Deiodinases: implications of the local control of thyroid hormone action

Bianco, Antonio C.; Kim, Brian W.

doi:10.1172/jci29812

Cited by 726 publications

(582 citation statements)

References 107 publications

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“…Compound 2 increased TG mRNA as effectively as TSH and increased mRNAs for TPO, NIS, and DIO2 somewhat less effectively than TSH. We also measured the effects of compound 2 on DIO2 by assaying its enzymatic activity to de-iodinate T4 to tri-iodothyronine (28). Both TSH and compound 2 increased DIO2 protein activity (Fig.…”

Section: Compound 2 Stimulates Thyroid-specific Gene Expression In Prmentioning

confidence: 99%

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Neumann¹,

Huang

Titus

et al. 2009

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

113

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Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.7TMR ͉ G protein-coupled receptor ͉ low-molecular-weight ligands ͉ radioiodide uptake ͉ TSH receptor S mall-molecule agonists and antagonists for 7-transmembrane-spanning receptors (7TMRs; G protein-coupled receptors) make up approximately 40% of the drugs in clinical use (1). The natural ligands for the 7TMRs for which drugs have been discovered are themselves primarily small molecules, such as norepinephrine, adenosine, and acetylcholine. Smallmolecule ligands for the subclass of 7TMRs for which the natural ligands are 30-kDa heterodimeric glycoprotein hormones have recently begun to be described, but none have been approved for use in humans. For example, small-molecule agonists (2-5) and an antagonist (6) for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), and small-molecule agonists (7-9) and antagonists (10-12) for the FSH receptor (FSHR) have been reported. The thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR) is the third member of the glycoprotein hormone receptor subfamily. We recently reported smallmolecule agonists (13) and an antagonist (14) for human TSHR; however, the agonists were of low affinity and were shown to activate TSHRs only in a model cell system in which human TSHRs were ectopically over-expressed.The physiologic role of TSHRs in the hypothalamic-pituitarythyroid axis is well known. TSH, which is produced in the thyrotrophs of the anterior pituitary gland, is secreted into the circulation in response to TSH-releasing hormone stimulation and in turn stimulates the function of the thyroid follicular cells (i.e., thyrocytes) leading, in particular, to increases in size ...

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Section: Compound 2 Stimulates Thyroid-specific Gene Expression In Prmentioning

confidence: 99%

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Neumann¹,

Huang

Titus

et al. 2009

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

113

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“…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.…”

mentioning

confidence: 99%

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.

152

139

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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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“…Recently, it has been shown that this reduction is regulated by biotinization of D2 [28]. D2 ubiquitination accelerates in proportion to T4 concentration, creating a feedback loop controlling D2-mediated T3 production [28,29].…”

Section: Semi-quantitative Rt-pcrmentioning

confidence: 99%

The effect of low dose lipopolysaccharide on thyroid hormone-regulated actin cytoskeleton modulation and type 2 iodothyronine deiodinase activity in astrocytes

Iwasaki

Shimokawa

et al. 2013

Endocr J

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Deiodinases: implications of the local control of thyroid hormone action

Cited by 726 publications

References 107 publications

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

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

The effect of low dose lipopolysaccharide on thyroid hormone-regulated actin cytoskeleton modulation and type 2 iodothyronine deiodinase activity in astrocytes

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