semi)metal trace essential elements because it is the only one for which incorporation into proteins is genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five selenoproteins have been identified so far in the human proteome. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic effect for human diseases. This review summarizes the most recent findings on the biochemistry of active selenium species in humans, and addresses the latest evidence on the link between selenium intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the interpretation of biochemical mechanisms rather than epidemiological/observational data. In this context, the review includes the following sections: (1) brief introduction; (2) general nutritional aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of human diseases.

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“…Through the activation of this G-protein-coupled receptor, BAs induce intracellular cAMP levels in brown adipose tissue (BAT) and skeletal muscle. This leads to activation of type 2 iodothyronine deiodinase (D2), the enzyme that converts inactive thyroxine into active 3,5,3Ј-triiodothyronine (20), which determines thyroid hormone receptor saturation, as well as the activation of the master regulator of mitochondrial biogenesis, the peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator-1␣ (PGC-1␣). Via this pathway, energy expenditure in BAT and skeletal muscle is stimulated, translating into weight loss and insulin sensitization (21).…”

mentioning

confidence: 99%

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

Watanabe

Horai

Houten

et al. 2011

Journal of Biological Chemistry

227

174

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We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.

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Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases

Cited by 1,417 publications

References 443 publications

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Selenium biochemistry and its role for human health

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

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