Thyroid hormone receptors and resistance to thyroid hormone disorders

Ortiga-Carvalho, Tânia M.; Sidhaye, Aniket; Wondisford, Fredric E.

doi:10.1038/nrendo.2014.143

Cited by 269 publications

(229 citation statements)

References 112 publications

(198 reference statements)

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“…THRs also act as transcription factors independent of the ligand (Ortiga-Carvalho et al 2015). THRA is the main isoform present in SM (Miyabara et al 2005, Amorim et al 2009, Dentice et al 2010, Milanesi et al 2016.…”

Section: Thyroid Hormone Action Pathway In Skeletal Musclementioning

confidence: 99%

Role of thyroid hormone in skeletal muscle physiology

Bloise

Cordeiro

Ortiga-Carvalho

2018

Journal of Endocrinology

139

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Thyroid hormones (TH) are crucial for development, growth, differentiation, metabolism and thermogenesis. Skeletal muscle (SM) contractile function, myogenesis and bioenergetic metabolism are influenced by TH. These effects depend on the presence of the TH transporters MCT8 and MCT10 in the plasma membrane, the expression of TH receptors (THRA or THRB) and hormone availability, which is determined either by the activation of thyroxine (T 4 ) into triiodothyronine (T 3 ) by type 2 iodothyronine deiodinases (D2) or by the inactivation of T 4 into reverse T 3 by deiodinases type 3 (D3). SM relaxation and contraction rates depend on T 3 regulation of myosin expression and energy supplied by substrate oxidation in the mitochondria. The balance between D2 and D3 expression determines TH intracellular levels and thus influences the proliferation and differentiation of satellite cells, indicating an important role of TH in muscle repair and myogenesis. During critical illness, changes in TH levels and in THR and deiodinase expression negatively affect SM function and repair. This review will discuss the influence of TH action on SM contraction, bioenergetics metabolism, myogenesis and repair in health and illness conditions.

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Section: Thyroid Hormone Action Pathway In Skeletal Musclementioning

confidence: 99%

Role of thyroid hormone in skeletal muscle physiology

Bloise

Cordeiro

Ortiga-Carvalho

2018

Journal of Endocrinology

139

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“…In humans, mutations of either THRA or THRB cause the resistance to thyroid hormone syndrome (RTH). The severity of the disease is determined by the precise location of the mutation (2), dictating the ability of the mutated TR to respond to T3 (3).…”

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confidence: 99%

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Guan

Guyot

Samarut

et al. 2017

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

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation. Interestingly, the differential ability of different TRα1 mutants to interact with TET3 might explain their differential dominant activity in patients carrying TR germline mutations. So this study evidences a mode of action for TET3 as a nonclassical coregulator of TRs, modulating its stability and access to chromatin, rather than its intrinsic transcriptional activity. This regulatory function might be more general toward nuclear receptors. Indeed, TET3 interacts with different members of the superfamily and also enhances their association to chromatin.thyroid hormone receptor | methylcytosine dioxygenase TET3 | protein stability | chromatin recruitment | RTH syndrome T hyroid hormone (T3) is the main natural iodinated compound possessing a biological activity. It exerts a pleiotropic action on development and homeostasis, acting on most, if not all, cell types (1). T3 acts directly on gene transcription by binding to the thyroid hormone receptors (TRs) TRα1, TRβ1, and TRβ2. They are, respectively, encoded by the THRA and THRB genes. In humans, mutations of either THRA or THRB cause the resistance to thyroid hormone syndrome (RTH). The severity of the disease is determined by the precise location of the mutation (2), dictating the ability of the mutated TR to respond to T3 (3).TRs, as the other members of the nuclear receptor superfamily, are ligand-regulated transcription factors consisting of three major functional domains: the amino-terminal A/B domain, the DNAbinding domain, and the ligand-binding domain. TRs can bind to DNA on a TR response element (TRE) the in absence of T3, and on most genes they repress transcription until T3 binds and leads to activation. Helix12 is the major structural element associated with this process. T3 triggers a dramatic shift of its position, leading to dissociation of corepressors and recruitment of coactivators, including coactivators that have the ability to change the chromatin microenvironment (4). T3 binding also induces a rapid proteasomemediated degradation of TRs that is associated with T3-dependent transcriptional activity (5). TR availability and chromatin access are thus possibly important levels of modulation of T3 cellular response.The goal of the present study was to identify epigenetic regulators that interact with, and therefore may modulate, TR transcriptional activity, using in vitro pull-down screening. This approach allowed us to identify TET3, a member of the ten-eleven translocation (TET) family proteins, as a partner for TRs....

