Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin

Abel, E. Dale; Kaulbach, Helen C.; Campos-Barros, Ángel; Ahima, Rexford S.; Boers, Mary Ellen; Hashimoto, Kazuhito; Forrest, Douglas; Wondisford, Fredric E.

doi:10.1172/jci5205

Cited by 85 publications

(43 citation statements)

References 53 publications

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“…If NCoR binding to the TR limits ligand-independent activation, then the inability of the R429 mutant to bind NCoR may help explain the enhanced ligandindependent activation seen in the presence of this mutation. This potential mechanism for enhanced ligand-independent activation is consistent with the finding of impaired ligand-independent activation in mice with pituitary-specific expression of ⌬337T, a GRTH mutant TR that constitutively binds to NCoR (55). Consistent with our findings with liver Gsta, Astapova et al (41) recently found that ligand-independent activation of hepatic TH target genes did not seem to be significantly affected by expression of L-NCoR⌬ID.…”

Section: Discussionsupporting

confidence: 93%

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A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

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

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Resistance to thyroid hormone (RTH) is most often due to point mutations in the ␤-isoform of the thyroid hormone (TH) receptor (TR-␤). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-␤ locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T 3 replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T 3 treatment failed to normally suppress these levels. T3 treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T 3 treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.corepressor ͉ homodimer ͉ negative regulation ͉ resistance to thyroid hormone T hyroid-stimulating hormone (thyrotropin or TSH) is a heterodimeric glycoprotein consisting of 2 non-covalently linked protein subunits (TSH-␣ and TSH-␤), synthesized in the pituitary thyrotroph, which regulates the thyroid. TSH-releasing hormone (TRH) is synthesized in the paraventricular nucleus of the hypothalamus and released into the portal circulation, where it regulates the synthesis and glycosylation pattern (bioactivity) of pituitary TSH. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback involving thyroid hormones (THs) (T 4 and T 3 ), which are produced by the thyroid gland. The major negative regulator of TSH secretion is T 3 , which directly inhibits the transcription of the TSH-␣ and -␤ subunit genes (1-5) and TRH (6-8).TH action is mediated by different isoforms of the TH receptor (TR), which are members of the nuclear receptor superfamily of ligand-modulated transcription factors. Two genes, by alternative splicing and transcriptional start site utilization, express the known ligand-binding TR isoforms, TR-␣1, TR-␤1, TR-␤2, and TR-␤3. Negative regulation of the HPT axis is principally mediated by the ␤ isoform of the TR (9-13).On genes with a positive TH response element, TR interacts with corepressor proteins (CoRs) in the absence of ligand, and this...

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Section: Discussionsupporting

confidence: 93%

“…Although CRTH is sometimes referred to as pituitary RTH (PRTH), we have in the past proposed that CRTH is a more appropriate term because isolated pituitary RTH is unable to elevate TH levels in mice (55). However, like PRTH, CRTH seems to be a misnomer.…”

Section: Discussionmentioning

confidence: 99%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

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

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“…The different TR isoforms play distinct roles in endocrine physiology (14,17,(21)(22)(23)(24). The TR␤2 isoform in the hypothalamus and pituitary plays a particularly crucial role in a negative feedback regulatory loop by which increases in circulating T 3 /T 4 thyroid hormone levels result in suppression of thyroid releasing hormone and thyroid stimulating hormone synthesis, thereby restoring proper endocrine homeostasis (19,20,22,(25)(26)(27)(28)(29).…”

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confidence: 99%

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Privalsky

Lee²,

Hahm³

et al. 2009

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that play multiple roles in vertebrate endocrinology and development. TRs are expressed as a series of distinct receptor isoforms that mediate different biological functions. The TR␤2 isoform is expressed primarily in the hypothalamus, pituitary, cochlea, and retina, and displays an enhanced response to hormone agonist relative to the other TR isoforms. We report here that the unusual transcriptional properties of TR␤2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TR␤1 isoform, in contrast, utilizes a single contact mechanism. Intriguingly, the PAS-B domain in the p160 N terminus plays a previously unanticipated role in permitting TR␤2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-␣. We propose that the PAS-B domain of the p160 coactivators is an important modulator of coactivator recruitment for a specific subset of nuclear receptors, permitting stronger transcriptional activation at lower hormone concentrations than would otherwise occur, and allowing isoform-specific mRNA splicing to customize the hormone response in different tissues.

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“…The THRB2 isoform participates in the positive and negative regulations of Gh and Tshb expressions, respectively (Abel et al 1999, Barra et al 2004. In humans, mutations in THRB isoforms led to the classic form of resistance to thyroid hormone (RTHB) characterized by high TH levels and normal or slightly elevated serum TSH concentration, due to the resistance of pituitary and hypothalamus to respond to the negative feedback triggered by TH (Forrest et al 1996, Refetoff et al 2014.…”

Section: Nuclear Thyroid Receptors and The Gene Expression Regulationmentioning

confidence: 99%

“…The lack of all THRB isoforms (Thrb −/− ) led to resistance to thyroid hormone (RTH-b) characterized by the enlargement of the thyroid gland (goiter), increased size and number of follicles, elevated T 4 and T 3 concentrations, normal or elevated serum TSH concentration and increased Tshb and Cga mRNA expressions due to defects in thyrotrophic response to THs (Forrest et al 1996, O'Shea & Williams 2002, Mendoza & Hollenberg 2017. The generation of THRB2 knockout (Thrb2 −/− ) mice provided evidence that this isoform plays a major role in the negative feedback exerted by T 3 in thyrotrophs and in the stimulation of Gh mRNA synthesis in somatotrophs (Abel et al 1999(Abel et al , 2003.…”

Section: Negative Transcriptional Regulation Of Cga and Tshb Genes Bymentioning

confidence: 99%

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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Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin

Cited by 85 publications

References 53 publications

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

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

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