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“…Clinical observations have shown that in patients with a mutation in the THRA, the HPT axis is minimally or not impaired, while the opposite is observed in patients with mutation of THRB isoform (Ortiga-Carvalho et al 2014).…”

Section: Negative Transcriptional Regulation Of Cga and Tshb Genes Bymentioning

confidence: 99%

“…The heterogeneous mRNAs are subjected to alternative splicing or alternative use of promoters generating nine different transcripts: Thra1, Thra2,Thra3,ThrΔa1,ThrΔa2,Thrb1,Thrb2,Thrb3 (found only in the kidney, liver and lung of rats) and ThrΔb (O'Shea & Williams 2002, Ortiga-Carvalho et al 2014. The expression of these transcripts changes during the development and cellular differentiation processes, being also transcriptionally and posttranscriptionally regulated.…”

Section: Nuclear Thyroid Receptors and The Gene Expression Regulationmentioning

confidence: 99%

“…The presence of ligand promotes a conformational change in THRB2 that results in the dissociation of corepressors (CoR) and recruitment of coactivators (CoA) such as the nuclear receptor coactivator 1 (NCoA-1 or SRC-1) establishing a new complex that leads to histone acetylation or methylation, which, in turn, changes the interaction between RNA polymerase and other transcriptional factors inducing the gene transcription (Ortiga-Carvalho et al 2014, Mendoza & Hollenberg 2017. It is worth mentioning that T 3 -mediated activation of rat Gh gene expression presents a synergism between transcriptional factor Pit-1 (POU domain, class 1, transcription factor 1) and T 3 , increasing the Gh mRNA content (Schaufele et al 1992, Sinha & Yen 2000, Yen 2001).…”

Section: Transcriptional Regulation Of Gh By Tmentioning

confidence: 99%

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Novel aspects of T3 actions on GH and TSH synthesis and secretion: physiological implications

Bargi‐Souza

Goulart-Silva

Nunes

2017

Journal of Molecular Endocrinology

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Thyroid hormones (THs) classically regulate the gene expression by transcriptional mechanisms. In pituitary, the encoding genes for growth hormone (GH) and thyroid-stimulating hormone (TSH) are examples of genes regulated by triiodothyronine (T3) in a positive and negative way, respectively. Recent studies have shown a rapid adjustment of GH and TSH synthesis/secretion induced by T3posttranscriptional actions. In somatotrophs, T3promotes an increase inGhmRNA content, poly(A) tail length and binding to the ribosome, associated with a rearrangement of actin cytoskeleton. In thyrotrophs, T3reducesTshbmRNA content, poly(A) tail length and its association with the ribosome. In parallel, it promotes a redistribution of TSH secretory granules to more distal regions of the cell periphery, indicating a rapid effect of T3inhibition of TSH secretion. T3was shown to affect the content of tubulin and the polymerization of actin and tubulin cytoskeletons in the whole anterior pituitary gland, and to increase intracellular alpha (CGA) content. This review summarizes genomic and non-genomic/posttranscriptional actions of TH on the regulation of several steps of GH and TSH synthesis and secretion. These distinct mechanisms induced by T3can occur simultaneously, even though non-genomic effects are promptly elicited and precede the genomic actions, coexisting in a functional network within the cells.

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Thyroid hormone receptors and resistance to thyroid hormone disorders

Cited by 269 publications

References 112 publications

Role of thyroid hormone in skeletal muscle physiology

Role of thyroid hormone in skeletal muscle physiology

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Novel aspects of T3 actions on GH and TSH synthesis and secretion: physiological implications

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